Author: druginteractionchecker_lgaiz4

valACYclovir 500 MG Oral Tablet

Generic Name: VALACYCLOVIR HYDROCHLORIDE
Brand Name: VALACYCLOVIR HYDROCHLORIDE
  • Substance Name(s):
  • VALACYCLOVIR HYDROCHLORIDE

DRUG INTERACTIONS

7. No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10. Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5), (8.6)]. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4)].

DESCRIPTION

11. Valacyclovir hydrochloride is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir. Valacyclovir hydrochloride tablets are for oral administration. Each tablet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients croscarmellose sodium, FD&C Blue No. 2 aluminium lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, talc and titanium dioxide. The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula: Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C13H20N6O4•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pkas for valacyclovir hydrochloride are 1.90, 7.47, and 9.43. Structure

CLINICAL STUDIES

14. 14.1 Cold Sores (Herpes Labialis) Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2. The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1- day regimen. No significant difference was observed between subjects receiving valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage. 14.2 Genital Herpes Infections Initial Episode: Six hundred and forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir hydrochloride 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days. Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode. In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial. In a third study, patients were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups. Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults. A double-blind, 12-month, placebo-and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5. Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months * Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn. 6 Months 12 Months Outcome Valacyclovir Hydrochloride 1 gram once daily (n = 269) Oral acyclovir 400 mg twice daily (n = 267) Placebo (n=134) Valacyclovir Hydrochloride 1 gram once daily (n = 269) Oral acyclovir 400 mg twice daily (n = 267) Placebo (n = 134) Recurrence free 55% 54% 7% 34% 34% 4% Recurrences 35% 36% 83% 46% 46% 85% Unknown* 10% 10% 10% 19% 19% 10% Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily. In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir hydrochloride 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received valacyclovir hydrochloride, the prestudy median CD4+ cell count was 336 cells/mm3; 11% had <100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had ≥500 cells/mm3. Outcomes for the overall study population are shown in Table 6. Table 6. Recurrence Rates in HIV-Infected Adults at 6 Months * Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn. Outcome Valacyclovir Hydrochloride Tablets 500 mg twice daily (n = 194) Placebo (n = 99) Recurrence free Recurrences Unknown* 65% 17% 18% 26% 57% 17% Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either valacyclovir hydrochloride 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7. Table 7. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints * Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with valacyclovir hydrochloride versus placebo. Individual results may vary based on consistency of safer sex practices. Endpoint Valacyclovir Hydrochloride* (n = 743) Placebo (n = 741) Symptomatic HSV-2 acquisition 4 (0.5%) 16 (2.2%) HSV-2 seroconversion 12 (1.6%) 24 (3.2%) Overall HSV-2 acquisition 14 (1.9%) 27 (3.6%) 14.3 Herpes Zoster Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir hydrochloride compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir hydrochloride or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir hydrochloride and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively. 14.4 Chickenpox The use of valacyclovir hydrochloride tablets for treatment of chickenpox in pediatric patients 2 to < 18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients. The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to < 12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to < 12 years of age) were lower (Cmax: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to < 18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children < 2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children < 2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available [see Use in Specific Populations (8.4)].

HOW SUPPLIED

16. /STORAGE AND HANDLING Valacyclovir hydrochloride tablets are blue, film-coated, capsule-shaped tablets containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir debossed with “W152” on one side and plain on other side. Bottle of 30 (NDC 53217-0054-30). Bottle of 60 (NDC 53217-0054-60). Bottle of 90 (NDC 53217-0054-90). Storage: Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature] Dispense in a well-closed container as defined in the USP.

RECENT MAJOR CHANGES

Warnings and Precautions, Central Nervous System Effects (5.3) 3/2010

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of valacyclovir hydrochloride tablets, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.3)].

DOSAGE FORMS AND STRENGTHS

3. Tablets: 500 mg (unscored), 1 gram (partially bisect) (3) Tablets: 500 mg: blue, film-coated, capsule-shaped tablets debossed with “W152” on one side and plain and other side. 1 gram: blue, film-coated, capsule-shaped tablets, debossed with “W153” on one side and partial bisect on both sides.

MECHANISM OF ACTION

12.1 Mechanism of Action Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

INDICATIONS AND USAGE

1. Valacyclovir hydrochloride is a nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients (1.1) ● Cold Sores (Herpes Labialis) ● Genital Herpes ● Treatment in immunocompetent patients (initial or recurrent episode) ● Suppression in immunocompetent or HIV-infected patients ● Reduction of transmission ● Herpes Zoster Pediatric Patients (1.2) ● Cold Sores (Herpes Labialis) ● Chickenpox Limitations of Use (1.3) ● The efficacy and safety of valacyclovir hydrochloride tablets have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. 1.1 Adult Patients Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir hydrochloride tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Genital Herpes: Initial Episode: Valacyclovir hydrochloride tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established. Recurrent Episodes: Valacyclovir hydrochloride tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir hydrochloride tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established. Suppressive Therapy: Valacyclovir hydrochloride tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of valacyclovir hydrochloride tablets for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established. Reduction of Transmission: Valacyclovir hydrochloride tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir hydrochloride tablets for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of valacyclovir hydrochloride tablets for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines). Herpes Zoster: Valacyclovir hydrochloride tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir hydrochloride tablets for treatment of disseminated herpes zoster have not been established. 1.2 Pediatric Patients Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients ≥12 years of age. The efficacy of valacyclovir hydrochloride tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Chickenpox: Valacyclovir hydrochloride tablets are indicated for the treatment of chickenpox in immunocompetent pediatric patients 2 to < 18 years of age. Based on efficacy data from clinical studies with oral acyclovir, treatment with valacyclovir hydrochloride tablets should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4)]. 1.3 Limitations of Use The efficacy and safety of valacyclovir hydrochloride tablets have not been established in: Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count ≥100 cells/mm3. Patients <12 years of age with cold sores (herpes labialis). Patients < 2 years of age or ≥ 18 years of age with chickenpox. Patients <18 years of age with genital herpes. Patients <18 years of age with herpes zoster. Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

PEDIATRIC USE

8.4 Pediatric Use Valacyclovir hydrochloride tablets are indicated for treatment of cold sores in pediatric patients≥12 years of age [see Indications and Usage (1.2), Dosage and Administration (2.2]. The use of valacyclovir hydrochloride tablets for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)]. The use of valacyclovir hydrochloride tablets for treatment of chickenpox in pediatric patients 2 to < 18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. The efficacy and safety of valacyclovir have not been established in pediatric patients: <12 years of age with cold sores <18 years of age with genital herpes <18 years of age with herpes zoster < 2 years of age with chickenpox for suppressive therapy following neonatal HSV infection. The pharmacokinetic profile and safety of valacyclovir oral suspension in children < 12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies. Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to < 12 years of age with clinically suspected varicella-zoster virus (VZV) infection [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to < 6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children 3 months to < 6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to < 3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir. Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to < 12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to < 12 years of age) were lower (Cmax: ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to < 12 years of age with recurrent genital herpes.

PREGNANCY

8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Valacyclovir hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.

NUSRING MOTHERS

8.3 Nursing Mothers Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of valacyclovir hydrochloride twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when valacyclovir hydrochloride is administered to a nursing woman.

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir hydrochloride in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (5.1) Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher than recommended doses of valacyclovir hydrochloride for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (2.4, 5.2) Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (2.4, 5.3) 5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir hydrochloride at doses of 8 grams per day. Treatment with valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur. 5.2 Acute Renal Failure Cases of acute renal failure have been reported in: Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4), Use in Specific Populations (8.5)]. Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)]. Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs. Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4), Adverse Reactions (6.3)]. 5.3 Central Nervous System Effects Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. 17.1 Importance of Adequate Hydration Patients should be advised to maintain adequate hydration. 17.2 Cold Sores (Herpes Labialis) Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir hydrochloride is not a cure for cold sores. 17.3 Genital Herpes Patients should be informed that valacyclovir hydrochloride is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir hydrochloride. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists. Valacyclovir hydrochloride has not been shown to reduce transmission of sexually transmitted infections other than HSV-2. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients. 17.4 Herpes Zoster There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. 17.5 Chickenpox Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox. Manufactured by: Wockhardt Limited Mumbai, India. Distributed by: Wockhardt USA LLC. 20 Waterview Blvd. Parsippany, NJ 07054 USA. Repackaged By : Aidarex Pharmaceuticals LLC, Corona, CA 92880 Rev.080213

DOSAGE AND ADMINISTRATION

2. Adult Dosage (2.1) Cold Sores 2 grams every 12 hours for 1 day Genital Herpes Initial episode 1 gram twice daily for 10 days Recurrent episodes 500 mg twice daily for 3 days Suppressive therapy Immunocompetent patients Alternate dose in patients with ≤9 recurrences/yr HIV-infected patients 1 gram once daily 500 mg once daily 500 mg twice daily Reduction of transmission 500 mg once daily Herpes Zoster 1 gram 3 times daily for 7 days Pediatric Dosage (2.2) Cold Sores (≥12 years of age) 2 grams every 12 hours for 1 day Chickenpox (2 to < 18 years of age) 20 mg/kg 3 times daily for 5 days; not to exceed 1 gram 3 times daily Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) can be prepared from valacyclovir hydrochloride tablets, 500 mg. (2.3) Valacyclovir hydrochloride tablets may be given without regard to meals. Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from valacyclovir hydrochloride tablets, 500 mg for use in pediatric patients for whom a solid dosage form is not appropriate [see Dosage and Administration (2.3)]. 2.1 Adult Dosing Recommendations Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). Genital Herpes: Initial Episode: The recommended dosage of valacyclovir hydrochloride tablets for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms. Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride tablets for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode. Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily. In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily. Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride tablets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner. Herpes Zoster: The recommended dosage of valacyclovir hydrochloride tablets for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash. 2.2 Pediatric Dosing Recommendations Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for the treatment of cold sores in pediatric patients≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). Chickenpox: The recommended dosage of valacyclovir hydrochloride tablets for treatment of chickenpox in immunocompetent pediatric patients 2 to < 18 years of age is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. 2.3 Extemporaneous Preparation of Oral Suspension Ingredients and Preparation per USP-NF: Valacyclovir hydrochloride tablets, 500 mg, cherry flavor, and Suspension Structured Vehicle USP-NF (SSV). Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of 100 mL. Prepare Suspension at Time of Dispensing as Follows: Prepare SSV according to the USP-NF. Using a pestle and mortar, grind the required number of valacyclovir hydrochloride tablets, 500 mg until a fine powder is produced (5 valacyclovir hydrochloride tablets for 25 mg/mL suspension; 10 valacyclovir hydrochloride tablets for 50 mg/mL suspension). Gradually add approximately 5 mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted. Continue to add approximately 5 mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25 mg/mL and 50 mg/mL suspensions. Transfer the mixture to a suitable 100 mL measuring flask. Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV. Once dissolved, add to the measuring flask. Rinse the mortar at least 3 times with approximately 5 mL aliquots of SSV, transferring the rinsing to the measuring flask between additions. Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix. Transfer the suspension to an amber glass medicine bottle with a child-resistant closure. The prepared suspension should be labeled with the following information "Shake well before using. Store suspension between 2° to 8°C (36° to 46°F) in a refrigerator. Discard after 28 days." *The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor. 2.4 Patients With Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of valacyclovir hydrochloride tablets in pediatric patients with a creatinine clearance <50 mL/min/1.73 m2. Table 1. Valacyclovir Hydrochloride Tablets Dosage Recommendations for Adults With Renal Impairment Normal Dosage Regimen Creatinine Clearance (mL/min) Indications (Creatinine Clearance ≥50 mL/min) 30-49 10-29 <10 Cold sores ( Herpes labialis ) Do not exceed 1 day of treatment . Two 2 gram doses taken 12 hours apart Two 1 gram doses taken 12 hours apart Two 500 mg doses taken 12 hours apart 500 mg single dose Genital herpes : Initial episode 1 gram every 12 hours no reduction 1 gram every 24 hours 500 mg every 24 hours Genital herpes : Recurrent episode 500 mg every 12 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Genital herpes : Suppressive therapy Immunocompetent patients 1 gram every 24 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Alternate dose for immunocompetent patients with ≤9 recurrences/year 500 mg every 24 hours no reduction 500 mg every 48 hours 500 mg every 48 hours HIV-infected patients 500 mg every 12 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Herpes zoster 1 gram every 8 hours 1 gram every 12 hours 1 gram every 24 hours 500 mg every 24 hours Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of valacyclovir hydrochloride tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride tablets are approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Peritoneal Dialysis: There is no information specific to administration of valacyclovir hydrochloride tablets in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of valacyclovir hydrochloride tablets should not be required following CAPD or CAVHD.

traZODone HCl 100 MG Oral Tablet

Generic Name: TRAZODONE HYDROCHLORIDE
Brand Name: Trazodone Hydrochloride
  • Substance Name(s):
  • TRAZODONE HYDROCHLORIDE

DRUG INTERACTIONS

7 MAOIs MAOIs should not be used within 14 days of trazodone [see Warnings and Precautions (5.8)]. Central Nervous System (CNS) Depressants Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants. Cytochrome P450 3A4 Inhibitors In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with cytochrome P450 3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4 fold, the half-life increased by 2.2 fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased [see Warnings and Precautions (5.4)] and a lower dose of trazodone should be considered. Cytochrome P450 Inducers (e.g., Carbamazepine) Carbamazepine induces CYP3A4. Following coadministration of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone and m-chlorophenlypiperazine (an active metabolite) by 76% and 60% respectively, compared to pre-carbamazepine values. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs. Digoxin and Phenytoin Increased serum digoxin or phenytoin levels have been reported in patients receiving trazodone concurrently with either of these drugs. Monitor serum levels and adjust dosages as needed. Serotonergic Drugs Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is coadministered with other drugs that may affect the neurotransmitter systems [see Warnings and Precautions (5.2)]. NSAIDs, Aspirin, or Other Drugs Affecting Coagulation or Bleeding Due to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be monitored for and cautioned about the potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Warnings and Precautions (5.7)]. Warfarin There have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone. • CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants (7). • CYP3A4 Inhibitors: May necessitate lower dose of trazodone hydrochloride tablets (7). • CYP3A4 Inducers (e.g., Carbamazepine): May necessitate higher dose of trazodone hydrochloride tablets (7). • Digoxin or Phenytoin: Monitor for increased serum levels (7). • Warfarin: Monitor for increased or decreased prothrombin time (7).

OVERDOSAGE

10 10.1 Human Experience Death from overdose has occurred in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; alcohol and chloral hydrate and diazepam; amobarbital; chlordiazepoxide; or meprobamate). The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions. 10.2 Management of Overdose There is no specific antidote for trazodone hydrochloride overdose. Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

DESCRIPTION

11 Trazodone hydrochloride, USP is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. Trazodone hydrochloride, USP is a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4, 3-a]pyridin-3(2H)-one hydrochloride. It is a white, odorless crystalline powder which is freely soluble in water. The structural formula is represented as follows: C19H22ClN5O · HCl M. W. 408.32 C19H22ClN5O · HCl M. W. 408.32 Each tablet, for oral administration, contains 50 mg, 100 mg or 150 mg of trazodone hydrochloride, USP. In addition, each tablet contains colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. structural formula

CLINICAL STUDIES

14 The efficacy and safety of trazodone hydrochloride was established from both inpatient and outpatient trials of the trazodone immediate release formulation in the treatment of major depressive disorder.

HOW SUPPLIED

16 /STORAGE AND HANDLING Trazodone Hydrochloride Tablets USP are available as follows: 50 mg: White, round, compressed tablet, debossed “PLIVA 433” on one side and scored on the other side. Available in bottles of 100, 500 and 1000. 100 mg: White, round, compressed tablet, debossed “PLIVA 434” on one side and scored on the other side. Available in bottles of 100, 500 and 1000 Tablets. 150 mg: White, trapezoid, flat-face, beveled edge tablet, scored and debossed as “PLIVA” bisect “441” on one side and tri-scored and debossed as “50” in each section on the other side. Available in bottles of 100 and 500 Tablets. Directions for using the correct score when breaking the tablet please refer to the following: – For 50 mg, break the score on either the left or right side of the tablet (one-third of a tablet). – For 75 mg, break the score down the middle of the tablet (one-half of a tablet). – For 100 mg, break the score on either the left or right side of the tablet (two-thirds of a tablet). – For 150 mg, use the entire tablet. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Image 1 Image 2 Image 3 Image 4

RECENT MAJOR CHANGES

Warnings and Precautions (5.12) 06/2014

GERIATRIC USE

8.5 Geriatric Use Reported clinical literature and experience with trazodone has not identified differences in responses between elderly and younger patients. However, as experience in the elderly with trazodone hydrochloride is limited, it should be used with caution in geriatric patients. Antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.10)].

DOSAGE FORMS AND STRENGTHS

3 Trazodone hydrochloride tablets are available in the following strengths: 50 mg- White, round, compressed tablet, debossed “PLIVA 433” on one side and scored on the other side. 100 mg- White, round, compressed tablet, debossed “PLIVA 434” on one side and scored on the other side. 150 mg- White, trapezoid, flat-face, beveled edge tablet, scored and debossed as “PLIVA” bisect “441” on one side and tri-scored and debossed as “50” in each section on the other side. Bisectable tablets of 50 mg, 100 mg and 150 mg (3).

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of trazodone’s antidepressant action is not fully understood, but is thought to be related to its potentiation of serotonergic activity in the CNS.

INDICATIONS AND USAGE

1 Trazodone Hydrochloride Tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of Trazodone Hydrochloride Tablets USP has been established in trials with the immediate release formulation of trazodone [see Clinical Studies (14)]. Trazodone Hydrochloride Tablets USP are indicated for the treatment of major depressive disorder (1). • Efficacy was established in trials of trazodone immediate release formulation in patients with major depressive disorder (14).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions (5.1)]. Trazodone hydrochloride should not be used in children or adolescents.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category C Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in two studies using the rat when given at dose levels approximately 30 to 50 times the proposed maximum human dose. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 to 50 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers Trazodone and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when trazodone is administered to a nursing woman.

BOXED WARNING

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone hydrochloride tablets are not approved for use in pediatric patients [see Warnings and Precautions (5.1) and Patient Counseling Information (17.1)]. WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1). • Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants. Discontinue trazodone hydrochloride tablets and initiate supportive treatment (5.2, 7). • Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania (5.3). • QT Prolongation: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval (5.4). • Use in Patients With Heart Disease: Use with caution in patients with cardiac disease (5.5). • Orthostatic Hypotension and Syncope: Have occurred. Warn patients of risk and symptoms of hypotension (5.6). • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk (5.7, 7). • Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors (5.8, 7). • Priapism: Has occurred. Warn male patients of this risk and how/when to seek medical attention (5.9). • Hyponatremia: Can occur in association with SIADH (5.10). • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery (5.11). •Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.12) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance. Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms (5.13). 5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for trazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions (5.8) and Drug Interactions (7)]. If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended. 5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that trazodone hydrochloride tablets are not approved for use in treating bipolar depression. 5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause torsade de pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc. Although torsade de pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of torsade de pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less. 5.5 Use in Patients With Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias. QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4)]. Clinical studies in patients with preexisting cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes. Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia. 5.6 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug. 5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. 5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI. 5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions (6.2) and Overdosage (10)]. Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease). 5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with antidepressants. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide 17.1 Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with trazodone hydrochloride and should counsel them in its appropriate use. Patients should be warned that: •There is a potential for increased risk of suicidal thoughts especially in children, teenagers and young adults. •The following symptoms should be reported to the physician: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania and mania. •They should inform their physician if they have a history of bipolar disorder, cardiac disease or myocardial infarction. •Serotonin syndrome could occur and symptoms may include changes in mental status (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). •Trazodone hydrochloride has been associated with the occurrence of priapism. •There is a potential for hypotension, including orthostatic hypotension and syncope. •There is a potential risk of bleeding (including life-threatening hemorrhages) and bleeding related events (including ecchymosis, hematoma, epistaxis, and petechiae) with the concomitant use of trazodone hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. •Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced. •Patients should be advised that taking trazodone hydrochloride tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [see Warnings and Precautions (5.12)] Patients should be counseled that: •Trazodone may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles until they are reasonably certain that the drug treatment does not affect them. •Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants. •Women who intend to become pregnant or who are breastfeeding should discuss with a physician whether they should continue to use trazodone, since use in pregnant and nursing women is not recommended. Important Administration Instructions: •Trazodone hydrochloride tablets should be swallowed whole or broken in half along the score line. •Trazodone hydrochloride tablets should be taken shortly after a meal or light snack. Manufactured In Croatia By: PLIVA HRVATSKA d.o.o. Zagreb, Croatia Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. E 5/2014

DOSAGE AND ADMINISTRATION

2 The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack. Dose Selection An initial dose of 150 mg/day in divided doses is suggested. The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses •Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response. •Patients should be monitored for withdrawal symptoms when discontinuing treatment with trazodone hydrochloride tablets. The dose should be gradually reduced whenever possible [see Warnings and Precautions (5.13)]. Maintenance Treatment The efficacy of trazodone hydrochloride tablets for the maintenance treatment of MDD has not been evaluated. While there is no body of evidence available to answer the question of how long a patient treated with trazodone hydrochloride tablets should continue the drug, it is generally recommended that treatment be continued for several months after an initial response. Patients should be maintained on the lowest effective dose and be periodically reassessed to determine the continued need for maintenance treatment. Important Administration Instructions Trazodone hydrochloride tablets are scored to provide flexibility in dosing. Trazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. • Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses (2). • Trazodone hydrochloride tablets should be taken shortly after a meal or light snack (2). • Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed (2). • When discontinued, gradual dose reduction is recommended (2).

Amitriptyline Hydrochloride 50 MG Oral Tablet

Generic Name: AMITRIPTYLINE HYDROCHLORIDE
Brand Name: Amitriptyline Hydrochloride
  • Substance Name(s):
  • AMITRIPTYLINE HYDROCHLORIDE

WARNINGS

Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Prescriptions for amitriptyline hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that amitriptyline hydrochloride tablets are not approved for use in treating bipolar depression. Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or similarly acting compounds. It should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention, angle-closure glaucoma or increased intraocular pressure. In patients with angle-closure glaucoma, even average doses may precipitate an attack. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with drugs of this class. Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication. Amitriptyline hydrochloride may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. Delirium has been reported with concurrent administration of amitriptyline and disulfiram. Usage in Pregnancy: Pregnancy Category C – Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose*). Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations. Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of the cranial bones. Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy. There are no adequate and well-controlled studies in pregnant women. Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers: Amitriptyline is excreted into breast milk. In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother's serum. Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant's serum. Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

DRUG INTERACTIONS

Drug Interactions: Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Monoamine oxidase inhibitors – see section. Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram – see section. CONTRAINDICATIONS WARNINGS When amitriptyline hydrochloride is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required. Hyperpyrexia has been reported when amitriptyline hydrochloride is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs. Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen. Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.

OVERDOSAGE

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. In addition, a rightward axis shift in the terminal QRS complex together with a prolonged QT interval and sinus tachycardia are specific and sensitive indicators of first generation tricyclic overdose. The absence of these findings is not exclusionary. Prolonged PR interval, ST-T wave changes, ventricular tachycardia and fibrillation may also occur. Other signs of overdose may include: impaired myocardial contractility, confusion, disturbed concentration, transient visual hallucinations, dilated pupils, disorders of ocular motility, agitation, hyperactive reflexes, polyradiculoneuropathy, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under . ADVERSE REACTIONS Management: General – Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during the period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED. Cardiovascular: A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). 2 In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with the acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS: In patients with CNS depression early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management: The principles of management of pediatric and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DESCRIPTION

Amitriptyline HCl is 3-(10,11-dihydro-5H-dibenzo [a, ] cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Its empirical formula is C H N•HCl, and its structural formula is: d 20 23 Amitriptyline HCl, a dibenzocycloheptadiene derivative, has a molecular weight of 313.87. It is a white, odorless, crystalline compound which is freely soluble in water. Amitriptyline HCl is supplied as 10 mg, 25 mg, 50 mg, 75 mg, 100 mg or 150 mg tablets. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, sodium starch glycolate and titanium dioxide. The 10 mg tablets also contain FD&C blue #1 lake. The 25 mg tablets also contain D&C yellow #10 lake and FD&C blue #2 lake. The 50 mg tablets also contain synthetic black iron oxide, synthetic red iron oxide and synthetic yellow iron oxide. The 75 mg tablets also contain FD&C yellow #6 lake. The 100 mg tablets also contain D&C red #33 lake and FD&C red #40 lake. The 150 mg tablets also contain FD&C blue #2 lake and FD&C yellow #6 lake. This is an image of the sturctural formula of Amitriptyline HCl.

GERIATRIC USE

Geriatric Use: Clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease and other drug therapy in elderly patients. Geriatric patients are particularly sensitive to the anticholinergic side effects of tricyclic antidepressants including amitriptyline hydrochloride. Peripheral anticholinergic effects include tachycardia, urinary retention, constipation, dry mouth, blurred vision, and exacerbation of narrow-angle glaucoma. Central nervous system anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation, and delirium. Elderly patients taking amitriptyline hydrochloride may be at increased risk for falls. Elderly patients should be started on low doses of amitriptyline hydrochloride and observed closely (see ). DOSAGE AND ADMINISTRATION

INDICATIONS AND USAGE

For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see and ). Anyone considering the use of amitriptyline hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. BOX WARNING WARNINGS- Clinical Worsening and Suicide Risk

PREGNANCY

Usage in Pregnancy: Pregnancy Category C – Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose*). Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations. Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of the cranial bones. Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy. There are no adequate and well-controlled studies in pregnant women. Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers: Amitriptyline is excreted into breast milk. In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother’s serum. Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant’s serum. Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Amitriptyline hydrochloride tablets are not approved for use in pediatric patients (see , , and .) Warnings: Clinical Worsening and Suicide Risk Precautions: Information for Patients Precautions: Pediatric Use

INFORMATION FOR PATIENTS

Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amitriptyline hydrochloride tablets and should counsel them in its appropriate use. A patient about is available for amitriptyline hydrochloride tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Medication Guide “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking amitriptyline hydrochloride tablets. While on therapy with amitriptyline hydrochloride, patients should be advised as to the possible impairment of mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.

DOSAGE AND ADMINISTRATION

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Initial Dosage for Adults: For outpatients 75 mg of amitriptyline HCl a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg per day. Increases are made preferably in the late afternoon and/or bedtime doses. A sedative effect may be apparent before the antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days to develop. An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline HCl at bedtime. This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day. Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalized patients may need as much as 300 mg a day. Adolescent and Elderly Patients: In general, lower dosages are recommended for these patients. Ten mg 3 times a day with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages. Maintenance: The usual maintenance dosage of amitriptyline HCl is 50 to 100 mg per day. In some patients 40 mg per day is sufficient. For maintenance therapy the total daily dosage may be given in a single dose preferably at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse. Usage in Pediatric Patients In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age. Plasma Levels Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected. Because of increased intestinal transit time and decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a given oral dose of amitriptyline hydrochloride than in younger patients. Elderly patients should be monitored carefully and quantitative serum levels obtained as clinically appropriate. Adjustment in dosage should be made according to the patient’s clinical response and not on the basis of plasma levels.**

Levetiracetam 500 MG Oral Tablet

Generic Name: LEVETIRACETAM
Brand Name: Levetiracetam
  • Substance Name(s):
  • LEVETIRACETAM

DRUG INTERACTIONS

7. No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications via human liver cytochrome P450 isoforms, epoxide hydrolase, UDP-glucuronidation enzymes, P-glycoprotein, or renal tubular secretion [see CLINICAL PHARMACOLOGY ( )]. 12.3

OVERDOSAGE

10. 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse events in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

DESCRIPTION

11. Levetiracetam USP is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (orange), and 1000 mg (white) tablets for oral administration. The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C H N O and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula: 8 14 2 2 Levetiracetam USP is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent). Levetiracetam tablets USP contain the labeled amount of levetiracetam. For 250 mg, 500 mg and 750 mg strengths: Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and additional agents listed below: 250 mg tablets: FD&C Blue No. 2 Aluminum Lake 500 mg tablets: Yellow Iron Oxide 750 mg tablets: FD&C Blue No. 2 Aluminum Lake, FD&C yellow No.6 Aluminum Lake, iron oxide red For 1000 mg strength: Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Image 2

CLINICAL STUDIES

14. In the following studies, statistical significance versus placebo indicates a p value <0.05. 14.1 Partial Onset Seizures Effectiveness in Partial Onset Seizures in Adults with Epilepsy The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization. The tablet formulation was used in all these studies. In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period. Study 1: Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing levetiracetam 1000 mg/day (N=97), levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Study 1 are displayed in Table 10. Table 9: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures In Study 1 Placebo ( N = 95 ) Levetiracetam 1000 mg / day ( N = 97 ) Levetiracetam 3000 mg / day ( N = 101 ) Percent reduction in partial seizure frequency over placebo – 26.1% statistically significant versus placebo 30.1% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1. Figure 1: Responder Rate (≥50% Reduction From Baseline) In Study 1 *statistically significant versus placebo Study 2: Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing levetiracetam 1000 mg/day (N=106), levetiracetam 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily. The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients were randomized to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 10. Table 10: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures In Study 2: Period A Placebo ( N = 111 ) Levetiracetam 1000 mg / day ( N = 106 ) Levetiracetam 2000 mg / day ( N = 105 ) Percent reduction in partial seizure frequency over placebo – 17.1% statistically significant versus placebo 21.4% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2. Figure 2: Responder Rate (≥50% Reduction From Baseline) In Study 2: Period A *statistically significant versus placebo The comparison of levetiracetam 2000 mg/day to levetiracetam 1000 mg/day for responder rate was statistically significant (P=0.02). Analysis of the trial as a cross-over yielded similar results. Study 3: Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients were randomized to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). Table 11 displays the results of the analysis of Study 3. Table 11: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures In Study 3 Placebo ( N = 104 ) Levetiracetam 3000 mg / day ( N = 180 ) Percent reduction in partial seizure frequency over placebo – 23.0% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3. Figure 3: Responder Rate (≥50% Reduction From Baseline) In Study 3 *statistically significant versus placebo Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years With Epilepsy The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Eligible patients on a stable dose of 1 to 2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either levetiracetam or placebo. The enrolled population included 198 patients (levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized. The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 12 displays the results of this study. Table 12: Reduction In Mean Over Placebo In Weekly Frequency of Partial Onset Seizures Placebo ( N = 97 ) Levetiracetam ( N = 101 ) Percent reduction in partial seizure frequency over placebo – 26.8% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4. Figure 4: Responder Rate (≥ 50% Reduction From Baseline) *statistically significant versus placebo Clinical trial information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.'s levetiracetam tablets. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 14.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Effectiveness of Myoclonic Seizures in Patients ≥12 Years of Age with Juvenile Myoclonic Epilepsy (JME) The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study, conducted at 37 sites in 14 countries. Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either levetiracetam or placebo (levetiracetam N=60, placebo N=60). Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses. The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 13 displays the results for the 113 patients with JME in this study. Table 13: Responder Rate (≥50% Reduction from Baseline) In Myoclonic Seizure Days Per Week for Patients with JME Placebo ( N = 59 ) Levetiracetam ( N = 54 ) Percentage of responders 23.7% 60.4% statistically significant versus placebo 14.3 Primary Generalized Tonic-Clonic Seizures Effectiveness in Primary Generalized Tonic-Clonic Seizures in Patients ≥6 Years of Age The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study, conducted at 50 sites in 8 countries. Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomized to either levetiracetam or placebo. The 8-week combined baseline period is referred to as "baseline" in the remainder of this section. The population included 164 patients (levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures. Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population. Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day. The primary measure of effectiveness was the percent reduction from baseline in weekly PGTC seizure frequency for levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam-treated patients compared to the placebo-treated patients. Table 14: Median Percent Reduction from Baseline In PGTC Seizure Frequency Per Week Placebo ( N = 84 ) Levetiracetam ( N = 78 ) Percent reduction in PGTC seizure frequency 44.6% 77.6% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 5. Figure 5: Responder Rate (≥50% Reduction From Baseline) In PGTC Seizure Frequency Per Week *statistically significant versus placebo Image 3 Image 4 Image 5 Image 6 Image 7

HOW SUPPLIED

16. /STORAGE AND HANDLING NDC:64725-1130-1 in a CONTAINER of 30 TABLET, FILM COATEDS 16.1 How Supplied Levetiracetam tablets USP, 250 mg are blue coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X01” on the other side. They are supplied as follows: NDC 68180-112-09 Bottles of 90’s NDC 68180-112-16 Bottles of 120’s NDC 68180-112-02 Bottles of 500’s Levetiracetam tablets USP, 500 mg are yellow coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X02” on the other side. They are supplied as follows: NDC 68180-113-09 Bottles of 90’s NDC 68180-113-16 Bottles of 120’s NDC 68180-113-02 Bottles of 500’s Levetiracetam tablets USP, 750 mg are orange coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X03” on the other side. They are supplied as follows: NDC 68180-114-09 Bottles of 90’s NDC 68180-114-16 Bottles of 120’s NDC 68180-114-02 Bottles of 500’s Levetiracetam tablets USP, 1000 mg are white to off-white coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X04” on the other side. They are supplied as follows: NDC 68180-115-07 Bottles of 60’s NDC 68180-115-02 Bottles of 500’s 16.2 Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with child-resistant closure along with medication guide provided separately. Pharmacist:

GERIATRIC USE

8.5 Geriatric Use There were 347 subjects in clinical studies of levetiracetam that were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . [see CLINICAL PHARMACOLOGY ( )] 12.3

DOSAGE FORMS AND STRENGTHS

3. 250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( ) 3 Levetiracetam tablets, 250 mg are blue coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X01” on the other side. Levetiracetam tablets, 500 mg are yellow coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X02” on the other side. Levetiracetam tablets, 750 mg are orange coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X03” on the other side. Levetiracetam tablets, 1000 mg are white to off-white coloured, oblong-shaped, biconvex, film-coated tablets, debossed with “L” and “U” on either side of the breakline on one side and “X04” on the other side.

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. and recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity. In vitro in vivo Levetiracetam at concentrations of up to 10 µM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

INDICATIONS AND USAGE

1. Levetiracetam tablets USP are antiepileptic drugs indicated for adjunctive therapy in the treatment of: Partial onset seizures in patients 4 years of age and older with epilepsy ( ) 1.1 Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( ) 1.2 Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( ) 1.3 1.1 Partial Onset Seizures Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. Information describing the use of levetiracetam in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.’s levetiracetam tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of levetiracetam in the adjunctive treatment of partial onset seizures in pediatric patients age 4 years to 16 years old with epilepsy have been established The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see CLINICAL STUDIES ( )]. 14.1 [see DOSAGE AND ADMINISTRATION ( )]. 2.2 Pediatric use information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.’s levetiracetam tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. The safety and effectiveness of levetiracetam as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see CLINICAL STUDIES ( )]. 14.2 The safety and effectiveness of levetiracetam as adjunctive therapy in the treatment of primary generalized tonic- clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see CLINICAL STUDIES ( )]. 14.3 A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam N=64, placebo N=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child’s memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6 to 18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6 to 18 indicated on average a worsening in levetiracetam treated patients in aggressive behavior, one of the eight syndrome scores. [see WARNINGS AND PRECAUTIONS ( )] 5.1 Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not indicate a potential for age-specific toxicity.

PREGNANCY

8.1 Pregnancy Levetiracetam levels may decrease during pregnancy [see WARNINGS AND PRECAUTIONS ( )]. 5.9 Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m basis). There was no overt maternal toxicity at the doses used in this study. 2 2 2 Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m basis). Maternal toxicity was also observed at 1800 mg/kg/day. 2 2 2 When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m basis). 2 Pregnancy Registries To provide information regarding the effects of exposure to levetiracetam, physicians are advised to recommend that pregnant patients taking levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at the website . in utero http://www.aedpregnancyregistry.org/

NUSRING MOTHERS

8.3 Nursing Mothers Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Psychiatric Symptoms: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms ( ) 5.1 Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior ( ) 5.2 Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam ( ) 5.3 Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( ) 5.6 5.1 Psychiatric Reactions In some patients levetiracetam causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult and pediatric partial onset seizure studies. A total of 13.3% of adult levetiracetam-treated patients and 37.6% of pediatric levetiracetam -treated patients (4 to 16 years of age) compared to 6.2% and 18.6% of adult and pediatric placebo patients respectively, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder). A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6 to 18). In pediatric patients 1 month to < 4 years of age, irritability was reported in 11.7% of the levetiracetam -treated patients compared to 0% of placebo patients. A total of 1.7% of adult levetiracetam-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult levetiracetam-treated patients and in 0.5% of placebo patients. Overall, 10.9% of levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients. One percent of adult levetiracetam-treated patients, 2% of children 4 to 16 years of age, and 17% of children 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% respectively, in the placebo patients. In the controlled study that assessed the neurocognitive and behavioral effects of levetiracetam in pediatric patients 4 to 16 years of age, 1 (1.6%) levetiracetam-treated patient experienced paranoia compared to no placebo patients. There were 2 (3.1%) levetiracetam-treated patients that experienced confusional state compared to no placebo patients . [see USE IN SPECIFIC POPULATIONS ( )] 8.4 Two (0.3%) adult levetiracetam-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. The above psychiatric signs and symptoms should be monitored. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including levetiracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk : Incidence of Events in Drug Patients / Incidence in Placebo Patients Risk Difference : Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.3 Somnolence and Fatigue In some patients, levetiracetam causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial onset seizure studies. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial onset seizure studies. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of levetiracetam-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery. 5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. 5.5 Coordination Difficulties Coordination difficulties were only observed in the adult partial onset seizure studies. A total of 3.4% of adult levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery. 5.6 Withdrawal Seizures Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. 5.7 Hematologic Abnormalities Partial Onset Seizures Adults: Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 /mm ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials. 6 3 A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 10 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 10 /L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. 9 9 Pediatric Patients 4 Years to < 16 Years: Statistically significant decreases in WBC and neutrophil counts were seen in levetiracetam-treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam-treated group were -0.4 x 10 /L and – 0.3 x 10 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant). 9 9 In the controlled trial, more levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3.0% levetiracetam-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% levetiracetam-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts. In the controlled cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the levetiracetam-treated group had high eosinophil count values that were possibly clinically significant (≥10% or≥0.7X10 /L). 9 Juvenile Myoclonic Epilepsy: Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients. 5.8 Blood Pressure Increases In a randomized, placebo-controlled study in patients aged 1 month to <4 years of age, a significantly higher risk of at least one measured increase in diastolic blood pressure was observed in the levetiracetam-treated patients (17%) compared to the placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults. 5.9 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Medication Guide). Counsel patients on the benefits and risks of receiving levetiracetam. Provide the Medication Guide to patients and/or caregivers, and instruct them to read the Medication Guide prior to taking levetiracetam. Instruct patients to take levetiracetam only as prescribed. Suicidal Behavior and Ideation Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including levetiracetam, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider. Psychiatric Reactions and Changes in Behavior Advise patients that levetiracetam may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases, psychotic symptoms have occurred. Effects on Driving or Operating Machinery Inform patients that levetiracetam may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery. Dermatological Adverse Reactions Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their physician immediately if a rash develops. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during levetiracetam therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States. MADE IN INDIA. June 2014 ID# 237668

DOSAGE AND ADMINISTRATION

2. Use the oral solution for pediatric patients with body weight ≤ 20 kg ( ). 2.1 For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) ( ) 2.1 Partial Onset Seizures : 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( ) 4 Years to < 16 Years 2.2 : 500 mg twice daily, increase as needed and tolerated in increments of 500 mg twice daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily ( ) Adults 16 Years and Older 2.2 Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( ) 2.3 Primary Generalized Tonic-Clonic Seizures : 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( ) 6 Years To < 16 Years 2.4 : 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( ) Adults 16 Years and Older 2.4 Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient's estimated creatinine clearance ( , ) 2.5 8.6 2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food. The levetiracetam dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function. Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. Levetiracetam tablets should be swallowed whole. Levetiracetam tablets should not be chewed or crushed. 2.2 Partial Onset Seizures Adults 16 Years and Older In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose , a consistent increase in response with increased dose has not been shown. [see CLINICAL STUDIES ( )] 14.1 Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit. Pediatric Patients Dosing information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.'s levetiracetam tablets. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 4 Years to < 16 Years: Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical efficacy trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day. For levetiracetam tablet dosing in pediatric patients weighing 20 to 40 kg, treatment should be initiated with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily). The daily dose should be increased every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily). For levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, treatment should be initiated with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily). The daily dose should be increased every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily). Levetiracetam Oral Solution Weight-Based Dosing Calculation For Pediatric Patients The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients: 2.3 Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied. 2.4 Primary Generalized Tonic-Clonic Seizures Adults 16 Years and Older Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied. Pediatric Patients Ages 6 to 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe <30 250 to 500 Every 12 hours ESRD patients using dialysis —– 500 to 1000 Following dialysis, a 250 to 500 mg supplemental dose is recommended. Every 24 hours Image 0 Image 1

tamsulosin hydrochloride 0.4 MG Modified Release Oral Capsule

Generic Name: TAMSULOSIN HYDROCHLORIDE
Brand Name: FLOMAX
  • Substance Name(s):
  • TAMSULOSIN HYDROCHLORIDE

DRUG INTERACTIONS

7 FLOMAX capsules 0.4 mg should not be used with strong inhibitors of CYP3A4 (e.g., ketoconazole). FLOMAX capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, or in patients known to be CYP2D6 poor metabolizers, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). (5.2, 7.1, 12.3) Concomitant use of PDE5 inhibitors with tamsulosin can potentially cause symptomatic hypotension (5.2, 7.3, 12.3) 7.1 Cytochrome P450 Inhibition Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. Cimetidine Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. 7.2 Other Alpha Adrenergic Blocking Agents The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. 7.3 PDE5 Inhibitors Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. 7.4 Warfarin A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. 7.5 Nifedipine, Atenolol, Enalapril Dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril [ see Clinical Pharmacology (12.3) ]. 7.6 Digoxin and Theophylline Dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline [ see Clinical Pharmacology (12.3) ]. 7.7 Furosemide FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage [ see Clinical Pharmacology (12.3) ].

OVERDOSAGE

10 Should overdosage of FLOMAX capsules lead to hypotension [ see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ], support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.

DESCRIPTION

11 Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate. Tamsulosin hydrochloride is (-)-( R )-5-[2-[[2-( o -Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether. The empirical formula of tamsulosin hydrochloride is C20H28N2O5S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is: Each FLOMAX capsule for oral administration contains tamsulosin hydrochloride 0.4 mg, and the following inactive ingredients: methacrylic acid copolymer dispersion, NF; microcrystalline cellulose, NF; triacetin, USP; calcium stearate, NF; talc, USP; FD&C blue No. 2; titanium dioxide; ferric oxide; gelatin, and trace amounts of black edible ink. Flomax Structure

CLINICAL STUDIES

14 Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe. In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction. Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose. Table 3 Mean (±S.D.) Changes from Baseline to Week 13 in Total AUA Symptom Score** and Peak Urine Flow Rate (mL/sec) Total AUA Symptom Score Peak Urine Flow Rate Mean Baseline Value Mean Change Mean Baseline Value Mean Change * Statistically significant difference from placebo (p-value ≤0.050; Bonferroni-Holm multiple test procedure). ** Total AUA Symptom Scores ranged from 0 to 35. † Peak urine flow rate measured 4 to 8 hours post dose at Week 13. ‡ Peak urine flow rate measured 24 to 27 hours post dose at Week 13. Week 13: For patients not completing the 13-week study, the last observation was carried forward. Study 1 † FLOMAX capsules 0.8 mg once daily 19.9 ± 4.9 n=247 -9.6* ± 6.7 n=237 9.57 ± 2.51 n=247 1.78* ± 3.35 n=247 FLOMAX capsules 0.4 mg once daily 19.8 ± 5.0 n=254 -8.3* ± 6.5 n=246 9.46 ± 2.49 n=254 1.75* ± 3.57 n=254 Placebo 19.6 ± 4.9 n=254 -5.5 ± 6.6 n=246 9.75 ± 2.54 n=254 0.52 ± 3.39 n=253 Study 2 ‡ FLOMAX capsules 0.8 mg once daily 18.2 ± 5.6 n=244 -5.8* ± 6.4 n=238 9.96 ± 3.16 n=244 1.79* ± 3.36 n=237 FLOMAX capsules 0.4 mg once daily 17.9 ± 5.8 n=248 -5.1* ± 6.4 n=244 9.94 ± 3.14 n=248 1.52 ± 3.64 n=244 Placebo 19.2 ± 6.0 n=239 -3.6 ± 5.7 n=235 9.95 ± 3.12 n=239 0.93 ± 3.28 n=235 Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B). In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo-controlled, 40-week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg, and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg, and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year. Figure 2A Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 1 * indicates significant difference from placebo (p-value ≤0.050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Total AUA Symptom Scores range from 0 to 35. Figure 2B Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 2 * indicates significant difference from placebo (p-value ≤0.050). Baseline measurement was taken Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Total AUA Symptom Scores range from 0 to 35. Figure 3A Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1 * indicates significant difference from placebo (p-value ≤0.050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: The uroflowmetry assessments at Week 0 were recorded 4 to 8 hours after patients received the first dose of double-blind medication. Measurements at each visit were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration). Note: Patients in the 0.8 mg treatment groups received 0.4 mg for the first week. Figure 3B Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2 * indicates significant difference from placebo (p-value ≤0.050). Baseline measurement was taken Week 0. Subsequent values are observed cases. LOCF = Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0.4 mg for the first week. Note: Week 1 and Week 2 measurements were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration). All other visits were scheduled 24 to 27 hours after dosing (approximate trough tamsulosin concentration). Figure 2a Figure 2b Figure 3a Figure 3b

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOMAX capsules 0.4 mg are supplied in high density polyethylene bottles containing 100 hard gelatin capsules with olive green opaque cap and orange opaque body. The capsules are imprinted on one side with Flomax 0.4 mg and on the other side with BI 58. FLOMAX capsules 0.4 mg, 100 capsules (NDC 0597-0058-01) Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature]. Keep FLOMAX capsules and all medicines out of reach of children.

RECENT MAJOR CHANGES

Dosage and Administration (2) 4/2009 Contraindications (4) 12/2009 Warnings and Precautions Drug Interactions (5.2) 12/2009 Screening for Prostate Cancer (5.4) 12/2009

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [ see Clinical Pharmacology (12.3) ].

DOSAGE FORMS AND STRENGTHS

3 Capsule: 0.4 mg, olive green and orange hard gelatin, imprinted on one side with Flomax 0.4 mg and on the other side with BI 58 Capsules: 0.4 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype. FLOMAX capsules are not intended for use as an antihypertensive drug.

INDICATIONS AND USAGE

1 Flomax® (tamsulosin hydrochloride) capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [ see Clinical Studies (14) ]. FLOMAX capsules are not indicated for the treatment of hypertension. FLOMAX is an alpha1 adrenoceptor antagonist indicated for treatment of the signs and symptoms of benign prostatic hyperplasia (1) FLOMAX capsules are not indicated for the treatment of hypertension (1)

PEDIATRIC USE

8.4 Pediatric Use FLOMAX capsules are not indicated for use in pediatric populations. Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H2O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H2O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation.

PREGNANCY

8.1 Pregnancy Teratogenic Effects, Pregnancy Category B. Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. FLOMAX capsules are not indicated for use in women.

NUSRING MOTHERS

8.3 Nursing Mothers FLOMAX capsules are not indicated for use in women.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Advise patients about the possibility of symptoms related to postural hypotension and to avoid situations where injury could result should syncope occur (5.1) Should not be used in combination with strong inhibitors of CYP3A4. Use with caution in combination with moderate inhibitors of CYP3A4, with strong or moderate inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers, or in combination with other cytochrome P450 inhibitors. (5.2, 7.1, 12.3) Should not be used in combination with other alpha adrenergic blocking agents (5.2, 7.2, 12.3) Exercise caution with concomitant administration of warfarin (5.2, 7.4, 12.3) Advise patients about the possibility and seriousness of priapism (5.3) Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients. Advise patients considering cataract surgery to tell their ophthalmologist that they have taken FLOMAX capsules. (5.5) Advise patients to be screened for the presence of prostate cancer prior to treatment and at regular intervals afterwards (5.4) 5.1 Orthostasis The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in FLOMAX capsule-treated patients than in placebo recipients. As with other alpha adrenergic blocking agents there is a potential risk of syncope [ see Adverse Reactions (6.1) ]. Patients beginning treatment with FLOMAX capsules should be cautioned to avoid situations in which injury could result should syncope occur [ see Patient Counseling Information (17.1) ]. 5.2 Drug Interactions Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. FLOMAX capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. FLOMAX capsules should be used with caution in combination with cimetidine, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. FLOMAX capsules should not be used in combination with other alpha adrenergic blocking agents [ see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [ see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ]. Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules [ see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ]. 5.3 Priapism Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition [ see Patient Counseling Information (17.2) ]. 5.4 Screening for Prostate Cancer Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards [ see Patient Counseling Information (17.3) ]. 5.5 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha1 blockers, including FLOMAX capsules [ see Adverse Reactions (6.2) ]. Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. The benefit of stopping alpha1 blocker therapy prior to cataract surgery has not been established. 5.6 Sulfa Allergy In patients with sulfa allergy, allergic reaction to FLOMAX capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering FLOMAX capsules.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.6). 17.1 Hypotension Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking FLOMAX capsules, and they should be cautioned about driving, operating machinery, or performing hazardous tasks [ see Warnings and Precautions (5.1) ]. 17.2 Priapism Patients should be advised about the possibility of priapism as a result of treatment with FLOMAX capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence) [ see Warnings and Precautions (5.3) ]. 17.3 Screening for Prostate Cancer Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards [ see Warnings and Precautions (5.4) ]. 17.4 Intraoperative Floppy Iris Syndrome Patients considering cataract surgery should be advised to tell their ophthalmologist that they have taken FLOMAX capsules [ see Warnings and Precautions (5.5) ]. 17.5 Administration Patients should be advised not to crush or chew the FLOMAX capsules. 17.6 FDA-approved Patient Labeling Patient labeling is provided as a tear-off leaflet at the end of this prescribing information.

DOSAGE AND ADMINISTRATION

2 FLOMAX capsules 0.4 mg once daily is recommended as the dose for the treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour following the same meal each day. For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of FLOMAX capsules can be increased to 0.8 mg once daily. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [ see Warnings and Precautions (5.2) ]. If FLOMAX capsules administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily dose. 0.4 mg once daily taken approximately one-half hour following the same meal each day (2) Can be increased to 0.8 mg once daily for patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing (2) If discontinued or interrupted for several days, therapy should start again with the 0.4 mg once-daily dose (2)

Warfarin Sodium 2.5 MG Oral Tablet

Generic Name: WARFARIN SODIUM
Brand Name: Warfarin Sodium
  • Substance Name(s):
  • WARFARIN SODIUM

DRUG INTERACTIONS

7 Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [ ]. see Boxed Warning Consult the labeling of all concurrently used drugs to obtain further information about interactions with warfarin sodium or adverse reactions pertaining to bleeding. Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4 ( ). • 7 Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding. ( ) • 7 7.1 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin -enantiomer is metabolized by CYP2C9 while the -enantiomer is metabolized by CYP1A2 and 3A4. S R Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin. • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin. • Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in ; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer. Table 2 Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.2 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in . Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin. Table 3 Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.3 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin. Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin. 7.4 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q , St. John’s wort, ginseng). Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort). 10 The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

OVERDOSAGE

10 10.1 Signs and Symptoms Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation. 10.2 Treatment The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K . 1 The use of vitamin K reduces response to subsequent warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy. 1 Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

DESCRIPTION

11 Warfarin sodium tablets USP contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. The chemical name of warfarin sodium is 3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt, which is a racemic mixture of the – and -enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its structural formula may be represented as follows: R S C H NaO M.W. 330.31 19 15 4 Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether. Each tablet, for oral administration, contains 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg or 10 mg warfarin sodium, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 1 mg also contains FD&C red no. 40. The 2 mg also contains FD&C blue no. 2 aluminum lake and FD&C red no. 40 aluminum lake. The 2.5 mg also contains D&C yellow no. 10 aluminum lake and FD&C blue no. 1 aluminum lake. The 3 mg also contains FD&C yellow no. 6 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, and D&C yellow no. 10 aluminum lake. The 4 mg also contains FD&C blue no. 1 aluminum lake and FD&C blue no. 2 aluminum lake. The 5 mg also contains FD&C yellow no. 6 aluminum lake, FD&C red no. 40 aluminum lake and D&C yellow no. 10 aluminum lake. The 6 mg also contains D&C yellow no. 10 aluminum lake and FD&C blue no. 1 aluminum lake. The 7.5 mg also contains FD&C yellow no. 5 (tartrazine) aluminum lake and FD&C red no. 40 aluminum lake. Warfarin Structural Formula

CLINICAL STUDIES

14 14.1 Atrial Fibrillation In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see ). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see ). Table 4 Table 4 Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks. N Thromboembolism % Major Bleeding Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction -value p Warfarin-Treated Patients Control Patients AFASAK 335 336 1.5 to 2 2.8 to 4.2 60 0.027 0.6 0 SPAF 210 211 1.3 to 1.8 2 to 4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2 to 1.5 1.5 to 2.7 86 < 0.05 0.9 0.5 CAFA 187 191 1.3 to 1.6 2 to 3 45 0.25 2.7 0.5 SPINAF 260 265 1.2 to 1.5 1.4 to 2.8 79 0.001 2.3 1.5 Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [ ]. see Dosage and Administration ( ) 2.2 14.2 Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p < 0.005) and pentoxifylline/aspirin-treated patients (p < 0.05). The results of this study are presented in . Table 5 Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin Event Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py Major Bleeding 2.5/100 py 0/100 py 0.9/100 py py = patient years In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in . Table 6 Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9 Thromboembolism 4/100 py 3.7/100 py Major Bleeding 0.95/100 py 2.1/100 py py = patient years In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2 to 2.25 vs. INR 2.5 to 4) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group. 14.3 Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in . Table 7 Table 7: WARIS – Endpoint Analysis of Separate Events % Risk Warfarin Placebo Reduction Event (N = 607) (N = 607) RR (95% CI) ( -value) p Total Patient Years of Follow-up 2018 1944 Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p = 0.030) Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p = 0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p = 0.001) Cerebrovascular Event 20 (1/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p = 0.002) RR = Relative risk; Risk reduction = (1 – RR); CI = Confidence interval; MI = Myocardial infarction; py = patient years WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in . Table 8 Table 8: WARIS II – Distribution of Events According to Treatment Group Event Aspirin (N = 1206) Warfarin (N = 1216) Aspirin plus Warfarin (N = 1208) Rate Ratio (95% CI) -value p No. of Events Major Bleeding Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. 8 33 28 3.35 (ND) The rate ratio is for aspirin plus warfarin as compared with aspirin. ND 4 (ND) The rate ratio is for warfarin as compared with aspirin. ND Minor Bleeding Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. 39 103 133 3.21 (ND) ND 2.55 (ND) ND Composite Endpoints Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke. 241 203 181 0.81 (0.69 to 0.95) 0.03 0.71 (0.60 to 0.83) 0.001 Reinfarction 117 90 69 0.56 (0.41 to 0.78) < 0.001 0.74 (0.55 to 0.98) 0.03 Thromboembolic Stroke 32 17 17 0.52 (0.28 to 0.98) 0.03 0.52 (0.28 to 0.97) 0.03 Death 92 96 95 0.82 CI = confidence interval ND = not determined There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC:54569-5868-0 in a BOTTLE of 30 TABLETS

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [ ]. Warfarin sodium is contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of warfarin sodium in elderly patients [ ]. see Clinical Pharmacology ( ) 12.3 see Dosage and Administration ( , ) 2.2 2.3

DOSAGE FORMS AND STRENGTHS

3 Warfarin Sodium Tablets USP, 1 mg are available as pink, capsule-shaped, biconvex scored tablets, debossed with TV/1 on the scored side and 1712 on the other side. Warfarin Sodium Tablets USP, 2 mg are available as lavender, capsule-shaped, biconvex scored tablets, debossed with TV/2 on the scored side and 1713 on the other side. Warfarin Sodium Tablets USP, 2.5 mg are available as green, capsule-shaped, biconvex scored tablets, debossed with TV/2 / on the scored side and 1714 on the other side. 1 2 Warfarin Sodium Tablets USP, 3 mg are available as tan, capsule-shaped, biconvex scored tablets, debossed with TV/3 on the scored side and 1715 on the other side. Warfarin Sodium Tablets USP, 4 mg are available as blue, capsule-shaped, biconvex scored tablets, debossed with TV/4 on the scored side and 1716 on the other side. Warfarin Sodium Tablets USP, 5 mg are available as peach, capsule-shaped, biconvex scored tablets, debossed with TV/5 on the scored side and 1721 on the other side. Warfarin Sodium Tablets USP, 6 mg are available as teal, capsule-shaped, biconvex scored tablets, debossed with TV/6 on the scored side and 1718 on the other side. Warfarin Sodium Tablets USP, 7.5 mg are available as yellow, capsule-shaped, biconvex scored tablets, debossed with TV/7 / on the scored side and 1719 on the other side. 1 2 Warfarin Sodium Tablets USP, 10 mg are available as white, capsule-shaped, biconvex scored tablets, debossed with TV/10 on the scored side and 1720 on the other side. Scored tablets: 1, 2, 2.5, 3, 4, 5, 6, 7.5, or 10 mg ( ) • 3

MECHANISM OF ACTION

12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K epoxide [ ]. 1 see Clinical Pharmacology ( ) 12.5

INDICATIONS AND USAGE

1 Warfarin sodium tablets are indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE). • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement. • Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. • Limitations of Use Warfarin sodium tablets have no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae. Warfarin sodium tablets are a vitamin K antagonist indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism ( ) • 1 Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement ( ) • 1 Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction ( ) • 1 Limitations of Use Warfarin sodium tablets have no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. ( ) 1

PEDIATRIC USE

8.4 Pediatric Use Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury. The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries. Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

PREGNANCY

8.1 Pregnancy Risk Summary Warfarin sodium is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin sodium may outweigh the risks [ ]. Warfarin sodium can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects are not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of warfarin sodium and possible risks to the fetus when prescribing warfarin sodium to a pregnant woman. see Warnings and Precautions ( ) 5.5 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the ]. second and third trimesters of pregnancy [ see Contraindications ( ) 4

BOXED WARNING

WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding . • [see Warnings and Precautions ( )] 5.1 Perform regular monitoring of INR in all treated patients . • [see Dosage and Administration ( )] 2.1 Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy . • [see Drug Interactions ( )] 7 Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding . • [see Patient Counseling Information ( )] 17 WARNING: BLEEDING RISK See full prescribing information for complete boxed warning. Warfarin sodium can cause major or fatal bleeding. ( ) • 5.1 Perform regular monitoring of INR in all treated patients. ( ) • 2.1 Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. ( ) • 7 Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. ( ) • 17

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS The 7.5 mg tablets contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue warfarin sodium and consider alternative anticoagulants if necessary. ( ) • 5.2 Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue warfarin sodium if such emboli occur. ( ) • 5.3 Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death. Warfarin sodium may be considered after platelet count has normalized. ( ) • 5.4 Pregnant women with mechanical heart valves: warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. ( ) • 5.5 5.1 Hemorrhage Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR > 4), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [ ], certain concomitant drugs [ ], and long duration of warfarin therapy. see Clinical Pharmacology ( ) 12.5 see Drug Interactions ( ) 7 Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [ ]. see Drug Interactions ( ) 7 Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [ ]. see Patient Counseling Information ( ) 17 5.2 Tissue Necrosis Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (< 0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported. Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue warfarin sodium therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.3 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue warfarin sodium therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.4 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with warfarin sodium may be considered after the platelet count has normalized. 5.5 Use in Pregnant Women with Mechanical Heart Valves Warfarin sodium can cause fetal harm when administered to a pregnant woman. While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [ ]. see Use in Specific Populations ( ) 8.1 5.6 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of warfarin sodium therapy may be increased: Moderate to severe hepatic impairment • Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) • Use of an indwelling catheter • Severe to moderate hypertension • Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients. • Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits. • Polycythemia vera • Vasculitis • Diabetes mellitus • 5.7 Endogenous Factors Affecting INR The following factors may be responsible for INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. increased The following factors may be responsible for INR response: increased vitamin K intake or hereditary warfarin resistance. decreased

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients to: Tell their physician if they fall often as this may increase their risk for complications. • Strictly adhere to the prescribed dosage schedule. Do not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician. • Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. • Contact their doctor • − immediately if they think they are pregnant − to discuss pregnancy planning − if they are considering breastfeeding Avoid any activity or sport that may result in traumatic injury. • Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy. • Carry identification stating that they are taking warfarin sodium. • If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses. • Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables. • Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever. • Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days. • Manufactured In Croatia By: PLIVA HRVATSKA d.o.o. Zagreb, Croatia Manufactured For: TEVA PHARMACEUTICALS USA, INC. North Wales, PA 19454 Rev. A 11/2015

DOSAGE AND ADMINISTRATION

2 Individualize dosing regimen for each patient, and adjust based on INR response. ( , ) • 2.1 2.2 Knowledge of genotype can inform initial dose selection. ( ) • 2.3 Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. ( ) • 2.4 Review conversion instructions from other anticoagulants. ( ) • 2.8 2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2 to 3) for all treatment durations. The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. • For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. • For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient. • Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2 to 3). In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. • For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors. • Mechanical and Bioprosthetic Heart Valves For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2 to 3) is recommended. • For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3 (range, 2.5 to 3.5) is recommended. • For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3 (range, 2.5 to 3.5) is recommended. • For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2 to 3) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range 2 to 3) is recommended. • Post-Myocardial Infarction For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2 to 3) warfarin plus low-dose aspirin (≤ 100 mg/day) for at least 3 months after the MI is recommended. • Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2 to 3) may be used for these patients. 2.3 Initial and Maintenance Dosing The appropriate initial dosing of warfarin sodium tablets varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities • Genetic factors (CYP2C9 and VKORC1 genotypes) [ ]. • see Clinical Pharmacology ( ) 12.5 Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [ ]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. see Use in Specific Populations ( ) and Clinical Pharmacology ( ) 8.5 12.3 Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [ ]. see Dosage and Administration ( ) 2.2 Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium tablets is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily. Dosing Recommendations with Consideration of Genotype displays three ranges of expected maintenance warfarin sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [ ]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (> 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants. Table 1 see Clinical Pharmacology ( ) 12.5 Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Tablets Daily Doses Based on CYP2C9 and VKORC1 Genotypes Ranges are derived from multiple published clinical studies. VKORC1 −1639G > A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5 to 7 mg 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg AG 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg AA 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg 2.4 Monitoring to Achieve Optimal Anticoagulation Warfarin sodium tablets have a narrow therapeutic range (index), and their action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium tablets therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin sodium tablets, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [ ]. see Dosage and Administration ( ) and Drug Interactions ( ) 2.8 7 Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium tablets therapy. 2.5 Missed Dose The anticoagulant effect of warfarin sodium tablets persists beyond 24 hours. If a patient misses a dose of warfarin sodium tablets at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose. 2.7 Treatment During Dentistry and Surgery Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium tablets therapy. Consider the benefits and risks when discontinuing warfarin sodium tablets even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium tablets to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation. 2.8 Conversion From Other Anticoagulants Heparin Since the full anticoagulant effect of warfarin sodium tablets is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium tablets, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium tablets may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium tablets therapy with heparin for 4 to 5 days and until warfarin sodium tablets has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued. As heparin may affect the INR, patients receiving both heparin and warfarin sodium tablets should have INR monitoring at least: 5 hours after the last intravenous bolus dose of heparin, or • 4 hours after cessation of a continuous intravenous infusion of heparin, or • 24 hours after the last subcutaneous heparin injection. • Warfarin sodium tablets may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (> 50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium tablets.

buPROPion HCl 150 MG 12HR Extended Release Oral Tablet

Generic Name: BUPROPION HYDROCHLORIDE
Brand Name: Bupropion Hydrochloride
  • Substance Name(s):
  • BUPROPION HYDROCHLORIDE

WARNINGS

Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age RangeDrug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients TreatedIncreases Compared to Placebo<1814 additional cases18-245 additional casesDecreases Compared to Placebo25-641 fewer case6 fewer casesNo suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.Prescriptions for bupropion hydrochloride extended-release tablets (XL) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: WELLBUTRINWELLBUTRIN SRand bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment, but bupropion under the name ZYBANis approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation (seeBOXED WARNING,ADVERSE REACTIONS).These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. When symptoms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy. These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of ZYBAN Advise patients and caregivers that the patient using bupropion for smoking cessation should contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms after discontinuation of ZYBANwas reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBANhas been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that bupropion hydrochloride extended-release tablets (XL) are not approved for use in treating bipolar depression. Bupropion-Containing Products: Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient found in ZYBANused as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (XL) should not be used in combination with ZYBANor any other medications that contain bupropion, such as WELLBUTRIN SR(bupropion hydrochloride), the sustained-release formulation or WELLBUTRIN(bupropion hydrochloride), the immediate-release formulation. Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extended-release tablets (XL). Bupropion hydrochloride extended-release tablets USP (XL) should be discontinued and not restarted in patients who experience a seizure while on treatment. As bupropion hydrochloride extended-release tablets (XL) bioequivalent to both the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion, the seizure incidence with bupropion hydrochloride extended-release tablets (XL), while not formally evaluated in clinical trials, may be similar to that presented below for the immediate-release and sustained-release formulations of bupropion. ● Dose: At doses up to 300 mg/day of the sustained-release formulation of bupropion (WELLBUTRIN SRthe incidence of seizure is approximately 0.1% (1/1,000). Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 to 450 mg/day. This seizure incidence (0.4%) may exceed that of some other marketed antidepressants. Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The 600 mg dose is twice the usual adult dose and one and one-third the maximum recommended daily dose (450 mg) of bupropion hydrochloride extended-release tablets (XL). This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing. ● Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold. ● Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin. ● Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold. Recommendations for Reducing the Risk of Seizure: Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if ● the total daily dose of bupropion hydrochloride extended-release tablets (XL) does not exceed 450 mg, ● the rate of incrementation of dose is gradual. Bupropion hydrochloride extended-release tablets (XL) should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold. Hepatic Impairment: Bupropion hydrochloride extended-release tablets (XL) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required as peak bupropion as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 150 mg every other day in these patients (seeCLINICAL PHARMACOLOGY,PRECAUTIONS, andDOSAGE AND ADMINISTRATION). Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.

DRUG INTERACTIONS

Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs. Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between bupropion hydrochloride extended-release tablets (XL) and drugs that are substrates of inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg tablets of the sustained-release formulation of bupropion with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion. In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (seeCLINICAL PHARMACOLOGY: Metabolism). While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin). Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers. Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs. Drugs Metabolized By Cytochrome P450IID6 (CYP2D6):Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied. Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index. Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites. MAO Inhibitors:Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (seeCONTRAINDICATIONS). Levodopa and Amantadine:Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of bupropion hydrochloride extended-release tablets (XL) to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases. Drugs That Lower Seizure Threshold:Concurrent administration of bupropion hydrochloride extended-release tablets (XL) and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (seeWARNINGS). Low initial dosing and gradual dose increases should be employed. Nicotine Transdermal System:(seePRECAUTIONS: Cardiovascular Effects). Alcohol:In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (XL) should be minimized or avoided (also seeCONTRAINDICATIONS).

OVERDOSAGE

Human Overdose Experience:Overdoses of up to 30 g or more of bupropion have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. Overdosage Management:Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known. Due to the dose-related risk of seizures with bupropion hydrochloride extended-release tablets (XL), hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’Desk Reference (PDR).

DESCRIPTION

hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNOHCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: Bupropion hydrochloride extended-release tablets (XL) are supplied for oral administration as 150 mg and 300-mg, off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: copovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, methacrylic acid copolymer type c, triethyl citrate, colloidal anhydrous silica, sodium bicarbonate, sodium lauryl sulfate, povidone, purified water, and hydrochloric acid. The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is eliminated in the feces. MM1

HOW SUPPLIED

Bupropion hydrochloride extended-release tablets (XL), 150 mg of bupropion hydrochloride, are off-white, round, tablets debossed into the surface with “141” in bottles of 30 tablets (NDC 67767-141-30) and 90 tablets (NDC 67767-141-90). Bupropion hydrochloride extended-release tablets (XL), 300 mg of bupropion hydrochloride, are off-white, oval, tablets debossed into the surface with “142” in bottles of 30 tablets (NDC 67767-142-30), 90 tablets (NDC 67767-142-90) and 500 tablets (NDC 67767-142-05).

GERIATRIC USE

Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 wereyears old and 47 wereyears old. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (seeCLINICAL PHARMACOLOGY). Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (seePRECAUTIONS: Renal Impairment andDOSAGE AND ADMINISTRATION).

INDICATIONS AND USAGE

INDICATIONS & USAGE Major Depressive Disorder:Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder. The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of inpatients and in one 6-week controlled trial of outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (seeCLINICAL TRIALS). A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation. The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial with the sustained-release formulation of bupropion (seeCLINICAL TRIALS). Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (XL) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Seasonal Affective Disorder:Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder. The efficacy of bupropion hydrochloride extended-release tablets (XL) for the prevention of seasonal major depressive episodes was established in 3 controlled trials of adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (seeCLINICAL TRIALS). Seasonal affective disorder is characterized by recurrent major depressive episodes, most commonly occurring during the autumn and/or winter months. Episodes may last up to 6 months in duration, typically beginning in the autumn and remitting in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the diagnosis of seasonal affective disorder requires that the number of seasonal episodes substantially outnumber the number of non-seasonal episodes during the individual’s lifetime.

PEDIATRIC USE

Safety and effectiveness in the pediatric population have not been established (seeBOX WARNINGandWARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders). Anyone considering the use of bupropion hydrochloride extended-release tablets (XL) in a child or adolescent must balance the potential risks with the clinical need.

PREGNANCY

Teratogenic Effects When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. One study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study showed no greater risk for congenital malformations overall, or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this study have not been corroborated. Bupropion hydrochloride extended-release tablets (XL) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

NURSING MOTHERS Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion hydrochloride extended-release tablets (XL), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING Suicidality and Antidepressant Drugs Use in Treating Psychiatric Disorders: WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders,PRECAUTIONS: Information for Patients, andPRECAUTIONS: Pediatric Use.) Use in Smoking Cessation Treatment: WELLBUTRINWELLBUTRIN SRand bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment, but bupropion under the name ZYBANis approved for this use. Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking bupropion for smoking cessation. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. All patients treated with bupropion for smoking cessation treatment should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking ZYBANin the post-marketing experience. When symptoms were reported, most were during treatment with ZYBANbut some were following discontinuation of treatment with ZYBAN Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in thinking or behaviorthat are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms after discontinuation of ZYBAN The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBANhas been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial. (SeeWARNINGS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation TreatmentandPRECAUTIONS: Information for Patients.)

INFORMATION FOR PATIENTS

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (XL) and should counsel them in its appropriate use. A patient Medication Guide aboutAntidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions, andWhat other important information should I know about bupropion hydrochloride extended-release tablets (XL) ?is available for bupropion hydrochloride extended-release tablets (XL) . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (XL). Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although bupropion hydrochloride extended-release tablets (XL) are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBANwhich is approved for this use. Patients should be informed that quitting smoking, with or without ZYBANmay be associated with nicotine withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing psychiatric illness. Furthermore some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBANIf patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately. Bupropion-Containing Products:Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contains the same active ingredient found in ZYBANused as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (XL) should not be used in combination with ZYBANor any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SRthe sustained-release formulation, and WELLBUTRINthe immediate-release formulation). Patients should be told that bupropion hydrochloride extended-release tablets (XL) should be discontinued and not restarted if they experience a seizure while on treatment. Patients should be told that any CNS-active drug like bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride extended-release tablets (XL) does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with bupropion hydrochloride extended-release tablets (XL). Patients should be advised that the consumption of alcohol should be minimized or avoided. Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion hydrochloride extended-release tablets (XL) and other drugs may affect each other’s metabolism. Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to swallow bupropion hydrochloride extended-release tablets (XL) whole so that the release rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of adverse effects, including seizures. Patients should be advised that they may notice in their stool something that looks like a tablet. This is normal. The medication in bupropion hydrochloride extended-release tablets (XL) is contained in a non-absorbable shell that has been specially designed to slowly release drug in the body. When this process is completed, the empty shell is eliminated from the body.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION General Dosing Considerations:It is particularly important to administer bupropion hydrochloride extended-release tablets (XL) in a manner most likely to minimize the risk of seizure (seeWARNINGS). Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. Bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) may be taken without regard to meals. Major Depressive Disorder:Initial Treatment:The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning. Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an increase to the 300-mg/day target dose, given as once daily, may be made as early as day 4 of dosing, as this may lead to an increased risk of adverse effects including seizures. There should be an interval of at least 24 hours between successive doses. Increasing the Dosage Above 300 mg/day:As with other antidepressants, the full antidepressant effect of bupropion hydrochloride extended-release tablets (XL) may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 450 mg/day, given as a single dose, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Maintenance Treatment:It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. It is unknown whether or not the dose of bupropion hydrochloride extended-release tablets (XL) needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Seasonal Affective Disorder:For the prevention of seasonal major depressive episodes associated with seasonal affective disorder, bupropion hydrochloride extended-release tablets (XL) should generally be initiated in the autumn prior to the onset of depressive symptoms. Treatment should continue through the winter season and should be tapered and discontinued in early spring. The timing of initiation and duration of treatment should be individualized based on the patient’s historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with significant impairment should not generally be treated prophylactically. Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, the dose of bupropion hydrochloride extended-release tablets (XL) should be increased to the 300-mg/day dose after 1 week. If the 300-mg dose is not adequately tolerated, the dose can be reduced to 150 mg/day. The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning. For patients taking 300 mg/day during the autumn-winter season, the dose should be tapered to 150 mg/day for 2 weeks prior to discontinuation. Doses of bupropion hydrochloride extended-release tablets (XL) above 300 mg/day have not been studied for the prevention of seasonal major depressive episodes. Switching Patients from WELLBUTRINTablets or from WELLBUTRIN SRSustained-Release Tablets:When switching patients from WELLBUTRINTablets to bupropion hydrochloride extended-release tablets (XL) or from WELLBUTRIN SRSustained-Release Tablets to bupropion hydrochloride extended-release tablets (XL), give the same total daily dose when possible. Patients who are currently being treated with WELLBUTRINTablets at 300 mg/day (for example, 100 mg 3 times a day) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily. Patients who are currently being treated with WELLBUTRIN SRSustained-Release Tablets at 300 mg/day (for example, 150 mg twice daily) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily. Dosage Adjustment for Patients with Impaired Hepatic Function:Bupropion hydrochloride extended-release tablets (XL) should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg every other day in these patients. bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (seeCLINICAL PHARMACOLOGY,WARNINGS, andPRECAUTIONS). Dosage Adjustment for Patients with Impaired Renal Function:Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (seeCLINICAL PHARMACOLOGYandPRECAUTIONS).

Lipitor (as atorvastatin calcium) 80 MG Oral Tablet

Generic Name: ATORVASTATIN CALCIUM
Brand Name: Lipitor
  • Substance Name(s):
  • ATORVASTATIN CALCIUM

DRUG INTERACTIONS

7 The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3) ]. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with LIPITOR (7). Digoxin: Patients should be monitored appropriately (7.8). Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased (7.9). Rifampin should be simultaneously co-administered with LIPITOR (7.7). 7.1 Strong Inhibitors of CYP 3A4 LIPITOR is metabolized by cytochrome P450 3A4. Concomitant administration of LIPITOR with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 80 mg with clarithromycin (500 mg twice daily) compared to that of LIPITOR alone [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking clarithromycin, caution should be used when the LIPITOR dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of LIPITOR alone [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LIPITOR should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LIPITOR and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of LIPITOR should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of LIPITOR should not exceed 40 mg and close clinical monitoring is recommended. Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. 7.2 Grapefruit Juice Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day). 7.3 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to that of LIPITOR alone [see Clinical Pharmacology (12.3) ]. The co-administration of LIPITOR with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1) ]. 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of LIPITOR with gemfibrozil should be avoided [see Warnings and Precautions (5.1) ]. 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, LIPITOR should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) ]. 7.6 Niacin The risk of skeletal muscle effects may be enhanced when LIPITOR is used in combination with niacin; a reduction in LIPITOR dosage should be considered in this setting [see Warnings and Precautions (5.1) ]. 7.7 Rifampin or other Inducers of Cytochrome P450 3A4 Concomitant administration of LIPITOR with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of LIPITOR with rifampin is recommended, as delayed administration of LIPITOR after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 7.8 Digoxin When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 7.9 Oral Contraceptives Co-administration of LIPITOR and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ]. These increases should be considered when selecting an oral contraceptive for a woman taking LIPITOR. 7.10 Warfarin LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. 7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.

OVERDOSAGE

10 There is no specific treatment for LIPITOR overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance LIPITOR clearance.

DESCRIPTION

11 LIPITOR is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H34 FN2O5)2Ca•3H2O and its molecular weight is 1209.42. Its structural formula is: Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. LIPITOR Tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

CLINICAL STUDIES

14 14.1 Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to either LIPITOR 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of LIPITOR on lipid levels was similar to that seen in previous clinical trials. LIPITOR significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the LIPITOR group) or non-fatal MI (108 events in the placebo group vs. 60 events in the LIPITOR group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for LIPITOR vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of LIPITOR was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive. Figure 1: Effect of LIPITOR 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) LIPITOR also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for LIPITOR and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of LIPITOR on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either LIPITOR 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of LIPITOR 10 mg/day on lipid levels was similar to that seen in previous clinical trials. LIPITOR significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the LIPITOR group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of LIPITOR was seen regardless of age, sex, or baseline lipid levels. LIPITOR significantly reduced the risk of stroke by 48% (21 events in the LIPITOR group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the LIPITOR group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the LIPITOR group vs. 82 deaths in the placebo group (HR 0.73, p=0.059). Figure 2: Effect of LIPITOR 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of LIPITOR 80 mg/day vs. LIPITOR 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with LIPITOR 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of LIPITOR and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of LIPITOR and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of LIPITOR. Treatment with LIPITOR 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 5). The overall risk reduction was consistent regardless of age ( 130 mg/dL. The number of LIPITOR-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%). LIPITOR significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 10). TABLE 10. Lipid-altering Effects of LIPITOR in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1.0 0.7 LIPITOR 140 -31.4 -39.6 2.8 -12.0 -34.0 The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the LIPITOR group compared to 228.5 mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase. The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of LIPITOR therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

HOW SUPPLIED

16 /STORAGE AND HANDLING 10 mg tablets: coded “PD 155” on one side and “10” on the other. NDC 0071-0155-23 bottles of 90 NDC 0071-0155-34 bottles of 5000 NDC 0071-0155-40 10 × 10 unit dose blisters 20 mg tablets: coded “PD 156” on one side and “20” on the other. NDC 0071-0156-23 bottles of 90 NDC 0071-0156-40 10 × 10 unit dose blisters NDC 0071-0156-94 bottles of 5000 40 mg tablets: coded “PD 157” on one side and “40” on the other. NDC 0071-0157-23 bottles of 90 NDC 0071-0157-73 bottles of 500 NDC 0071-0157-88 bottles of 2500 NDC 0071-0157-40 10 × 10 unit dose blisters 80 mg tablets: coded “PD 158” on one side and “80” on the other. NDC 0071-0158-23 bottles of 90 NDC 0071-0158-73 bottles of 500 NDC 0071-0158-88 bottles of 2500 NDC 0071-0158-92 8 × 8 unit dose blisters Storage Store at controlled room temperature 20 – 25°C (68 – 77°F) [see USP].

RECENT MAJOR CHANGES

Dosage and Administration (2.6) 10/2012 Warnings and Precautions (5.1) 10/2012 Drug Interactions (7) 02/2012

GERIATRIC USE

8.5 Geriatric Use Of the 39,828 patients who received LIPITOR in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, LIPITOR should be prescribed with caution in the elderly.

DOSAGE FORMS AND STRENGTHS

3 White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium. 10, 20, 40, and 80 mg tablets (3).

MECHANISM OF ACTION

12.1 Mechanism of Action LIPITOR is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk. In animal models, LIPITOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; LIPITOR also reduces LDL production and the number of LDL particles. LIPITOR reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s). A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. LIPITOR reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. LIPITOR also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. LIPITOR reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

INDICATIONS AND USAGE

1 Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, LIPITOR can be started simultaneously with diet. LIPITOR is an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk factors (1.1). Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors (1.1). Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD (1.1). Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (1.2). Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia (1.2). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) (1.2). Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy (1.2). Limitations of Use LIPITOR has not been studied in Fredrickson Types I and V dyslipidemias. 1.1 Prevention of Cardiovascular Disease In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, LIPITOR is indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, LIPITOR is indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In patients with clinically evident coronary heart disease, LIPITOR is indicated to: Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina 1.2 Hyperlipidemia LIPITOR is indicated: As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C remains ≥ 190 mg/dL or LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in patients 10–17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10–17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age) (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on LIPITOR therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ]. LIPITOR has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5) ].

PREGNANCY

4.3 Pregnancy Women who are pregnant or may become pregnant. LIPITOR may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of LIPITOR use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. LIPITOR SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, LIPITOR should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ].

NUSRING MOTHERS

4.4 Nursing mothers It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require LIPITOR treatment should not breastfeed their infants [see Use in Specific Populations (8.3) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. LIPITOR therapy should be discontinued if myopathy is diagnosed or suspected (5.1, 8.5). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter (5.2). A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the LIPITOR 80 mg group vs. placebo (5.5). 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with LIPITOR and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing LIPITOR. LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with LIPITOR and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Drug Interactions (7) ). Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.6), Drug Interactions (7) , Clinical Pharmacology (12.3) ]. Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavirUse with caution and with the lowest dose necessary (12.3), darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11) ]. LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). 5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of LIPITOR. It is recommended that liver enzyme tests be obtained prior to initiating therapy with LIPITOR and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIPITOR, promptly interrupt therapy. If an alternate etiology is not found, do not restart LIPITOR. LIPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of LIPITOR [see Contraindications (4.1) ]. 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIPITOR. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that LIPITOR does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. 5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where LIPITOR 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Patients taking LIPITOR should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking LIPITOR. 17.1 Muscle Pain All patients starting therapy with LIPITOR should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing LIPITOR. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of LIPITOR and if signs or symptoms of liver injury occur. All patients treated with LIPITOR should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LIPITOR. Discuss future pregnancy plans with your patients, and discuss when to stop LIPITOR if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking LIPITOR and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should be advised to not use LIPITOR. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.

DOSAGE AND ADMINISTRATION

2 Dose range: 10 to 80 mg once daily (2.1). Recommended start dose: 10 or 20 mg once daily (2.1). Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily (2.1). Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily (2.2). 2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The recommended starting dose of LIPITOR is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of LIPITOR is 10 to 80 mg once daily. LIPITOR can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of LIPITOR should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation and/or upon titration of LIPITOR, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. 2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age) The recommended starting dose of LIPITOR is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines, Clinical Pharmacology (12) , and Indications and Usage (1.2) ]. Adjustments should be made at intervals of 4 weeks or more. 2.3 Homozygous Familial Hypercholesterolemia The dosage of LIPITOR in patients with homozygous FH is 10 to 80 mg daily. LIPITOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 2.4 Concomitant Lipid-Lowering Therapy LIPITOR may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ]. 2.5 Dosage in Patients With Renal Impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of LIPITOR; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (5.1), Clinical Pharmacology, Pharmacokinetics (12.3) ]. 2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with LIPITOR should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing LIPITOR and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with LIPITOR should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with LIPITOR should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ].

Viagra 100 MG (as sildenafil citrate) Oral Tablet

Generic Name: SILDENAFIL CITRATE
Brand Name: Viagra
  • Substance Name(s):
  • SILDENAFIL CITRATE

WARNINGS

There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. VIAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), (see CLINICAL PHARMACOLOGY: Pharmacodynamics ). While this normally would be expected to be of little consequence in most patients, prior to prescribing VIAGRA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators including VIAGRA – those with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There is no controlled clinical data on the safety or efficacy of VIAGRA in the following groups; if prescribed, this should be done with caution. Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; Patients with resting hypotension (BP 170/110); Patients with cardiac failure or coronary artery disease causing unstable angina; Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); Patients with sickle cell or related anemias. Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Visual disturbances occurred more commonly at higher levels of sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200–800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in sildenafil dosage is recommended (see Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ).

DRUG INTERACTIONS

Drug Interactions Effects of Other Drugs on VIAGRA In vitro studies Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. In vivo studies Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with VIAGRA (50 mg) to healthy volunteers. When a single 100 mg dose of VIAGRA was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with VIAGRA (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. VIAGRA had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) (see DOSAGE AND ADMINISTRATION ). In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION ). Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of VIAGRA on Other Drugs In vitro studies Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. In vivo studies Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent. In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8mg (2 subjects). The mean subject age was 66.5 years. For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg Supine 7.4 (-0.9, 15.7) Standing 6.0 (-0.8, 12.8) Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of 30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP 30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years. Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI) Supine 9.08 (5.48, 12.68) Standing 11.62 (7.34, 15.90) Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of 30mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years. Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg). For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg Supine 7.9 (4.6, 11.1) Standing 4.3 (-1.8,10.3) Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of 30mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study. When VIAGRA 100 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. Sildenafil at steady state (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan (125 mg b.i.d.).

OVERDOSAGE

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

DESCRIPTION

VIAGRA®, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. VIAGRA (sildenafil citrate) is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake. Chemical Structure Figure Figure Figure Figure Figure Figure Figure Figure

CLINICAL STUDIES

Clinical Studies In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function – IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 3, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 3 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 3. Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 4. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. Figure 4. Percentage of Patients Reporting an Improvement in Erections. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, VIAGRA improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo. A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics. Analysis of the safety database showed no apparent difference in the side effect profile in patients taking VIAGRA with and without antihypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.

HOW SUPPLIED

VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: 25 mg 50 mg 100 mg Obverse VGR25 VGR50 VGR100 Reverse PFIZER PFIZER PFIZER Bottle of 30 NDC-0069-4200-30 NDC-0069-4210-30 NDC-0069-4220-30 Bottle of 100 N/A NDC-0069-4210-66 NDC-0069-4220-66 Recommended Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations ). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered (see DOSAGE AND ADMINISTRATION ).

MECHANISM OF ACTION

Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics ). In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

INDICATIONS AND USAGE

INDICATION AND USAGE VIAGRA is indicated for the treatment of erectile dysfunction.

PREGNANCY

Pregnancy, Nursing Mothers and Pediatric Use VIAGRA is not indicated for use in newborns, children, or women.

INFORMATION FOR PATIENTS

Information for Patients Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of organic nitrates. Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose. Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician. Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see POST-MARKETING EXPERIENCE/Special Senses ). Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, CLINICAL TRIALS and POST-MARKETING EXPERIENCE ). Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO. Sildenafil is also marketed as REVATIO for the treatment of pulmonary arterial hypertension. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied. The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

DOSAGE AND ADMINISTRATION

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day. The following factors are associated with increased plasma levels of sildenafil: age >65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance <30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors [ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%)]. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients. Ritonavir greatly increased the systemic level of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC, see Drug Interactions .) Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period. VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose (see Drug Interactions ).

metoprolol succinate 200 MG 24 HR Extended Release Oral Tablet

Generic Name: METOPROLOL SUCCINATE
Brand Name: TOPROL XL
  • Substance Name(s):
  • METOPROLOL SUCCINATE

DRUG INTERACTIONS

7 •Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. (7.1) •CYP2D6 Inhibitors are likely to increase metoprolol concentration. (7.2) •Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. (7.3) •Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. (7.3) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 CYP2D6 Inhibitors Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol. 7.3 Digitalis, Clonidine, and Calcium Channel Blockers Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia. If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped [see Warnings and Precautions (5.11) ].

OVERDOSAGE

10 Signs and Symptoms – Overdosage of TOPROL-XL may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting. Treatment – Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures. There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound. Bradycardia: Administer intravenous atropine; repeat to effect. If the response is inadequate, consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need for transvenous pacemaker insertion. Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine. Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral theophylline derivative. Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic shock, consider IV dobutamine, isoproterenol, or glucagon.

DESCRIPTION

11 TOPROL-XL, metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended-release tablets. TOPROL-XL has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1- (isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is: Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin.

CLINICAL STUDIES

14 In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL and immediate-release metoprolol were compared in terms of the extent and duration of beta1- blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate-release metoprolol per day. In these studies, TOPROL-XL was administered once a day and immediate-release metoprolol was administered once to four times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. TOPROL-XL administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, TOPROL-XL produced significantly higher total beta1-blockade over 24 hours than immediate-release metoprolol. For TOPROL-XL, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once a day, respectively. In contrast to TOPROL-XL, immediate-release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with TOPROL-XL over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of TOPROL-XL produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol. In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL® (felodipine extended-release tablets), the combination, or placebo. After 9 weeks, TOPROL-XL alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of TOPROL-XL with PLENDIL has greater effects on blood pressure. In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, TOPROL-XL administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration. 14.1 Angina Pectoris By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. In controlled clinical trials, an immediate-release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily. 14.2 Heart Failure MERIT-HF was a double-blind, placebo-controlled study of TOPROL-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of TOPROL-XL was 159 mg. The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects. Clinical Endpoints in the MERIT-HF Study Clinical Endpoint Number of Patients Relative Risk (95% Cl) Risk Reduction With TOPROL-XL Nominal P-value Placebo n=2001 TOPROL-XL n=1990 All-cause mortality plus all-caused hospitalizationTime to first event 767 641 0.81(0.73- 0.90) 19% 0.00012 All-cause mortality 217 145 0.66(0.53- 0.81) 34% 0.00009 All-cause mortality plus heart failure hospitalization 439 311 0.69(0.60- 0.80) 31% 0.0000008 Cardiovascular mortality 203 128 0.62(0.50- 0.78) 38% 0.000022 Sudden death 132 79 0.59(0.45- 0.78) 41% 0.0002 Death due to worsening heart failure 58 30 0.51(0.33- 0.79) 49% 0.0023 Hospitalizations due to worsening heart failureComparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative risk and risk reduction are not applicable. 451 317 N/A N/A 0.0000076 Cardiovascular hospitalization 773 649 N/A N/A 0.00028

HOW SUPPLIED

16 /STORAGE AND HANDLING Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. Tablet Shape Engraving Bottle of 100 NDC 0186- Unit Dose Packages of 100 NDC 0186- 25 mg Oval A/ β 1088-05 1088-39 50 mg Round A/ mo 1090-05 1090-39 100 mg Round A/ ms 1092-05 1092-39 200 mg Oval A/ my 1094-05 N/A Store at 25°C (77°F). Excursions permitted to 15-30°C (59- 86°F). (See USP Controlled Room Temperature.)

RECENT MAJOR CHANGES

Indications and Usage: Benefits of lowering blood pressure (1.1) 10/2012

GERIATRIC USE

8.5 Geriatric Use Clinical studies of TOPROL-XL in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. Of the 1,990 patients with heart failure randomized to TOPROL-XL in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients. In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”. 50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”. 100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”. 200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”. •TOPROL-XL Extended-Release Tablets (metoprolol succinate): 25 mg, 50 mg, 100 mg and 200 mg. (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.

INDICATIONS AND USAGE

1 TOPROL-XL, metoprolol succinate, is a beta1-selective adrenoceptor blocking agent. TOPROL-XL is indicated for the treatment of: •Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1) •Angina Pectoris. (1.2) •Heart Failure – for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. (1.3) 1.1 Hypertension TOPROL-XL is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. TOPROL-XL may be administered with other antihypertensive agents. 1.2 Angina Pectoris TOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 Heart Failure TOPROL-XL is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, TOPROL-XL decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

PEDIATRIC USE

8.4 Pediatric Use One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of TOPROL-XL (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including: •Dose-response for reduction in DBP, •mg/kg vs. placebo for change in SBP, and •mg/kg vs. placebo for change in SBP and DBP. The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see Dosage and Administration (2.1)]. No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients. Safety and effectiveness of TOPROL-XL have not been established in patients < 6 years of age.

PREGNANCY

8.1 Pregnancy Pregnancy Category C Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.

NUSRING MOTHERS

8.3 Nursing Mothers Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when TOPROL-XL is administered to a nursing woman.

BOXED WARNING

WARNING: ISCHEMIC HEART DISEASE: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered TOPROL-XL, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 – 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, TOPROL-XL administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue TOPROL-XL therapy abruptly even in patients treated only for hypertension (5.1). WARNING: ISCHEMIC HEART DISEASE (See Full Prescribing Information for complete boxed warning) Following abrupt cessation of therapy with beta-blocking agents, exacerbations of angina pectoris and myocardial infarction have occurred. Warn patients against interruption or discontinuation of therapy without the physician’s advice. (5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Heart Failure: Worsening cardiac failure may occur. (5.2) •Bronchospastic Disease: Avoid beta blockers. (5.3) •Pheochromocytoma: If required, first initiate therapy with an alpha blocker. (5.4) •Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery because it has been associated with bradycardia, hypotension, stroke and death. Do not routinely withdraw chronic beta blocker therapy prior to surgery. (5.5, 6.1) •Diabetes and Hypoglycemia: May mask tachycardia occurring with hypoglycemia. (5.6) •Patients with Hepatic Impairment: (5.7) •Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. (5.8) •Anaphylactic Reactions: Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. (5.9) •Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. (5.10) •Calcium Channel Blockers: Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly. (5.11) 5.1 Ischemic Heart Disease Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered TOPROL-XL, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 – 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate TOPROL-XL, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing TOPROL-XL in patients treated only for hypertension. 5.2 Heart Failure Worsening cardiac failure may occur during up-titration of TOPROL-XL. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of TOPROL-XL [see Dosage and Administration (2)]. It may be necessary to lower the dose of TOPROL-XL or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of TOPROL-XL. 5.3 Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, TOPROL-XL may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of TOPROL-XL. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)]. 5.4 Pheochromocytoma If TOPROL-XL is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. 5.5 Major Surgery Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death. Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.6 Diabetes and Hypoglycemia Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 5.7 Hepatic Impairment Consider initiating TOPROL-XL therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events. 5.8 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. 5.9 Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction. 5.10 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.11 Calcium Channel Blockers Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients to take TOPROL-XL regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue TOPROL-XL without consulting the physician. Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with TOPROL-XL has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking TOPROL-XL. Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. TOPROL-XL and PLENDIL are trademarks of the AstraZeneca group of companies. © AstraZeneca 2012 Distributed by: AstraZeneca LP Wilmington, DE 19850 Rev. 10/2012

DOSAGE AND ADMINISTRATION

2 TOPROL-XL is an extended-release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to TOPROL-XL, use the same total daily dose of TOPROL-XL. Individualize the dosage of TOPROL-XL. Titration may be needed in some patients. TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole or half tablet. •Administer once daily. Dosing of TOPROL-XL should be individualized. (2) •Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled every two weeks to the highest dose tolerated or up to 200 mg. (2.3) •Hypertension: Usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied. (2.1) •Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is an unacceptable bradycardia. Dosages above 400 mg per day have not been studied. (2.2) •Switching from immediate-release metoprolol to TOPROL-XL: use the same total daily dose of TOPROL-XL. (2) 2.1 Hypertension Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied. Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose of TOPROL-XL is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)]. TOPROL-XL is not recommended in pediatric patients < 6 years of age [see Use in Specific Populations (8.4)]. 2.2 Angina Pectoris Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 – 2 weeks [see Warnings and Precautions (5)]. 2.3 Heart Failure Dosage must be individualized and closely monitored during up-titration. Prior to initiation of TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended starting dose of TOPROL-XL is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of TOPROL-XL. Initial difficulty with titration should not preclude later attempts to introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have been stabilized.