Category: drugs

Itraconazole 100 MG Oral Capsule

Generic Name: ITRACONAZOLE
Brand Name: SPORANOX
  • Substance Name(s):
  • ITRACONAZOLE

WARNINGS

SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

DRUG INTERACTIONS

Drug Interactions Concomitant administration of SPORANOX® (itraconazole) Capsules or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, methadone and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles.

OVERDOSAGE

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses.

DESCRIPTION

SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28.

HOW SUPPLIED

SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs × 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°–25°C (59°–77°F). Protect from light and moisture. Keep out of reach of children.

GERIATRIC USE

Geriatric Use Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3-week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.

PEDIATRIC USE

Pediatric Use The efficacy and safety of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Category C Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.)

NUSRING MOTHERS

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions: SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with SPORANOX® (itraconazole) Capsules or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.

INFORMATION FOR PATIENTS

Information for Patients The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. Instruct patients to take SPORANOX® Capsules with a full meal. Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately. Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

DOSAGE AND ADMINISTRATION

SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX®. Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)

letrozole 2.5 MG Oral Tablet

Generic Name: LETROZOLE
Brand Name: Letrozole
  • Substance Name(s):
  • LETROZOLE

DRUG INTERACTIONS

7 Tamoxifen Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. Other anticancer agents There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.

OVERDOSAGE

10 Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias.

DESCRIPTION

11 Letrozole tablets USP for oral administration contain 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4′-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile, and its structural formula is C17H11N5 M.W. 285.31 Letrozole is a white to yellowish crystalline powder, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a melting range of 184° to 185°C. Letrozole tablets USP are available as 2.5 mg tablets for oral administration. Inactive Ingredients: colloidal silicon dioxide, FD&C blue #2 aluminum lake, FD&C yellow #5 aluminum lake, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, starch, talc, and titanium dioxide. Sturctural Formula of Letrozole

CLINICAL STUDIES

14 14.1 Updated Adjuvant Treatment of Early Breast Cancer In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner: Option 1: A. tamoxifen for 5 years B. letrozole for 5 years C. tamoxifen for 2 years followed by letrozole for 3 years D. letrozole for 2 years followed by tamoxifen for 3 years Option 2: A. tamoxifen for 5 years B. letrozole for 5 years The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5. The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM). The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P = 0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06). In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with letrozole (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with letrozole (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to letrozole or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to letrozole to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with letrozole (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the Monotherapy Arms Analysis (MAA). The PCA allowed the results of letrozole for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to letrozole. The updated results for the MAA are summarized in Table 6. Median follow-up for this analysis is 73 months. The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy. Table 5: Adjuvant Study – Patient and Disease Characteristics (ITT Population) Characteristic Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA) Letrozole N = 4003 n (%) Tamoxifen N = 4007 n (%) Letrozole N = 2463 n (%) Tamoxifen N = 2459 n (%) Age (median, years) 61 61 61 61 Age range (years) 38 to 89 39 to 90 38 to 88 39 to 90 Hormone receptor status (%) ER+ and/or PgR+ 99.7 99.7 99.7 99.7 Both unknown 0.3 0.3 0.3 0.3 Nodal status (%) Node negative 52 52 50 52 Node positive 41 41 43 41 Nodal status unknown 7 7 7 7 Prior adjuvant chemotherapy (%) 24 24 24 24 Table 6: Updated Adjuvant Study Results – Monotherapy Arms Analysis (Median Follow-up 73 Months) Letrozole N = 2463 Tamoxifen N = 2459 Hazard ratio Events (%) 5 year rate Events (%) 5 year rate (95% CI) P Disease-free survivalDisease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event ITT 445 (18.1) 87.4 500 (20.3) 84.7 0.87 (0.76, 0.99) 0.03 Censor 445 87.4 483 84.2 0.84 (0.73, 0.95) 0 positive nodes ITT 165 92.2 189 90.3 0.88 (0.72, 1.09) 1 to 3 positive nodes ITT 151 85.6 163 83.0 0.85 (0.68, 1.06) ≥ 4 positive nodes ITT 123 71.2 142 62.6 0.81 (0.64, 1.03) Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77 (0.60, 0.98) No chemotherapy ITT 326 87.8 350 86.1 0.91 (0.78, 1.06) Systemic DFSSystemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event ITT 401 88.5 446 86.6 0.88 (0.77, 1.01) Time to distant metastasisTime to distant metastasis: Interval from randomization to distant metastasis ITT 257 92.4 298 90.1 0.85 (0.72, 1.00) Adjuvant chemotherapy ITT 84 – 109 – 0.75 (0.56 to 1.00) No chemotherapy ITT 173 – 189 – 0.90 (0.73, 1.11) Distant DFSDistant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause ITT 385 89.0 432 87.1 0.87 (0.76, 1.00) Contralateral breast cancer ITT 34 99.2 44 98.6 0.76 (0.49, 1.19) Overall survival ITT 303 91.8 343 90.9 0.87 (0.75, 1.02) Censor 303 91.8 338 90.1 0.82 (0.70, 0.96) 0 positive nodes ITT 107 95.2 121 94.8 0.90 (0.69, 1.16) 1 to 3 positive nodes ITT 99 90.8 114 90.6 0.81 (0.62, 1.06) ≥ 4 positive nodes ITT 92 80.2 104 73.6 0.86 (0.65, 1.14) Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79 (0.58, 1.06) No chemotherapy ITT 227 91.9 247 91.8 0.91 (0.76, 1.08) Definition of: ITT analysis ignores selective crossover in tamoxifen arms Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005 Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis Figure 1. Disease-Free Survival (Median follow-up 73 months, ITT Approach) DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers). The medians of overall survival for both arms were not reached for the Monotherapy Arms Analysis (MAA). There was no statistically significant difference in overall survival. The hazard ratio for survival in the letrozole arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 6 ). There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] letrozole 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole 2 years followed by] tamoxifen 3 years versus letrozole beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22). There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses. 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months A double-blind, randomized, placebo-controlled trial of letrozole was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen. The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up. Selected baseline characteristics for the study population are shown in Table 7. Table 7: Selected Study Population Demographics (Modified ITT Population) Baseline Status Letrozole N = 2582 Placebo N = 2586 Hormone Receptor Status (%) ER+ and/or PgR+ 98 98 Both Unknown 2 2 Nodal Status (%) Node Negative 50 50 Node Positive 46 46 Nodal Status Unknown 4 4 Chemotherapy 46 46 Table 8 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival. Table 8: Extended Adjuvant Study Results Letrozole N = 2582 Placebo N = 2586 Hazard Ratio (95% CI) P-Value Disease Free Survival (DFS)First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified logrank test. 0.00003 Local Breast Recurrence 9 22 Local Chest Wall Recurrence 2 8 Regional Recurrence 7 4 Distant Recurrence 55 92 0.61 (0.44 to 0.84) 0.003 Contralateral Breast Cancer 19 29 Deaths Without Recurrence or Contralateral Breast Cancer 30 38 CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole). 14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months Table 9: Update of Extended Adjuvant Study Results Letrozole N = 2582 (%) Placebo N = 2586 (%) Hazard Ratio Adjusted by receptor status, nodal status and prior chemotherapy (95% CI) P-ValueStratified logrank test, stratified by receptor status, nodal status and prior chemotherapy Disease Free Survival (DFS) events DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole in 60% of the placebo arm. 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12 Breast Cancer Recurrence (Protocol definition of DFS eventsProtocol definition does not include deaths from any cause ) 209 286 0.75 (0.63, 0.89) 0.001 Local Breast Recurrence 15 44 Local Chest Wall Recurrence 6 14 Regional Recurrence 10 8 Distant Recurrence 140 167 Distant Recurrence (first or subsequent events) 142 169 0.88 (0.70, 1.10) 0.246 Contralateral Breast Cancer 37 53 Deaths Without Recurrence or Contralateral Breast Cancer 135 116 Updated analyses were conducted at a median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to letrozole. In this updated analysis shown in Table 9, letrozole significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P = 0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to letrozole and accounting for 64% of the total placebo patient- years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival. 14.4 First-Line Treatment of Advanced Breast Cancer A randomized, double-blind, multinational trial compared letrozole 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 10. Table 10: Selected Study Population Demographics Baseline Status Letrozole N = 458 Tamoxifen N = 458 Stage of Disease IIIB 6% 7% IV 93% 92% Receptor Status ER and PgR Positive 38% 41% ER or PgR Positive 26% 26% Both Unknown 34% 33% ER- or PgR-/Other Unknown < 1% 0 Previous Antiestrogen Therapy Adjuvant 19% 18% None 81% 82% Dominant Site of Disease Soft Tissue 25% 25% Bone 32% 29% Viscera 43% 46% Letrozole was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11 ). Table 11 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.) Table 11: Results of First-Line Treatment of Advanced Breast Cancer Letrozole 2.5 mg N = 453 Tamoxifen 20 mg N = 454 Hazard or Odds Ratio (95% CI) P-Value (2-Sided) Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)Hazard ratio P < 0.0001 Objective Response Rate (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)Odds ratio P = 0.0002 (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47) P = 0.0004 Duration of Objective Response Median 18 months(N = 145) 16 months(N = 95) Overall Survival 35 months(N = 458) 32 months(N = 458) P = 0.5136Overall logrank test Figure 2 shows the Kaplan-Meier curves for TTP. Figure 2. Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study) Table 12 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 13, results by disease site and Table 14, the results by receptor status. Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy Variable Letrozole 2.5 mg N = 84 Tamoxifen 20 mg N = 83 Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2) Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84) Objective Response Rate (CR + PR) 22 (26%) 7 (8%) Odds Ratio for Response (95% CI) 3.85 (1.50, 9.60) Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Table 13: Efficacy by Disease Site Letrozole 2.5 mg Tamoxifen 20 mg Dominant Disease Site Soft Tissue: N = 113 N = 115 Median TTP 12.1 months 6.4 months Objective Response Rate 50% 34% Bone: N = 145 N = 131 Median TTP 9.5 months 6.3 months Objective Response Rate 23% 15% Viscera: N = 195 N = 208 Median TTP 8.3 months 4.6 months Objective Response Rate 28% 17% Table 14: Efficacy by Receptor Status Variable Letrozole 2.5 mg Tamoxifen 20 mg Receptor Positive N = 294 N = 305 Median Time to Progression (95% CI) 9.4 months (8.9, 11.8) 6.0 months (5.1, 8.5) Hazard Ratio for TTP (95% CI) 0.69 (0.58, 0.83) Objective Response Rate (CR+PR) 97 (33%) 66 (22%) Odds Ratio for Response 95% CI) 1.78 (1.20, 2.60) Receptor Unknown N = 159 N = 149 Median Time to Progression (95% CI) 9.2 months (6.1, 12.3) 6.0 months (4.1, 6.4) Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99) Objective Response Rate (CR+PR) 48 (30%) 29 (20%) Odds Ratio for Response (95% CI) 1.79 (1.10, 3.00) Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Figure 3 shows the Kaplan-Meier curves for survival. Figure 3. Survival by Randomized Treatment Arm Legend: Randomized letrozole: n = 458, events 57%, median overall survival 35 months (95% CI 32 to 38 months) Randomized tamoxifen: n = 458, events 57%, median overall survival 32 months (95% CI 28 to 37 months) Overall logrank P = 0.5136 (i.e., there was no significant difference between treatment arms in overall survival). The median overall survival was 35 months for the letrozole group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n = 219, 95% CI 29 to 43 months) vs 20 months with tamoxifen (n = 229, 95% CI 16 to 26 months). 14.5 Second-Line Treatment of Advanced Breast Cancer Letrozole was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative Phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with letrozole 2.5 mg daily in Phase I/II trials achieved an objective tumor response (complete or partial response). Two large randomized, controlled, multinational (predominantly European) trials were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to letrozole 0.5 mg daily, letrozole 2.5 mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg b.i.d. with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 15. Table 15: Selected Study Population Demographics Parameter megestrol acetate study aminoglutethimide study No. of Participants 552 557 Receptor Status ER/PR Positive 57% 56% ER/PR Unknown 43% 44% Previous Therapy Adjuvant Only 33% 38% Therapeutic +/- Adj. 66% 62% Sites of Disease Soft Tissue 56% 50% Bone 50% 55% Viscera 40% 44% Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response. Table 16 shows the results for the first trial, with a minimum follow-up of 15 months, that compared letrozole 0.5 mg, letrozole 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.) Table 16: Megestrol Acetate Study Results Letrozole 0.5 mg N = 188 Letrozole 2.5 mg N = 174 Megestrol acetate N = 190 Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%) Median Duration of Response 552 days (Not reached) 561 days Median Time to Progression 154 days 170 days 168 days Median Survival 633 days 730 days 659 days Odds Ratio for Response letrozole 2.5: letrozole 0.5 = 2.33 (95% CI: 1.32, 4.17); P = 0.004two-sided P-value letrozole 2.5: megestrol = 1.58 (95% CI: 0.94, 2.66); P = 0.08 Relative Risk of Progression letrozole 2.5: letrozole 0.5 = 0.81 (95% CI: 0.63, 1.03); P = 0.09 letrozole 2.5: megestrol = 0.77 (95% CI: 0.60, 0.98); P = 0.03 The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4. Figure 4. Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) The results for the study comparing letrozole to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.) Table 17: Aminoglutethimide Study Results Letrozole 0.5 mg N = 193 Letrozole 2.5 mg N = 185 Aminoglutethimide N = 179 Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%) Median Duration of Response 619 days 706 days 450 days Median Time to Progression 103 days 123 days 112 days Median Survival 636 days 792 days 592 days Odds Ratio for Response letrozole 2.5: letrozole 0.5 = 1.05 (95% CI: 0.62, 1.79); P = 0.85two-sided P-value letrozole 2.5: aminoglutethimide = 1.61 (95% CI: 0.90, 2.87); P = 0.11 Relative Risk of Progression letrozole 2.5: letrozole 0.5 = 0.86 (95% CI: 0.68, 1.11); P = 0.25 letrozole 2.5: aminoglutethimide = 0.74 (95% CI: 0.57, 0.94); P = 0.02 The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5. Figure 5. Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study) Figure 1. Disease-Free Survival (Median follow-up 73 months, ITT Approach) Figure 2 Kaplan-Meier Esitmates of Time to Progression (Tamoxifen Study) Figure 3 Survival by Randomized Treatment Arm Figure 4. Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

HOW SUPPLIED

16 /STORAGE AND HANDLING Letrozole tablets USP, 2.5 mg are available as follows: 2.5 mg – dark-yellow, standard convex round, film-coated tablets, debossed with “TEVA” on one side and “B1” on the other side of the tablet, in bottles of 30. 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).

GERIATRIC USE

8.5 Geriatric Use The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were ≥ 70 years old. In the first-line study, patients ≥ 70 years of age experienced longer time to tumor progression and higher response rates than patients < 70. For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and 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. In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

DOSAGE FORMS AND STRENGTHS

3 2.5 mg tablets – dark-yellow, standard convex round, film-coated tablet, debossed with “TEVA” on one side and “B1” on the other side of the tablet. 2.5 milligram tablets (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

INDICATIONS AND USAGE

1 Letrozole tablets are an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer (1.1) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy (1.2) First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer (1.3) 1.1 Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 1.2 Extended Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies (14.2, 14.3)]. 1.3 First and Second-Line Treatment of Advanced Breast Cancer Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)].

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy category X [See Contraindications (4)]. Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. 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. Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well. Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: intrauterine mortality; increased resorptions and postimplantation loss; decreased numbers of live fetuses; and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs [see Nonclinical Toxicology (13.2)]. Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from letrozole, 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. 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. Decreases in bone mineral density may occur. Consider bone mineral density monitoring (5.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.2) Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery (5.4) 5.1 Bone Effects Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [see Adverse Reactions (6.1)]. Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6.2)]. In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6.1)]. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions (6.3)]. 5.2 Cholesterol Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3 to 4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥ 1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., ≤ 1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [see Adverse Reactions (6.1)]. 5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined [see Dosage and Administration (2.5)]. 5.4 Fatigue and Dizziness Because fatigue, dizziness, and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use. 5.5 Laboratory Test Abnormalities No dose-related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Information for Patients Pregnancy: Letrozole is contraindicated in women of premenopausal endocrine status. The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established. Fatigue and Dizziness: Since fatigue and dizziness have been observed with the use of letrozole and somnolence was uncommonly reported, caution is advised when driving or using machinery. Bone Effects: Consideration should be given to monitoring bone mineral density. Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. B 12/2011 Repackaged by: REBEL DISTRIBUTORS CORP. Thousand Oaks, CA 91320

DOSAGE AND ADMINISTRATION

2 Letrozole tablets USP are taken orally without regard to meals (2): Recommended dose: 2.5.mg once daily (2.1) Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day (2.5, 5.3) 2.1 Recommended Dose The recommended dose of letrozole tablets USP is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see Clinical Studies (14.1)]. 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with letrozole tablets USP is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)]. 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer In patients with advanced disease, treatment with letrozole tablets USP should continue until tumor progression is evident [see Clinical Studies (14.4, 14.5)]. 2.5 Use in Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets USP in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of letrozole tablets USP for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined. 2.6 Use in Renal Impairment No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥ 10 mL/min [see Clinical Pharmacology (12.3)].

Cyclobenzaprine hydrochloride 5 MG Oral Tablet

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

WARNINGS

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or (MAO) inhibitors. The concomitant use of Cyclobenzaprine Hydrochloride with MAO inhibitors is contraindicated (see CONTRAINDICATIONS). Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see PRECAUTIONS, Drug Interactions). Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see , below, and ADVERSE REACTIONS). Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants.

OVERDOSAGE

Although rare, deaths may occur from overdosage with cyclobenzaprine hydrochloride. Multiple drug ingestion (including alcohol) is common in deliberate cyclobenzaprine overdose. As management of overdose 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 may develop rapidly after cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible. The acute oral LD50 of cyclobenzaprine hydrochloride is approximately 338 and 425 mg/kg in mice and rats, respectively. MANIFESTATIONS The most common effects associated with cyclobenzaprine overdose are drowsiness and tachycardia. Less frequent manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity. Other potential effects of overdosage include any of the symptoms listed under ADVERSE REACTIONS. MANAGEMENT General As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. In order to protect against the rare but potentially critical manifestations described above, obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. 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 this period, extended monitoring is required. Monitoring of plasma drug levels should not guide management of the patient. Dialysis is probably of no value because of low plasma concentrations of the drug. Gastrointestinal Decontamination All patients suspected of an overdose with cyclobenzaprine hydrochloride 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 and 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. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO2 <20 mmHg 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). 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 close 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 child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DESCRIPTION

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C20H21N • HCl and a molecular weight of 311.9. It has a melting point of 217°C, and a pKa of 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl is designated chemically as 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Yellow #6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide; 5 mg tablets also contain FD&C Red #40 and 10 mg tablets contain D&C Yellow #10 and polysorbate.

INDICATIONS AND USAGE

INDICATIONS & USAGE Cyclobenzaprine hydrochloride tablets are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living. Cyclobenzaprine hydrochloride tablets should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. Cyclobenzaprine hydrochloride tablets have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION For most patients, the recommended dose of cyclobenzaprine hydrochloride tablets is 5 mg three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day. Use of cyclobenzaprine hydrochloride tablets for periods longer than two or three weeks is not recommended (see INDICATIONS AND USAGE). Less frequent dosing should be considered for hepatically impaired or elderly patients (see PRECAUTIONS, Impaired Hepatic Function, and Use in the Elderly).

Percocet 5 MG / 325 MG Oral Tablet

Generic Name: OXYCODONE HYDROCHLORIDE AND ACETAMINOPHEN
Brand Name: PERCOCET
  • Substance Name(s):
  • OXYCODONE HYDROCHLORIDE
  • ACETAMINOPHEN

WARNINGS

Misuse, Abuse and Diversion of Opioids Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing PERCOCET tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Concerns about misuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Administration of PERCOCET (Oxycodone and Acetaminophen Tablets, USP) tablets should be closely monitored for the following potentially serious adverse reactions and complications: Respiratory Depression Respiratory depression is a hazard with the use of oxycodone, one of the active ingredients in PERCOCET tablets, as with all opioid agonists. Elderly and debilitated patients are at particular risk for respiratory depression as are non-tolerant patients given large initial doses of oxycodone or when oxycodone is given in conjunction with other agents that depress respiration. Oxycodone should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disorder (COPD), cor pulmonale, or preexisting respiratory impairment. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of worsening in patients with head injuries. Hypotensive Effect Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Oxycodone may produce orthostatic hypotension in ambulatory patients. Hepatotoxicity Precaution should be taken in patients with liver disease. Hepatotoxicity and severe hepatic failure occurred in chronic alcoholics following therapeutic doses.

DRUG INTERACTIONS

Interactions with Other CNS Depressants Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with PERCOCET tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

OVERDOSAGE

Signs and Symptoms Serious overdose with PERCOCET (Oxycodone and Acetaminophen Tablets, USP) is characterized by signs and symptoms of opioid and acetaminophen overdose. Oxycodone overdosage can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction (pupils may be dilated in the setting of hypoxia), and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and thrombocytopenia may also occur. In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams and fatalities with less than 15 grams. Plasma acetaminophen levels >300 mcg/ml at 4 hours post-ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are <120 mcg/ml or <30 mcg/ml at 12 hours after ingestion. Importantly, young children seem to be more resistant than adults to the hepatotoxic effect of an acetaminophen overdose. Despite this, the measures outlined below should be initiated in any adult or child suspected of having ingested an acetaminophen overdose. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. Supportive measures (including oxygen, intravenous fluids, and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids including oxycodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory of circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including oxycodone, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. Gastric emptying and/or lavage may be useful in removing unabsorbed drug. This procedure is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than three hours have passed since ingestion. Charcoal adsorption should not be employed prior to lavage and emesis. If an acetaminophen overdose is suspected, the stomach should be promptly emptied by lavage. A serum acetaminophen assay should be obtained as soon as possible, but no sooner than 4 hours following ingestion. Liver function studies should be obtained initially and repeated at 24-hour intervals. The antidote N-acetylcysteine (NAC) should be administered as early as possible, preferably within 16 hours of the overdose ingestion, but in any case within 24 hours. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since ingestion on a nomogram (Rumack-Matthew). The upper toxic line on the nomogram is equivalent to 200 mcg/ml at 4 hours while the lower line is equivalent to 50 mcg/ml at 12 hours. If serum level is above the lower line, and entire course of N-acetylcysteine treatment should be instituted. NAC therapy should be withheld if the acetaminophen level is below the lower line. The toxicity of oxycodone and acetaminophen in combination is unknown.

DESCRIPTION

Each tablet, for oral administration, contains oxycodone hydrochloride and acetaminophen in the following strengths: Oxycodone Hydrochloride, USP 2.5 mg* Acetaminophen, USP 325 mg *2.5 mg oxycodone HCl is equivalent to 2.2409 mg of oxycodone. Oxycodone Hydrochloride, USP 5 mg* Acetaminophen, USP 325 mg *5 mg oxycodone HCl is equivalent to 4.4815 mg of oxycodone. Oxycodone Hydrochloride, USP 7.5 mg* Acetaminophen, USP 325 mg *7.5 mg oxycodone HCl is equivalent to 6.7228 mg of oxycodone. Oxycodone Hydrochloride, USP 7.5 mg* Acetaminophen, USP 500 mg *7.5 mg oxycodone HCl is equivalent to 6.7228 mg of oxycodone. Oxycodone Hydrochloride, USP 10 mg* Acetaminophen, USP 325 mg *10 mg oxycodone HCl is equivalent to 8.9637 mg of oxycodone. Oxycodone Hydrochloride, USP 10 mg* Acetaminophen, USP 650 mg *10 mg oxycodone HCl is equivalent to 8.9637 mg of oxycodone. All strengths of PERCOCET also contain the following inactive ingredients: Colloidal silicon dioxide, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, pregelatinized cornstarch, and stearic acid. In addition, the 2.5 mg/325 mg strength contains FD&C Red No. 40 Aluminum Lake and the 5 mg/325 mg strength contains FD&C Blue No. 1 Aluminum Lake. The 7.5 mg/325 mg and the 7.5 mg/500 mg strengths contain FD&C Yellow No. 6 Aluminum Lake. The 10 mg/325 mg and the 10 mg/650 mg strengths contain D&C Yellow No. 10 Aluminum Lake. Oxycodone, 14-hydroxydihydrocodeinone, is a semisynthetic opioid analgesic which occurs as a white, odorless, crystalline powder having a saline, bitter taste. The molecular formula for oxycodone hydrochloride is C18H21NO4•HCl and the molecular weight 351.83. It is derived from the opium alkaloid thebaine, and may be represented by the following structural formula: Acetaminophen, 4’-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. The molecular formula for acetaminophen is C8H9NO2 and the molecular weight is 151.17. It may be represented by the following structural formula: Oxycodone Hydrochloride Structural Formula Acetaminophen Structural Formula

HOW SUPPLIED

PERCOCET (Oxycodone and Acetaminophen Tablets, USP) is supplied as follows: 2.5 mg/325 mg Pink, oval, tablet debossed with “PERCOCET” on one side and “2.5” on the other. Bottles of 100 NDC 63481-627-70 5 mg/325 mg Blue, round, tablet, debossed with “PERCOCET” and “5” on one side and bisect on the other. Bottles of 100 NDC 63481-623-70 Bottles of 500 NDC 63481-623-85 Unit dose package of 100 tablets NDC 63481-623-75 7.5 mg/325 mg Peach, oval-shaped, tablet debossed with “PERCOCET” on one side and “7.5/325” on the other. Bottles of 100 NDC 63481-628-70 7.5 mg/500 mg Peach, capsule-shaped, tablet debossed with “PERCOCET” on one side and “7.5” on the other. Bottles of 100 NDC 63481-621-70 10 mg/325 mg Yellow, capsule-shaped, tablet debossed with “PERCOCET” on one side and “10/325” on the other. Bottles of 100 NDC 63481-629-70 10 mg/650 mg Yellow, oval, tablet debossed with “PERCOCET” on one side and “10” on the other. Bottles of 100 NDC 63481-622-70 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). DEA Order Form Required. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 PERCOCET® is a Registered Trademark of Endo Pharmaceuticals Inc. Copyright © Endo Pharmaceuticals Inc. 2006 Printed in U.S.A. 2000055/November, 2006

GERIATRIC USE

Geriatric Use Special precaution should be given when determining the dosing amount and frequency of PERCOCET tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients.

INDICATIONS AND USAGE

PERCOCET is indicated for the relief of moderate to moderately severe pain.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Animal reproductive studies have not been conducted with PERCOCET. It is also not known whether PERCOCET can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. PERCOCET should not be given to a pregnant woman unless in the judgment of the physician, the potential benefits outweigh the possible hazards Nonteratogenic Effects Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms.

NUSRING MOTHERS

Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving PERCOCET tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Acetaminophen is also excreted in breast milk in low concentrations.

INFORMATION FOR PATIENTS

Information for Patients/Caregivers The following information should be provided to patients receiving PERCOCET tablets by their physician, nurse, pharmacist, or caregiver: Patients should be aware that PERCOCET tablets contain oxycodone, which is a morphine-like substance. Patients should be instructed to keep PERCOCET tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately. When PERCOCET tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician. Patients should be advised that PERCOCET tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). Patients should not combine PERCOCET tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, PERCOCET tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death. The safe use of PERCOCET tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking PERCOCET tablets. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue PERCOCET tablets because of the potential for serious adverse reactions to nursing infants. Patients who are treated with PERCOCET tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication. Patients should be advised that PERCOCET tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. PERCOCET tablets are given orally. Percocet 2.5 mg/325 mg The usual adult dosage is one or 2 tablets every 6 hours. The total daily dose of acetaminophen should not exceed 4 grams. Percocet 5 mg/325 mg; Percocet 7.5 mg/500 mg; Percocet 10 mg/650 mg The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. Percocet 7.5 mg/325 mg; Percocet 10 mg/325 mg The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. Strength Maximal Daily Dose Percocet 2.5 mg/325 mg 12 Tablets Percocet 5 mg/325 mg 12 Tablets Percocet 7.5 mg/325 mg 8 Tablets Percocet 7.5 mg/500 mg 8 Tablets Percocet 10 mg/325 mg 6 Tablets Percocet 10 mg/650 mg 6 Tablets Cessation of Therapy In patients treated with PERCOCET tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

Pseudoephedrine Hydrochloride 30 MG Oral Tablet

Generic Name: PSEUDOEPHEDRINE HCL
Brand Name: SudoGest
  • Substance Name(s):
  • PSEUDOEPHEDRINE HYDROCHLORIDE

WARNINGS

Warnings : Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

INDICATIONS AND USAGE

Indications and Usage : Temporarily relieves nasal congestion due to the common cold, hay fever or other upper respiratory allergies, and nasal congestion associated with sinusitis Temporarily relieves sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive Ingredients : acacia, calcium sulfate, carnauba Wax. colloidal silicon dioxide, corn starch, D-C red no. 27, D-C yellow no.10, FD-C red no.40, FD-C yellow no 6, iron oxide black, iron oxide red, iron oxide yellow (iron oxide ochre) Kaolin, microcrystalline cellulose, polyethylene glycol (PEG) 400, , pregelatinized starch, sodium starch glycolate, stearic acid, sugar, talc, titanium dioxide

PURPOSE

Purpose Nasal Decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away

DOSAGE AND ADMINISTRATION

Dosage and Administration : Directions – take every 4-6 hours -Do not take more than 4 does in 24 hours Adults and children 12 years and over – 2 tablets Children 6 to under 12 years – 1 tablet Children under 6 years – do not use

ACTIVE INGREDIENTS

Active Ingredient In each tablet Pseudoephedrine HCl 30 mg

Clonazepam 1 MG Oral Tablet

Generic Name: CLONAZEPAM
Brand Name: Clonazepam
  • Substance Name(s):
  • CLONAZEPAM

WARNINGS

Interference With Cognitive and Motor Performance Since clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam therapy (see PRECAUTIONS, Drug Interactions and Information for Patients). Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including clonazepam, 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 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1: 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 Patient/Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events per 1000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 clonazepam or any other AED must balance the risk of suicidal thoughts or behavior 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. Pregnancy Risks Data from several sources raise concerns about the use of clonazepam during pregnancy. Animal Findings In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended daily human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis). General Concerns and Considerations About Anticonvulsants Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors (e.g., genetic factors or the epileptic condition itself) may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus. General Concerns About Benzodiazepines An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies. There may also be nonteratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Advice Regarding the Use of Clonazepam in Women of Childbearing Potential In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women. Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. 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 the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug. Withdrawal Symptoms Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

DRUG INTERACTIONS

Drug Interactions Effect of Clonazepam on the Pharmacokinetics of Other Drugs Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated. Effect of Other Drugs on the Pharmacokinetics of Clonazepam Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics. In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone. Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving clonazepam. Pharmacodynamic Interactions The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

OVERDOSAGE

Human Experience Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes. Overdose Management Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Dialysis is of no known value. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use. Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures. Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

DESCRIPTION

Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72 clonazepam tablets structural formula

CLINICAL STUDIES

Clinical Trials Panic Disorder The effectiveness of clonazepam in the treatment of panic disorder was demonstrated in two double-blind, placebo-controlled studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia. In these studies, clonazepam was shown to be significantly more effective than placebo in treating panic disorder on change from baseline in panic attack frequency, the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global Impression Improvement Score. Study 1 was a 9 week, fixed-dose study involving clonazepam doses of 0.5, 1, 2, 3 or 4 mg/day or placebo. This study was conducted in four phases: a 1 week placebo lead-in, a 3 week upward titration, a 6 week fixed dose and a 7 week discontinuance phase. A significant difference from placebo was observed consistently only for the 1 mg/day group. The difference between the 1 mg dose group and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic attacks, compared to 56% of placebo-treated patients. Study 2 was a 6 week, flexible-dose study involving clonazepam in a dose range of 0.5 to 4 mg/day or placebo. This study was conducted in three phases: a 1 week placebo lead-in, a 6 week optimal-dose and a 6 week discontinuance phase. The mean clonazepam dose during the optimal dosing period was 2.3 mg/day. The difference between clonazepam and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of full panic attacks, compared to 37% of placebo-treated patients. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of race or gender.

HOW SUPPLIED

Clonazepam tablets USP 0.5 mg are available as yellow, round, flat beveled, single-scored tablets debossed “832” above the scored line and “TEVA” on the unscored side. Packaged in blistercards of 30. Clonazepam tablets USP 1 mg are available as mottled green, round, flat beveled, single-scored tablets debossed “833” above the scored line and “TEVA” on the unscored side. Packaged in blistercards of 30. Clonazepam tablets USP 2 mg are available as white to off-white, round, flat beveled, single-scored tablets debossed “834” above the scored line and “TEVA” on the unscored side. Packaged in blistercards of 30. 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). Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. Q 9/2012

GERIATRIC USE

Geriatric Use Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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, renal, or cardiac function, and of concomitant disease or other drug therapy. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam and observed closely.

INDICATIONS AND USAGE

Seizure Disorders Clonazepam tablets USP are useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam tablets USP may be useful. In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy. Panic Disorder Clonazepam tablts USP are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of clonazepam tablets USP was established in two 6 to 9 week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY, Clinical Trials). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. The effectiveness of clonazepam tablets USP in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use clonazepam tablets USP for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

PEDIATRIC USE

Pediatric Use Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION). Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category D (See WARNINGS, Pregnancy Risks). To provide information regarding the effects of in utero exposure to clonazepam, physicians are advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on this registry can also be found at the website http://www.aedpregnancyregistry.org/.

NUSRING MOTHERS

Nursing Mothers Mothers receiving clonazepam should not breastfeed their infants.

INFORMATION FOR PATIENTS

Information for Patients A clonazepam tablets, USP Medication Guide must be given to the patient each time clonazepam tablets, USP are dispensed, as required by law. Patients should be instructed to take clonazepam only as prescribed. Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam: Dose Changes To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. Interference With Cognitive and Motor Performance Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely. Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including clonazepam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with clonazepam (see WARNINGS, Pregnancy Risks). Patients should be encouraged 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 (see PRECAUTIONS, Pregnancy). Nursing Patients should be advised not to breastfeed an infant if they are taking clonazepam. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol Patients should be advised to avoid alcohol while taking clonazepam.

DOSAGE AND ADMINISTRATION

Clonazepam tablets USP should be administered with water by swallowing the tablet whole. Seizure Disorders Adults The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg. The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding clonazepam to an existing anticonvulsant regimen. Pediatric Patients Clonazepam is administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring. Geriatric Patients There is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS, Geriatric Use). Panic Disorder Adults The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. Nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable. Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn. There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Pediatric Patients There is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age. Geriatric Patients There is no clinical trial experience with clonazepam in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS, Geriatric Use).

Loratadine 10 MG Oral Tablet

Generic Name: LORATADINE
Brand Name: Signature Care Allergy Relief
  • Substance Name(s):
  • LORATADINE

WARNINGS

Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: •runny nose •itchy, watery eyes •sneezing •itching of the nose or throat

INACTIVE INGREDIENTS

Inactive ingredients lactose monohydrate, magnesium stearate, povidone, pregelatinized starch

PURPOSE

Purpose Antihistamine

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)

ASK DOCTOR

Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose.

DOSAGE AND ADMINISTRATION

Directions adults and children 6 years and over 1 tablet daily; not more than 1 tablet in 24 hours children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you have ever had an allergic reaction to this product or any of its ingredients

STOP USE

Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away.

ACTIVE INGREDIENTS

Active ingredient (in each tablet) Loratadine 10 mg

Propranolol Hydrochloride 20 MG Oral Tablet

Generic Name: PROPRANOLOL HYDROCHLORIDE
Brand Name: Propranolol Hydrochloride
  • Substance Name(s):
  • PROPRANOLOL HYDROCHLORIDE

WARNINGS

Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS ). Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure. Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli in propranololtreated patients may augment the risks of general anesthesia and surgical procedures. Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3 and decreasing T3. Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.

DRUG INTERACTIONS

Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Coadministration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following co-administration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heartrate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by betablockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

OVERDOSAGE

Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.

DESCRIPTION

Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (±)-1-(Isopropylamino)-3-(1-naphthyloxy)-2- propanol hydrochloride. Its structural formula is: C16H21NO2 • HCl M.W. 295.80 Propranolol hydrochloride is a stable, white crystalline solid which is readily soluble in water and ethanol. Propranolol hydrochloride is available as 10 mg, 20 mg, 40 mg and 80 mg tablets for oral administration. Propranolol Hydrochloride Tablets USP 10 mg, 20 mg, 40 mg, and 80 mg contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose and stearic acid. Propranolol Hydrochloride Tablets USP 10 mg and 80 mg also contain FD&C Yellow No. 6. Propranolol Hydrochloride Tablets USP 20 mg and 40 mg also contain FD&C Blue No. 1.

HOW SUPPLIED

Propranolol Hydrochloride Tablets USP 10 mg are 9/32″, scored, round, orange tablets imprinted DAN 5554 and 10 . Propranolol Hydrochloride Tablets USP 20 mg are 9/32″, scored, round, blue tablets imprinted DAN 5555 and 20. Propranolol Hydrochloride Tablets USP 40 mg are 11/32″, scored, round, green tablets imprinted DAN 5556 and 40 . Propranolol Hydrochloride Tablets USP 80 mg are 12/32″, scored, round, yellow tablets imprinted DAN 5557 and 80 . They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod. Code 53808-0771-1 20 mg 30 Tablets in a Blister Pack blue 0591-5555 53808-0772-1 40 mg 30 Tablets in a Blister Pack green 0591-5556 Dispense in a well-closed, light-resistant container with child-resistant closure. Store at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from light. Manufactured By: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed By: Watson Pharma, Inc. Corona, CA 92880 USA This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 United States

GERIATRIC USE

Geriatric Use Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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, renal, or cardiac function, and of concomitant disease or other drug therapy.

MECHANISM OF ACTION

Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable. In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of betaadrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. The mechanism of the antimigraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain. The specific mechanism of propranolol’s antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that propranolol is of benefit in exaggerated physiological and essential (familial) tremor.

INDICATIONS AND USAGE

Hypertension Propranolol hydrochloride tablets are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride is not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Propranolol hydrochloride tablets are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Propranolol is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Propranolol is indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Propranolol is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol causes a reduction in the tremor amplitude but not in the tremor frequency. Propranolol is not indicated for the treatment of tremor associated with Parkinsonism. Hypertrophic Subaortic Stenosis Propranolol improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Propranolol is indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients.

PREGNANCY

Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing woman.

DOSAGE AND ADMINISTRATION

General Because of the variable bioavailability of propranolol, the dose should be individualized based on response. Hypertension The usual initial dosage is 40 mg propranolol hydrochloride twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg per day. In some instances a dosage of 640 mg a day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks. While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3-times-daily therapy may achieve better control. Angina Pectoris Total daily doses of 80 mg to 320 mg propranolol hydrochloride, when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS .) Atrial Fibrillation The recommended dose is 10 mg to 30 mg propranolol hydrochloride three or four times daily before meals and at bedtime. Myocardial Infarction In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1 month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg propranolol hydrochloride per day in divided doses. Although a t.i.d. regimen was used in BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see PHARMACOKINETICS AND DRUG METABOLISM ). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension (see above). Migraine The initial dose is 80 mg propranolol hydrochloride daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, propranolol therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks. Essential Tremor The initial dosage is 40 mg propranolol hydrochloride twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary to administer 240 mg to 320 mg per day. Hypertrophic Subaortic Stenosis The usual dosage is 20 mg to 40 mg propranolol hydrochloride three or four times daily before meals and at bedtime. Pheochromocytoma The usual dosage is 60 mg propranolol hydrochloride daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade.

Diphenhydramine Hydrochloride 25 MG Oral Tablet

Generic Name: DIPHENHYDRAMINE HCL
Brand Name: Allergy Antihistamine
  • Substance Name(s):
  • DIPHENHYDRAMINE HYDROCHLORIDE

WARNINGS

Warnings Do not use with any other product containing diphenhydramine, even one used on skin Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to an enlargement of the prostate gland Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product excitability may occur especially in children drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness use caution when operating machinery or driving a motor vehicle If pregnant of breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms of the common cold: runny nose sneezing temporarily relieves symptoms due to hay fever or other upper respiratory allergies: runny nose sneezing itching nose or throat itchy, watery eyes

INACTIVE INGREDIENTS

Inactive ingredients carnauba wax, colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Aluminum Lake, dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol (PEG) 400, polysorbate 80 and titanium dioxide May also contain: polyvinyl alcohol and talc.

PURPOSE

Purpose Antihistamine

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

ASK DOCTOR

Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to an enlargement of the prostate gland

OTHER SAFETY INFORMATION

Other information each tablet contains: calcium 25 mg/ tablet store at room temperature 15°-30°C (59°-86°F) protect from light and moisture

DOSAGE AND ADMINISTRATION

Directions take every 4 to 6 hours, not more than 6 doses in 24 hours adults and children 12 years of age and over take 1 or 2 tablets children 6 to under 12 years of age take 1 tablet children under 6 years of age consult a doctor children under 4 years of age do not use

PREGNANCY AND BREAST FEEDING

If pregnant of breast-feeding, ask a health professional before use.

DO NOT USE

Do not use with any other product containing diphenhydramine, even one used on skin

ACTIVE INGREDIENTS

Active ingredient (in each tablet) Diphenhydramine HCl 25 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

Methylprednisolone 4 MG Oral Tablet

Generic Name: METHYLPREDNISOLONE
Brand Name: Medrol
  • Substance Name(s):
  • METHYLPREDNISOLONE

WARNINGS

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated. Corticosteroids may mask some signs of infection, and new infections may appear during their use. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function.1 These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.2 There may be decreased resistance and inability to localize infection when corticosteroids are used. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Usage in pregnancy Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism. Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the response to such vaccines may be diminished. Indicated immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids. The use of MEDROL Tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

DRUG INTERACTIONS

Drug Interactions The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of methylprednisolone and may require increases in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

DESCRIPTION

MEDROL Tablets contain methylprednisolone which is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Methylprednisolone occurs as a white to practically white, odorless, crystalline powder. It is sparingly soluble in alcohol, in dioxane, and in methanol, slightly soluble in acetone, and in chloroform, and very slightly soluble in ether. It is practically insoluble in water. The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and the molecular weight is 374.48. The structural formula is represented below: Each MEDROL Tablet for oral administration contains 2 mg, 4 mg, 8 mg, 16 mg or 32 mg of methylprednisolone. Inactive ingredients: 2 mg 4 mg and 8 mg Calcium Stearate Calcium Stearate Corn Starch Corn Starch Erythrosine Sodium Lactose Lactose Sucrose Mineral Oil Sorbic Acid Sucrose 16 mg and 32 mg Calcium Stearate Corn Starch Lactose Mineral Oil Sucrose Chemical Structure ACTIONS Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune responses to diverse stimuli.

HOW SUPPLIED

MEDROL Tablets are available in the following strengths and package sizes: 2 mg (pink, elliptical, scored, imprinted MEDROL 2) Bottles of 100 NDC 0009-0049-02 4 mg (white, elliptical, scored, imprinted MEDROL 4) Bottles of 100 NDC 0009-0056-02 Bottles of 500 NDC 0009-0056-03 Unit dose packages of 100 NDC 0009-0056-05 DOSEPAK™ Unit of Use (21 tablets) NDC 0009-0056-04 8 mg (white, elliptical, scored, imprinted MEDROL 8) Bottles of 25 NDC 0009-0022-01 16 mg (white, elliptical, scored, imprinted MEDROL 16) Bottles of 50 NDC 0009-0073-01 32 mg (white, elliptical, scored, imprinted MEDROL 32) Bottles of 25 NDC 0009-0176-01 Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

INDICATIONS AND USAGE

MEDROL Tablets are indicated in the following conditions: 1. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance). Congenital adrenal hyperplasia Nonsuppurative thyroiditis Hypercalcemia associated with cancer 2. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Synovitis of osteoarthritis Acute nonspecific tenosynovitis Post-traumatic osteoarthritis Psoriatic arthritis Epicondylitis Acute gouty arthritis 3. Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis 4. Dermatologic Diseases Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Severe seborrheic dermatitis Exfoliative dermatitis Mycosis fungoides Pemphigus Severe psoriasis 5. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Drug hypersensitivity reactions Serum sickness Contact dermatitis Bronchial asthma Atopic dermatitis 6. Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic corneal marginal ulcers Herpes zoster ophthalmicus Anterior segment inflammation Diffuse posterior uveitis and choroiditis Sympathetic ophthalmia Keratitis Optic neuritis Allergic conjunctivitis Chorioretinitis Iritis and iridocyclitis 7. Respiratory Diseases Symptomatic sarcoidosis Berylliosis Loeffler’s syndrome not manageable by other means Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration pneumonitis 8. Hematologic Disorders Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 9. Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 10. Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. 11. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis 12. Nervous System Acute exacerbations of multiple sclerosis 13. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Trichinosis with neurologic or myocardial involvement.

PREGNANCY

Usage in pregnancy Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.

INFORMATION FOR PATIENTS

Information for the Patient Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

DOSAGE AND ADMINISTRATION

The initial dosage of MEDROL Tablets may vary from 4 mg to 48 mg of methylprednisolone per day depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, MEDROL should be discontinued and the patient transferred to other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of MEDROL for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. Multiple Sclerosis In treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone). ADT® (Alternate Day Therapy) Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for reestablishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day. A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenal cortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenal cortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight. The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenal cortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects. During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every six hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenal cortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenal cortical suppression for 1¼ to 1½ days following a single dose) and thus are recommended for alternate day therapy. The following should be kept in mind when considering alternate day therapy: 1)Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids. 2)ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated. 3)In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to ADT and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable. 4)Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (eg, patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum. 5)As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg, dexamethasone and betamethasone). 6)The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am). 7)In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed. 8)In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be reinstituted. 9)Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.