Drug Intercation

EDURANT 25 MG Oral Tablet

DRUG INTERACTIONS

7 [See Dosage and Administration (2), Contraindications (4) and Clinical Pharmacology (12.3).] Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Co-administration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with EDURANT are also included in Table 4. Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3)] Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment ↑ = increase, ↓ = decrease, ↔ = no change HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosineThe interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily. ↔ rilpivirine ↔ didanosine No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal). HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTI (delavirdine) ↑ rilpivirine ↔ delavirdine It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs. Other NNRTIs (efavirenz, etravirine, nevirapine) ↓ rilpivirine ↔ other NNRTIs HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir) darunavir/ritonavir ↑ rilpivirine ↔ boosted darunavir Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir. lopinavir/ritonavir ↑ rilpivirine ↔ boosted lopinavir Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir. other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) ↑ rilpivirine ↔ boosted PI Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) ↑ rilpivirine ↔ unboosted PI Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. Other Agents Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT. ↓ rilpivirine (concomitant intake) Antimycobacterials: rifabutin ↓ rilpivirine Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily. Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ rilpivirine ↓ ketoconazole Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT. H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) The combination of EDURANT and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT. ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) Macrolide or ketolide antibiotics: clarithromycin erythromycin telithromycin ↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. Narcotic Analgesics: methadone ↓ R(-) methadone ↓ S(+) methadone No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. In addition to the drugs included in Table 4, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when EDURANT is co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine. EDURANT should not be used in combination with NNRTIs. (7) Co-administration of EDURANT with drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine. (7) Co-administration of EDURANT with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine. (7) Refer to the Full Prescribing Information for other drugs that should not be co-administered with EDURANT and for other drugs that may require a change in dose or regimen. (7) QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology (12.2)]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

OVERDOSAGE

10 There is no specific antidote for overdose with EDURANT. Human experience of overdose with EDURANT is limited. Treatment of overdose with EDURANT consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

DESCRIPTION

11 EDURANT (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin. Chemical Structure

CLINICAL STUDIES

14 14.1 Treatment-Naïve Adult Subjects The evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR. In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 10 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms. Table 10: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis) Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials EDURANT + BR N=686 Efavirenz + BR N=682 BR=background regimen Demographic Characteristics Median Age, years (range) 36 (18–78) 36 (19–69) Sex Male 76% 76% Female 24% 24% Race White 61% 60% Black/African American 24% 23% Asian 11% 14% Other 2% 2% Not allowed to ask per local regulations 1% 1% Baseline Disease Characteristics Median Baseline Plasma HIV-1 RNA (range), log10 copies/mL 5.0 (2–7) 5.0 (3–7) Percentage of Patients with Baseline Plasma Viral Load: ≤ 100,000 54% 48% > 100,000 to ≤ 500,000 36% 40% > 500,000 10% 12% Median Baseline CD4+ Cell Count (range), cells/mm3 249 (1–888) 260 (1–1137) Percentage of Subjects with: Hepatitis B/C Virus Co-infection 7% 10% Percentage of Patients with the following background regimens: tenofovir disoproxil fumarate plus emtricitabine 80% 80% zidovudine plus lamivudine 15% 15% abacavir plus lamivudine 5% 5% Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 11. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment. Table 11: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96 EDURANT + BR N=686 Efavirenz + BR N=682 N = total number of subjects per treatment group; BR = background regimen. Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively. HIV-1 RNA < 50 copies/mLCI = Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96. 76% 77% HIV-1 RNA ≥ 50 copies/mLIncludes subjects who had ≥ 50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. 16% 10% No virologic data at Week 96 window Reasons Discontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. 4% 8% Discontinued study for other reasons and last available HIV-1 RNA < 50 copies/mL (or missing)Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 4% 5% Missing data during window but on study < 1% < 1% HIV-1 RNA < 50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤ 100,000 82% 78% > 100,000 70% 75% HIV-1 RNA ≥ 50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤ 100,000 9% 8% > 100,000 24% 11% HIV-1 RNA < 50 copies/mL by CD4+ cell count (cells/mm3) < 200 68% 74% ≥ 200 81% 77% HIV-1 RNA ≥ 50 copies/mL by CD4+ cell count (cells/mm3) < 200 27% 10% ≥ 200 10% 9% At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm3 for EDURANT-treated subjects and 219 cells/mm3 for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials. Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine. Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs. At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving EDURANT 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm3 in subjects receiving EDURANT 25 mg and 160 cells/mm3 in subjects receiving efavirenz. At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group. 14.2 Treatment-Naïve Pediatric Subjects (12 to less than 18 years of age) The pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected background regimen (BR) containing two NRTIs, was evaluated in trial TMC278-C213, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg. Thirty six (36) subjects were enrolled in the trial to complete at least 48 weeks of treatment. The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 55.6% female, 88.9% Black and 11.1% Asian. In the efficacy analysis, most subjects (75%; 28/36) had baseline HIV RNA <100,000 copies/mL. For these 28 subjects the median baseline plasma HIV-1 RNA was 44,250 (range: 2,060–92,600 copies/mL) and the median baseline CD4+ cell count was 445.5 cells/mm3 (range: 123 to 983 cells/mm3). Among the subjects who had baseline HIV RNA ≤ 100,000, the proportion with HIV-1 RNA <50 copies/mL at Week 48 was 79% (22/28), versus 50.0% (4/8) in those with >100,000 copies/mL. The proportion of virologic failures among subjects with a baseline viral load ≤100,000 copies/mL was 21.4% (6/28), versus 37.5% (3/8) in those with >100,000 copies/mL. At Week 48, the mean increase in CD4+ cell count from baseline was 201.2 cells/mm3.

HOW SUPPLIED

16 /STORAGE AND HANDLING EDURANT (rilpivirine) tablets are supplied as white to off-white, film-coated, round, biconvex, 6.4 mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each tablet is debossed with “TMC” on one side and “25” on the other side. EDURANT tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01). Store EDURANT tablets in the original bottle in order to protect from light. Store EDURANT tablets at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP controlled room temperature].

RECENT MAJOR CHANGES

Indications and Usage (1) 08/2015 Dosage and Administration (2) 08/2015 Warnings and Precautions, Skin and Hypersensitivity Reactions (5.2) 05/2015 Warnings and Precautions, Depressive Disorders (5.3) 08/2015

GERIATRIC USE

8.5 Geriatric Use Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with “TMC” on one side and “25” on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. 25 mg tablets (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Rilpivirine is an antiviral drug [see Microbiology (12.4)].

INDICATIONS AND USAGE

1 EDURANT®, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. EDURANT is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated – in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve patients with HIV-1 RNA less than or equal to 100,000 copies/mL (1). Limitations of Use: More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥ 50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. (1, 14) Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to subjects with CD4+ cell count greater than or equal to 200 cells/mm3. (1, 14) The observed virologic failure rate in EDURANT treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz. (1, 12.4) More subjects treated with EDURANT developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz. (1, 12.4, 14) Limitations of Use: More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥ 50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14.1)]. Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm3 experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm3 [see Clinical Studies (14.1)]. The observed virologic failure rate in EDURANT treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [see Microbiology (12.4)]. More subjects treated with EDURANT developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz [see Microbiology (12.4)].

PEDIATRIC USE

8.4 Pediatric Use The safety, efficacy and pharmacokinetics of EDURANT were evaluated in a single arm, open-label, Phase 2 trial that enrolled 36 antiretroviral treatment-naïve, HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg [see Adverse Reactions (6.2), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Please see Dosage and Administration (2) for dosing recommendations for pediatric patients 12 years of age and older. Safety and effectiveness in pediatric patients less than 12 years of age have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category B No adequate and well-controlled or pharmacokinetic studies of EDURANT use in pregnant women have been conducted. Studies in animals have shown no evidence of relevant embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. EDURANT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to EDURANT, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

NUSRING MOTHERS

8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving EDURANT.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Caution should be given to prescribing EDURANT with drugs that may reduce the exposure of rilpivirine. (5.1) Caution should be given to prescribing EDURANT with drugs with a known risk of Torsade de Pointes. (5.1) Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develop and closely monitor clinical status, including hepatic serum biochemistries. (5.2) Depressive Disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. (5.3) Hepatotoxicity: Hepatic adverse events have been reported in patients with underlying liver disease, including hepatitis B or C co-infection, or in patients with elevated baseline transaminases. A few cases of hepatotoxicity have occurred in patients with no pre-existing hepatic disease. Monitor liver function tests before and during treatment with EDURANT in patients with underlying hepatic disease, such as hepatitis B or C co-infection, or marked elevations in transaminase. Also consider monitoring liver functions tests in patients without pre-existing hepatic dysfunction or other risk factors. (5.4) Patients may develop redistribution/accumulation of body fat (5.5) or immune reconstitution syndrome. (5.6) 5.1 Drug Interactions Caution should be given to prescribing EDURANT with drugs that may reduce the exposure of rilpivirine [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]. In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. 5.2 Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT. No grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6 and 6.2)]. Discontinue EDURANT immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated. 5.3 Depressive Disorders The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with EDURANT. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to EDURANT, and if so, to determine whether the risks of continued therapy outweigh the benefits. During the Phase 3 trials in adults (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among EDURANT (n = 686) or efavirenz (n = 682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both EDURANT and efavirenz. The incidence of discontinuation due to depressive disorders among EDURANT or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the EDURANT arm. During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N = 36) receiving EDURANT through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject. 5.4 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT. A few cases of hepatic toxicity have been reported in adult patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with EDURANT is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 5.5 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EDURANT. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with EDURANT from your healthcare provider. A Patient Package Insert for EDURANT is available for patient information. Patients should be informed that EDURANT is not a cure for HIV infection. Patients must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using EDURANT. Female patients should be advised not to breastfeed because it is unknown if EDURANT can be passed to the baby in the breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Patients should be advised to take EDURANT with a meal once a day as prescribed. A protein drink alone does not replace a meal. EDURANT must always be used in combination with other antiretroviral drugs. Patients should not alter the dose of EDURANT or discontinue therapy with EDURANT without consulting their physician. If the patient misses a dose of EDURANT within 12 hours of the time it is usually taken, the patient should take EDURANT with a meal as soon as possible and then take the next dose of EDURANT at the regularly scheduled time. If a patient misses a dose of EDURANT by more than 12 hours, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of EDURANT at any one time. EDURANT may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort. EDURANT should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to EDURANT or to the class of NNRTIs: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the antimycobacterials rifampin, rifapentine; proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; the glucocorticoid systemic dexamethasone (more than a single dose); or St. John’s wort (Hypericum perforatum). For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg once daily, taken with a meal. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal. Patients should be informed that skin reactions ranging from mild to severe, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported with rilpivirine-containing regimens. Instruct patients to immediately stop taking EDURANT tablets and seek medical attention if they develop a rash associated with any of the following symptoms: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing a swelling of the face, eyes, lips, mouth, tongue or throat, which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems as it may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated. Patients should be informed that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with EDURANT. If they experience depressive symptoms, they should seek immediate medical evaluation. Patients should be informed that hepatotoxicity has been reported with EDURANT. Patients should also be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including EDURANT, and that the cause and long-term health effects of these conditions are not known at this time.

DOSAGE AND ADMINISTRATION

2 The recommended dosage of EDURANT in patients 12 years of age and older and weighing at least 35 kg is one 25 mg tablet once daily taken orally with a meal [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. EDURANT is not recommended for patients less than 12 years of age. Rifabutin Co-administration: For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) once daily, taken with a meal. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal [see Drug Interactions (7), Clinical Pharmacology (12.3)]. 25 mg (one 25 mg tablet) taken once daily with a meal. (2) EDURANT is not recommended for patients less than 12 years of age. (8.4) With rifabutin co-administration, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) taken once daily with a meal. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg taken once daily with a meal. (2, 7, 12.3)

swordfish allergenic extract 0.1 GM/ML Injectable Solution

Generic Name: CARP

Brand Name: Carp

Substance Name(s):
COMMON CARP

WARNINGS

DO NOT INJECT INTRAVENOUSLY. Epinephrine 1:1000 should be available. Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing. All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.(4) (See Adverse Reactions) An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

OVERDOSAGE

Overdose can cause both local and systemic reactions. An overdose may be prevented by careful observation and questioning of the patient about the previous injection. If systemic or anaphylactic reaction, does occur, apply a tourniquet above the site of injection and inject intramuscularly or subcutaneously 0.3 to 0.5ml of 1:1000 Epinephrine Hydrochloride into the opposite arm. The dose may be repeated in 5-10 minutes if necessary. Loosen the tourniquet at least every 10 minutes. The Epinephrine Hydrochloride 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml, for children 2 to 6 years it is 0.15 ml, for children 6-12 years it is 0.2 ml. Patients unresponsive to Epinephrine may be treated with Theophylline. Studies on asthmatic subjects reveal that plasma concentrations of Theophylline of 5 to 20 µg/ml are associated with therapeutic effects. Toxicity is particularly apparent at concentrations greater than 20 µg/ml. A loading dose of Aminophylline of 5.8 mg/kg intravenously followed by 0.9 mg/kg per hour results in plasma concentrations of approximately 10 µg/ml for patients not previously receiving theophylline. (Mitenko and Ogilive, Nicholoson and Chick,1973) Other beta-adrenergic drugs such as Isoproterenol, Isoetharine, or Albuterol may be used by inhalation. The usual dose to relieve broncho-constriction in asthma is 0.5 ml of the 0.5% solution for Isoproterenol HCl. The Albuterol inhaler delivers approximately 90 mcg of Albuterol from the mouthpiece. The usual dosage for adults and children would be two inhalations repeated every 4-6 hours. Isoetharine supplied in the Bronkometer unit delivers approximately 340 mcg Isoetharine. The average dose is one to two inhalations. Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require oxygen, intubation and the use of life support systems.

DESCRIPTION

Allergenic extracts are sterile solutions consisting of the extractable components from various biological sources including pollens, inhalants, molds, animal epidermals and insects. Aqueous extracts are prepared using cocas fluid containing NaCl 0.5%, NaHCO3 0.0275%, WFI, preservative 0.4% Phenol. Glycerinated allergenic extracts are prepared with cocas fluid and glycerin to produce a 50% (v/v) allergenic extract. Allergenic Extracts are supplied as concentrations designated as protein nitrogen units (PNU) or weight/volume (w/v) ratio. Standardized extracts are designated in Bioequivalent Allergy Units (BAU) or Allergy Units (AU). (See product insert for standardized extracts) For diagnostic purposes, allergenic extracts are to be administered by prick-puncture or intradermal routes. Allergenic extracts are administered subcutaneously for immunotherapy injections.

HOW SUPPLIED

Allergenic extracts are supplied with units listed as: Weight/volume (W/V), Protein Nitrogen Units (PNU/ml), Allergy Units (AU/ml) or Bioequivalent Allergy Units (BAU/ml). Sizes: Diagnostic Scratch: 5 ml dropper application vials Diagnostic Intradermal: 5 ml or 10 ml vials. Therapeutic Allergens: 5 ml, 10 ml, 50 ml multiple dose vials.

INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnostic testing and as part of a treatment regime for allergic disease, as established by allergy history and skin test reactivity. Allergenic extracts are indicated for the treatment of allergen specific allergic disease for use as hyposensitization or immunotherapy when avoidance of specific allergens can not be attained. The use of allergenic extracts for therapeutic purpose has been established by well-controlled clinical studies. Allergenic extracts may be used as adjunctive therapy along with pharmacotherapy which includes antihistamines, corticosteroids, and cromoglycate, and avoidance measures. Allergenic extracts for therapeutic use should be given using only the allergen selection to which the patient is allergic, has a history of exposure and are likely to be exposed to again.

BOXED WARNING

WARNING Diagnostic and therapeutic allergenic extracts are intended to be administered by a physician who is an allergy specialist and experienced in allergenic diagnostic testing and immunotherapy and the emergency care of anaphylaxis. This product should not be injected intravenously. Deep subcutaneous routes have been safe. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death. (See Adverse Reactions) Serious adverse reactions should be reported to Nelco Laboratories immediately and a report filed to: MedWatch, The FDA Medical Product Problem Reporting Program, at 5600 Fishers Lane, Rockville, Md. 20852-9787, call 1-800-FDA-1088. Extreme caution should be taken when using allergenic extracts for patients who are taking beta-blocker medications. In the event of a serious adverse reaction associated with the use of allergenic extracts, patients receiving beta-blockers may not be responsive to epinephrine or inhaled brochodialators.(1) (See Precautions) Allergenic extracts should be used with caution for patients with unstable or steroid-dependent asthma or underlying cardiovascular disease. (See Contraindications)

DOSAGE AND ADMINISTRATION

General Precautions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits. The dosage of allergenic extracts is dependent upon the purpose of the administration. Allergenic extracts can be administered for diagnostic use or for therapeutic use. When allergenic extracts are administered for diagnostic use, the dosage is dependent upon the method used. Two methods commonly used are scratch testing and intradermal testing. Both types of tests result in a wheal and flare response at the site of the test which usually develops rapidly and may be read in 20-30 minutes. Diagnostic Use : Scratch Testing Method Scratch testing is considered a simple and safe method although less sensitive than the intradermal test. Scratch testing can be used to determine the degree of sensitivity to a suspected allergen before using the intradermal test. This combination lessens the severity of response to an allergen which can occur in a very sensitive patient. The most satisfactory testing site is the patient’s back or volar surface of the arms from the axilla to 2.5 or 5cm above the wrist, skipping the anti-cubital space. If using the back as a testing site, the most satisfactory area are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. Allergenic extracts for diagnostic use are to be administered in the following manner: To scratch surface of skin, use a circular scarifier. Do not draw blood. Tests sites should be 4 cm apart to allow for wheal and flare reaction. 1-30 scratch tests may be done at a time. A separate sterile scratch instrument is to be used on each patient to prevent transmission of homologous serum hepatitis or other infectious agents from one patient to another. The recommended usual dosage for Scratch testing is one drop of allergen applied to each scratch site. Do not let dropper touch skin. Always apply a control scratch with each test set. Sterile Diluent (for a negative control) is used in exactly the same way as an active test extract. Histamine may be used as a positive control. Scratch or prick test sites should be examined at 15 and 30 minutes. To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears. Record the size of the reaction. Interpretation of Scratch Test Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes. Wheal and erythema size may be recorded by actual measurement as compared with positive and negative controls. A positive reaction consists of an area of erythema surrounding the scarification that is larger than the control site. For uniformity in reporting reactions, the following system is recommended. (6) REACTION SYMBOL CRITERIA Negative – No wheal. Erythema absent or very slight (not more than 1 mm diameter). One Plus + Wheal absent or very slight erythema present (not more than 3 mm diameter). Two Plus ++ Wheal not more than 3mm or erythema not more than 5mm diameter. Three Plus +++ Wheal between 3mm and 5mm diameter, with erythema. Possible pseudopodia and itching. Four Plus ++++ A larger reaction with itching and pain. Diagnostic Use: Intradermal Skin Testing Method Do not perform intradermal test with allergens which have evoked a 2+ or greater response to a Scratch test. Clean test area with alcohol, place sites 5 cm apart using separate sterile tuberculin syringe and a 25 gauge needle for each allergen. Insert needle tip, bevel up, into intracutaneous space. Avoid injecting into blood vessel, pull back gently on syringe plunger, if blood enters syringe change position of needle. The recommended dosage and range for intradermal testing is 0.05 ml of not more than 100 pnu/ml or 1:1000 w/v (only if puncture test is negative) of allergenic extract. Inject slowly until a small bleb is raised. It is important to make each bleb the same size. Interpretation of Intradermal Test: The patient’s reaction is graded on the basis of size of wheal and flare as compared to control. Use 0.05 ml sterile diluent as a negative control to give accurate interpretation. The tests may be accurately interpreted only when the saline control site has shown a negative response. Observe patient for at least 30 minutes. Tests can be read in 15-20 minutes. Edema, erythema and presence of pseudopods, pain and itching may be observed in 4 plus reactions. For uniformity in reporting reactions the following system is recommended. (6) REACTION SYMBOL CRITERIA Negative – No increase in size of bleb since injection. No erythema. One Plus + An increase in size of bleb to a wheal not more than 5mm diameter, with associated erythema. Two Plus ++ Wheal between 5mm and 8mm diameter with erythema. Three Plus +++ Wheal between 8mm and 12mm diameter with erythema and possible pseudopodia and itching or pain. Four Plus ++++ Any larger reaction with itch and pain, and possible diffuse blush of the skin surrounding the reaction area. Therapeutic Use: Recommended dosage & range Check the listed ingredients to verify that it matches the prescription ordered. When using a prescription set, verify the patient’s name and the ingredients listed with the prescription order. Assess the patient’s physical and emotional status prior to giving as injection. Do not give injections to patients who are in acute distress. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response and tolerance to the extract administered during the early phases of an injection regimen. The dosage must be reduced when transferring a patient from non-standardized or modified extract to standardized extract. Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy as well as during maintenance therapy. After therapeutic injections patients should be observed for at least 20 minutes for reaction symptoms. SUGGESTED DOSAGE SCHEDULE The following schedule may act as a guide. This schedule has not been proven to be safe or effective. Sensitive patients may begin with smaller doses of weaker solutions and the dosage increments can be less. STRENGTH DOSE VOLUME Vial #1 1 0.05 1:100,000 w/v 2 0.10 10 pnu/ml 3 0.15 1 AU/ml 4 0.20 1 BAU/ml 5 0.30 6 0.40 7 0.50 Vial #2 8 0.05 1:10,000 w/v 9 0.10 100 pnu/ml 10 0.15 10 AU/ml 11 0.20 10 BAU/ml 12 0.30 13 0.40 14 0.50 Vial #3 15 0.05 1:1,000 w/v 16 0.10 1,000 pnu/ml 17 0.15 100 AU/ml 18 0.20 100 BAU/ml 19 0.30 20 0.40 21 0.50 Vial #4 22 0.05 1:100 w/v 23 0.07 10,000 pnu/ml 24 0.10 1,000 AU/ml 25 0.15 1,000 BAU/ml 26 0.20 27 0.25 Maintenance Refill 28 0.25 1:100 w/v 29 0.25 10,000 pnu/ml 30 0.25 1,000 AU/ml 31 0.25 1,000 BAU/ml 32 0.25 subsequent doses 33 0.25 Preparation Instructions: All dilutions may be made using sterile buffered diluent. The calculation may be based on the following ratio: Volume desired x Concentration desired = Volume needed x Concentration available. Example 1: If a 1:10 w/v extract is available and it is desired to use a 1:1,000 w/v extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 0.001 = Vn x 0.1 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 1:10 vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting ratio will be a 10 ml vial of 1:1,000 w/v. Example 2: If a 10,000 pnu/ml extract is available and it is desired to use a 100 pnu/ml extract substitute as follows: 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 pnu/ml vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting concentration will be a 10 ml vial of 100 pnu/ml. Example 3: If a 10,000 AU/ml or BAU/ml extract is available and it is desired to use a 100 AU/ml or BAU/ml extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 AU/ml or BAU/ml vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting concentration will be 10ml vial of 100 AU/ml or BAU/ml. Intervals between doses: The optimal interval between doses of allergenic extract has not been definitely established. The amount of allergenic extract is increased at each injection by not more than 50%-100% of the previous amount and the next increment is governed by the response to the last injection. There are three generally accepted methods of pollen hyposensitizing therapy. 1. PRESEASONAL Treatment starts each year 6 to 8 weeks before onset of seasonal symptoms. Maximal dose reached just before symptoms are expected. Injections discontinued during and following season until next year. 2. CO-SEASONAL Patient is first treated during season with symptoms. Low initial doses are employed to prevent worsening of condition. This is followed by an intensive schedule of therapy (i.e. injections given 2 to 3 times per week). Fewer Allergists are resorting to this Co-seasonal therapy because of the availability of more effective, symptomatic medications that allow the patient to go through a season relatively symptom free. 3. PERENNIAL Initially this is the same as pre seasonal. The allergen is administered twice weekly or weekly for about 20 injections to achieve the maximum tolerated dose. Then, maintenance therapy may be administered once a week or less frequently. Duration of Treatment: The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.

Quinidine Sulfate 200 MG Oral Tablet

Generic Name: QUINIDINE SULFATE

Brand Name: Quinidine Sulfate

Substance Name(s):
QUINIDINE SULFATE

WARNINGS

Mortality In many trials of antiarrhythmic therapy for non-life-threatening arrhythmias, active antiarrhythmic therapy has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, the best available data come from a meta-analysis described under CLINICAL PHARMACOLOGY/Clinical Effects above. In the patients studied in the trials there analyzed, the mortality associated with the use of quinidine was more than three times as great as the mortality associated with the use of placebo. Another meta-analysis, also described under CLINICAL PHARMACOLOGY/Clinical Effects , showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics. Proarrhythmic effects Like many other drugs (including all other class IA antiarrhythmics), quinidine prolongs the QT interval, and this can lead to a life-threatening ventricular arrhythmia (see ). The risk of is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, or high serum levels of quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QT interval, and quinidine should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT interval. Estimation of the incidence of in patients with therapeutic levels of quinidine is not possible from the available data. C torsades de pointes, OVERDOSAGE torsades C torsades de pointes C torsades Other ventricular arrhythmias that have been reported with quinidine include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation. Paradoxical increase in ventricular rate in atrial flutter/fibrillation When quinidine is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles. The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of quinidine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a ß-receptor blocking agent. Exacerbated bradycardia in sick sinus syndrome In patients with the sick sinus syndrome, quinidine has been associated with marked sinus node depression and bradycardia. Pharmacokinetic considerations Renal or hepatic dysfunction causes the elimination of quinidine to be slowed, while congestive heart failure causes a reduction in quinidine’s apparent volume of distribution. Any of these conditions can lead to quinidine toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of quinidine, leading either to toxicity or to lack of efficacy if the dose of quinidine is not appropriately modified. (See ) PRECAUTIONS/Drug Interactions . Vagolysis Because quinidine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine.

OVERDOSAGE

Overdoses with various oral formulations of quinidine have been well described. Death has been described after a 5-gram ingestion by a toddler, while an adolescent was reported to survive after ingesting 8 grams of quinidine. The most important ill effects of acute quinidine overdoses are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. Arrhythmias Serum quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QT interval is a better predictor of quinidine-induced ventricular arrhythmias. C The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including ) is withdrawal of treatment with quinidine and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QT interval. torsades de pointes C Quinidine-associated ventricular tachyarrhythmias with normal underlying QT intervals have not been adequately studied. Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in quinidine overdose has not been reported, it is reasonable to expect that the α-blocking properties of bretylium might be additive to those of quinidine, resulting in problematic hypotension. C If the post-cardioversion QT interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are likely to exacerbate the situation. Factors contributing to QT prolongation (especially hypokalemia, hypomagnesemia, and hypocalcemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min). C torsades de pointes. C torsades Hypotension Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Simple repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine, metaraminol) and the Military Anti-Shock Trousers. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient. Physicians’ Desk Reference (PDR). Accelerated removal Adequate studies of orally-administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit. Quinidine is not usefully removed from the circulation by dialysis. Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

DESCRIPTION

Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with class 1A activity; it is the -isomer of quinine, and its molecular weight is 324.43. d Quinidine sulfate is the sulfate salt of quinidine; its chemical name is cinchonan-9-ol, 6’-methoxy-, (9 )-, sulfate(2:1) dihydrate; its structural formula is: S Its molecular formula is: C H N O •H SO •2H O; and its molecular weight is 782.96, of which 82.9% is quinidine base. 40 48 4 4 2 4 2 Quinidine sulfate occurs as fine needle-like, white crystals, frequently cohering in masses, or fine, white powder. It is odorless, has a very bitter taste, and darkens on exposure to light. It is slightly soluble in water, soluble in alcohol and in chloroform, and insoluble in ether. Each tablet, for oral administration, contains 200 mg and 300 mg of quinidine sulfate (equivalent to 166 mg or 249 mg of quinidine base). In addition, each tablet contains the following inactive ingredients: calcium stearate, microcrystalline cellulose, sodium starch glycolate and starch (corn). Quinidine Sulfate Structural Formula

HOW SUPPLIED

NDC:68151-1991-0 in a PACKAGE of 1 TABLETS

INDICATIONS AND USAGE

Conversion of atrial fibrillation/flutter In patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response, quinidine sulfate is indicated as a means of restoring normal sinus rhythm. If this use of quinidine sulfate does not restore sinus rhythm within a reasonable time (see ), then quinidine sulfate should be discontinued. DOSAGE AND ADMINISTRATION Reduction of frequency of relapse into atrial fibrillation/flutter Chronic therapy with quinidine sulfate is indicated for some patients at high risk of symptomatic atrial fibrillation/flutter, generally patients who have had previous episodes of atrial fibrillation/flutter that were so frequent and poorly tolerated as to outweigh, in the judgment of the physician and the patient, the risks of prophylactic therapy with quinidine sulfate. The increased risk of death should specifically be considered. Quinidine sulfate should be used only after alternative measures ( use of other drugs to control the ventricular rate) have been found to be inadequate. e.g., In patients with histories of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy should be an increase in the average time between episodes. In most patients, the tachyarrhythmia during therapy, and a single recurrence should not be interpreted as therapeutic failure. will recur Suppression of ventricular arrhythmias Quinidine sulfate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of quinidine, its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise. Antiarrhythmic drugs (including quinidine sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias. Treatment of malaria Quinidine sulfate is also indicated in the treatment of life-threatening malaria. Plasmodium falciparum

DOSAGE AND ADMINISTRATION

Treatment of P. falciparum malaria Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening malaria. The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection. P. falciparum Conversion of atrial fibrillation/flutter to sinus rhythm Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine sulfate only after ventricular rate control ( with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms. e.g., Adequate trials have not identified an optimal regimen of quinidine sulfate for conversion of atrial fibrillation/flutter to sinus rhythm. In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate every six hours. If this regimen has not resulted in conversion after 4 or 5 doses, then the dose is cautiously increased. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine sulfate is discontinued, and other means of conversion ( direct-current cardioversion) are considered. C e.g., Reduction of frequency of release into atrial fibrillation/flutter In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine sulfate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia during therapy with quinidine sulfate, and a single recurrence should not be interpreted as therapeutic failure. will recur Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged. Therapy with quinidine sulfate should be begun with 200 mg (equivalent to 166 mg of quinidine base) every six hours. If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension. C Suppression of ventricular arrhythmias Dosing regimens for the use of quinidine sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

digoxin 500 MCG in 2 ML Injection

WARNINGS

Sinus Node Disease and AV Block Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin. Accessory AV Pathway (Wolff-Parkinson-White Syndrome) After intravenous digoxin therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), digoxin should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion. Use in Patients with Preserved Left Ventricular Systolic Function Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin.

OVERDOSAGE

Treatment of Adverse Reactions Produced by Overdosage Digoxin should be temporarily discontinued until the adverse reaction resolves. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte disturbances or concurrent medications). Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a careful reassessment of dose. Withdrawal of digoxin may be all that is required to treat the adverse reaction. However, when the primary manifestation of digoxin overdosage is a cardiac arrhythmia, additional therapy may be needed. If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin Immune Fab (Ovine) (see below), the use of atropine, or the insertion of a temporary cardiac pacemaker. However, asymptomatic bradycardia or heart block related to digoxin may require only temporary withdrawal of the drug and cardiac monitoring of the patient. If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the correction of electrolyte disorders, particularly if hypokalemia (see below) or hypomagnesemia is present. Digoxin Immune Fab (Ovine) is a specific antidote for digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to digoxin overdosage. Administration of Potassium Every effort should be made to maintain the serum potassium concentration between 4 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and the serum potassium concentration is low, potassium may be administered cautiously by the intravenous route. The electrocardiogram should be monitored for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Potassium salts may be dangerous in patients who manifest bradycardia or heart block due to digoxin (unless primarily related to supraventricular tachycardia) and in the setting of massive digitalis overdosage (see Massive Digitalis Overdosage subsection). Massive Digitalis Overdosage Manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart block. The administration of more than 10 mg of digoxin in a previously healthy adult, or more than 4 mg in a previously healthy child, or a steady-state serum concentration greater than 10 ng/mL often results in cardiac arrest. Digoxin Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a massive overdose. The decision to administer Digoxin Immune Fab (Ovine) to a patient who has ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity should depend on the likelihood that life-threatening toxicity will occur (see above). Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation. Emesis or gastric lavage may be indicated especially if ingestion has occurred within 30 minutes of the patient’s presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents more than 2 hours after ingestion or already has toxic manifestations, it may be unsafe to induce vomiting or attempt passage of a gastric tube, because such maneuvers may induce an acute vagal episode that can worsen digitalis-related arrhythmias. Severe digitalis intoxication can cause a massive shift of potassium from inside to outside the cell, leading to life-threatening hyperkalemia. The administration of potassium supplements in the setting of massive intoxication may be hazardous and should be avoided. Hyperkalemia caused by massive digitalis toxicity is best treated with Digoxin Immune Fab (Ovine); initial treatment with glucose and insulin may also be required if hyperkalemia itself is acutely life-threatening.

DESCRIPTION

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term“digitalis” is used to designate the whole group of glycosides. The glycosides are composed of two portions: a sugar and a cardenolide (hence “glycosides”). Digoxin has the chemical name: 3B-[(O-2,6-Dideoxy-B-D-ribo-hexopyranosyl-(1-4)-O-2,6-dideoxy-B-D-ribo-hexopyranosyl- (1-4)-2,6-dideoxy-B-D-ribo-hexopyranosyl)oxy]-12B,14-dihydroxy-5B-card-20(22)-enolide, and the following structural formula: Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. Digoxin Injection is a sterile solution for slow intravenous or deep intramuscular injection. Each mL contains digoxin 250 mcg (0.25 mg), alcohol 0.1 mL, propylene glycol 0.4 mL, dibasic sodium phosphate, anhydrous 3 mg and citric acid, anhydrous 0.8 mg in Water for Injection. pH 6.7-7.3; citric acid and/or sodium phosphate added, if necessary, for pH adjustment. Dilution is not required. Formula

HOW SUPPLIED

Digoxin Injection, USP is available as: 500 mcg/2 mL (250 mcg/mL) ampuls packaged in 25s (NDC 0641-1410-35) Storage Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689. Manufactured by: HIKMA FARMACEUTICA (PORTUGAL), S.A. Estrada do Rio da Mo, 8, 8A e 8B – Fervenca – 2705-906 Terrugem SNT, PORTUGAL Distributed by: WEST-WARD PHARMACEUTICALS Eatontown, NJ 07724 USA Revised January 2012 462-636-00 PIN299-WES/1

INDICATIONS AND USAGE

Heart Failure Digoxin is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified. Atrial Fibrillation Digoxin is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

DOSAGE AND ADMINISTRATION

General Recommended dosages of digoxin may require considerable modification because of individual sensitivity of the patient to the drug, the presence of associated conditions, or the use of concurrent medications. Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred. If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage. No more than 500 mcg (2 mL) should be injected into a single site. Digoxin Injection can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate use of the diluted product is recommended. If tuberculin syringes are used to measure very small doses, one must be aware of the problem of inadvertent overadministration of digoxin. The syringe should not be flushed with the parenteral solution after its contents are expelled into an indwelling vascular catheter. Slow infusion of Digoxin Injection is preferable to bolus administration. Rapid infusion of digitalis glycosides has been shown to cause systemic and coronary arteriolar constriction, which may be clinically undesirable. Caution is thus advised and Digoxin Injection should probably be administered over a period of 5 minutes or longer. Mixing of Digoxin Injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. In selecting a dose of digoxin, the following factors must be considered: 1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight. 2. The patient’s renal function, preferably evaluated on the basis of estimated creatinine clearance. 3. The patient’s age. Infants and children require different doses of digoxin than adults. Also, advanced age may be indicative of diminished renal function even in patients with normal serum creatinine concentration (i.e., below 1.5 mg/dL). 4. Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin (see PRECAUTIONS). Serum Digoxin Concentrations In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging from 0.8 to 2 ng/mL. However, digoxin may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicity have serum digoxin concentrations greater than 2 ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2 ng/mL, values below 2 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin therapy. Rarely, there are patients who are unable to tolerate digoxin at serum concentrations below 0.8 ng/mL. Consequently, the serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug. To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities: 1. Analytical problems in the assay procedure. 2. Inappropriate serum sampling time. 3. Administration of a digitalis glycoside other than digoxin. 4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the sensitivity of the patient to digoxin. 5. Serum digoxin concentration may decrease acutely during periods of exercise without any associated change in clinical efficacy due to increased binding of digoxin to skeletal muscle. Heart Failure Adults Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body. 1. If rapid digitalization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose. 2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks. Rapid Digitalization with a Loading Dose Digoxin Injection is frequently used to achieve rapid digitalization, with conversion to digoxin tablets or digoxin capsules for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see Table 1, CLINICAL PHARMACOLOGY, Pharmacokinetics and dosing Table 5 below). Intramuscular injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated. Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) [see PRECAUTIONS]. The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given. A single initial intravenous dose of 400 to 600 mcg (0.4 to 0.6 mg) of Digoxin Injection usually produces a detectable effect in 5 to 30 minutes that becomes maximal in 1 to 4 hours. Additional doses of 100 to 300 mcg (0.1 to 0.3 mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of Digoxin Injection that a 70-kg patient requires to achieve 8- to 12-mcg/kg peak body stores is 600 to 1000 mcg (0.6 to 1 mg). Maintenance Dosing The doses of oral digoxin used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the digoxin dose has been generally titrated according to the patient’s age, lean body weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response. In a subset of approximately 1800 patients enrolled in the DIG trial (wherein dosing was based on an algorithm similar to that in Table 5) the mean (±SD) serum digoxin concentrations at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively. The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use: Maintenance Dose = Peak Body Stores (i.e., Loading Dose) x % Daily Loss/100 Where: % Daily Loss = 14 + Ccr/5 (Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area.) Table 5 provides average daily maintenance dose requirements of Digoxin Injection for patients with heart failure based upon lean body weight and renal function: Lean Body Weight Corrected Ccr kg 50 60 70 80 90 100 Number of Days Before Steady State Achieved‡ (mL/min per 70 kg)† lb 110 132 154 176 198 220 0 75§ 75 100 100 125 150 22 10 75 100 100 125 150 150 19 20 100 100 125 150 150 175 16 30 100 125 150 150 175 200 14 40 100 125 150 175 200 225 13 50 125 150 175 200 225 250 12 60 125 150 175 200 225 250 11 70 150 175 200 225 250 275 10 80 150 175 200 250 275 300 9 90 150 200 225 250 300 325 8 100 175 200 250 275 300 350 7 * Daily maintenance doses have been rounded to the nearest 25-mcg increment † Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. Note: This equation cannot be used for estimating creatinine clearance in infants or children. ‡ If no loading dose administered § 75 mcg = 0.075 mg EXAMPLE: Based on the above table, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 mL/min should be given a dose of 175 mcg (0.175 mg) daily of Digoxin Injection. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11 days Infants and Children See the full prescribing information for pediatric digoxin injection (not available from West-Ward) for specific recommendations. It cannot be overemphasized that dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient. Atrial Fibrillation Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects. Data are not available to establish the appropriate resting or exercise target rates that should be achieved. Dosage Adjustment When Changing Preparations The difference in bioavailability between injectable digoxin and oral digoxin must be considered when changing patients from one dosage form to another (see Table 1 in CLINICAL PHARMACOLOGY, Pharmacokinetics). Intramuscular injection of digoxin is extremely painful and offers no advantage unless other routes of administration are contraindicated. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Sulfur 50 MG/ML Topical Solution

Generic Name: SULFUR, BENZOYL PEROXIDE, SALICYLIC ACID

Brand Name: Acne Clearning Treatment Face

Substance Name(s):
SALICYLIC ACID
SULFUR
BENZOYL PEROXIDE

WARNINGS

Warnings: For external use only. Do not use if you have sensitive skin and/or are sensitive to [active ingredient] When using this product skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time. If irritation occurs, only use one topical acne medication at a time avoid unnecessary sun exposure and use sun screen, Acne Clearing Moisture with SPF 45 skin irritation may occur, characterized by redness, burning, itching, peeling, and possibly swelling. Irritation may be reduced by using the product less frequently or in a lower concentration Stop use and ask a doctor if irritation becomes severe

INDICATIONS AND USAGE

Directions: Acne Clearing Cleanser Acne Clearing Tonic Acne Clearing Treatment 101

INACTIVE INGREDIENTS

Ingredients: Purified Water, Ethyl Alcohol, Hamammelis Extract, Chamomile Extract, Salicyl Alcohol, Ethhylene Glycol, Propylene Glycol, Dodecyl Benzene Sulfonate, EDTA, Methylparaben, Propylparaben. Purified Water, Sulfer, Catalase, Aqueous extract of arnica, Glycerin, Cetyl Alcohol, Ceteareth-12, Bromelain, Ultrez 21, Mineral Oil, Ethhylene Glycol, Propylene Glycol, Sodium Ascorbyl Phosphate, Triethanolamine, Ascorbic Acid, Dodecyl Benzene Sulfonate, Peppermint oil, Piperine, Mint Base, EDTA, BHT, BHA, Methylparaben, Propylparaben.Purified Water, Sulfer, Catalase, Aqueous extract of arnica, Glycerin, Cetyl Alcohol, Ceteareth-12, Bromelain, Ultrez 21, Mineral Oil, Ethhylene Glycol, Propylene Glycol, Sodium Ascorbyl Phosphate, Triethanolamine, Ascorbic Acid, Dodecyl Benzene Sulfonate, Peppermint oil, Piperine, Mint Base, EDTA, BHT, BHA, Methylparaben, Propylparaben.

PURPOSE

Uses:For the management of acne helps clear up acne blemishes, black heads, helps prevent the development of new acne pimples penetrates pores to reduce the number of acne pimples, white heads and black heads help keep skin clear of new acne pimples, white heads and black heads helps prevent new acne pimples, white heads and black heads from forming help prevent the development of new pimples, white heads and black heads

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.If swallowed get medical help or contact a Poison Control center immediately.

DOSAGE AND ADMINISTRATION

Three Bottles Acne Clearing Cleanser 240 mL Acne Clearing Tonic 120 mL Acne Clearing Treatment 101 60 mL

ACTIVE INGREDIENTS

Active Ingredient………………………………Purpose Sulphur 5%………………………………………..Acne medication Benzoyl Peroxide 2.5%………………………….Acme medication Salicylic acid 2%………………………………….Acne medication

Revonto 0.333 MG/ML Injectable Solution

WARNINGS

The use of Revonto in the management of malignant hyperthermia crisis is not a substitute for previously known supportive measures. These measures must be individualized, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance. Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. dantrolene sodium preoperatively should have vital signs monitored. If patients judged malignant hyperthermia susceptible are administered intravenous or oral dantrolene sodium preoperatively, anesthetic preparation must still follow a standard malignant hyperthermia susceptible regimen, including the avoidance of known triggering agents. Monitoring for early clinical and metabolic signs of malignant hyperthermia is indicated because attenuation of malignant hyperthermia, rather than prevention, is possible. These signs usually call for the administration of additional i.v. dantrolene.

DRUG INTERACTIONS

Drug Interactions Dantrolene sodium is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect dantrolene sodium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide. Cardiovascular collapse in association with marked hyperkalemia has been reported in patients receiving dantrolene in combination with calcium channel blockers. It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, not be used together during the management of malignant hyperthermia crisis. Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.

OVERDOSAGE

Because Revonto must be administered at a low concentration in a large volume of fluid, acute toxicity of dantrolene sodium could not be assessed in animals. In 14-day (subacute) studies, the intravenous formulation of dantrolene sodium was relatively non-toxic to rats at doses of 10 mg/kg/day and 20 mg/kg/day. While 10 mg/kg/day in dogs for 14 days evoked little toxicity, 20 mg/kg/day for 14 days caused hepatic changes of questionable biologic significance. Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria. For acute overdosage, general supportive measures should be employed. Intravenous fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment should be at hand. Electrocardiographic monitoring should be instituted, and the patient carefully observed. The value of dialysis in dantrolene sodium overdose is not known.

DESCRIPTION

Revonto is a sterile, non-pyrogenic, lyophilized formulation of dantrolene sodium for injection. Revonto is supplied in 65 mL vials containing 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 ml sterile water for injection USP (without a bacteriostatic agent). Dantrolene sodium is classified as a direct-acting skeletal muscle relaxant. Chemically, dantrolene sodium is hydrated 1-[[[5-(4-nitrophenyl)-2-furanyl] methylene] amino]-2,4-imidazolidinedione sodium salt. The structural formula for the hydrated salt is: The hydrated salt contains approximately 15% water (3.5 moles) and has a molecular weight of 399. The anhydrous salt (dantrolene) has a molecular weight of 336. Chemical Structure

HOW SUPPLIED

Revonto (NDC 27505-003-68) is available in vials containing a sterile lyophilized mixture of 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent). Store unreconstituted product at 20-25° C (68-77° F) [see USP Controlled Room Temperature] and avoid prolonged exposure to light.

GERIATRIC USE

Geriatric Use Clinical studies of Revonto 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 reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

INDICATIONS AND USAGE

Revonto (dantrolene sodium for injection) is indicated, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages. Revonto should be administered by continuous rapid intravenous push as soon as the malignant hyperthermia reaction is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber, cyanosis and mottling of the skin, and, in many cases, fever). Revonto is also indicated preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.

PREGNANCY

Pregnancy Pregnancy Category C Dantrolene sodium has been shown to be embryocidal in the rabbit and has been shown to decrease pup survival in the rat when given at doses seven times the human oral dose. There are no adequate and well-controlled studies in pregnant women. Revonto® (dantrolene sodium for injection) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Dantrolene has been detected in human milk at low concentrations (less than 2 micrograms per milliliter) during repeat intravenous administration over 3 days. Because of the potential for serious adverse reactions in nursing infants from dantrolene, 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.

INFORMATION FOR PATIENTS

Information for Patients Based upon data in human volunteers, perioperatively, it is appropriate to tell patients who receive Revonto that symptoms of muscle weakness should be expected postoperatively (i.e. decrease in grip strength and weakness of leg muscles, especially walking down stairs). In addition, symptoms such as “lightheadedness” may be noted. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time. Caution is also indicated at meals on the day of administration because difficulty swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents. Hepatotoxicity seen with dantrolene sodium capsules: Dantrolene sodium has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to dantrolene sodium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to dantrolene sodium. Dantrolene sodium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with dantrolene sodium therapy.

DOSAGE AND ADMINISTRATION

As soon as the malignant hyperthermia reaction is recognized, all anesthetic agents should be discontinued; the administration of 100% oxygen is recommended. Revonto should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached. If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of Revonto should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual’s degree of susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crisis and initiation of treatment. Pediatric Dose Experience to date indicates that the dose of Revonto for pediatric patients is the same as for adults. Preoperatively Revonto and/or dantrolene sodium capsules may be administered preoperatively to patients judged malignant hyperthermia susceptible as part of the overall patient management to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia. Revonto The recommended prophylactic dose of Revonto is 2.5 mg/kg, starting approximately 1.25 hours before anticipated anesthesia and infused over approximately 1 hour. This dose should prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia provided that the usual precautions, such as avoidance of established malignant hyperthermia triggering agents, are followed. Additional Revonto may be indicated during anesthesia and surgery because of the appearance of early clinical and/or blood gas signs of malignant hyperthermia or because of prolonged surgery (see also CLINCAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS). Additional doses must be individualized. Oral Administration of Dantrolene Sodium Capsules Administer 4 to 8 mg/kg/day of oral dantrolene sodium in three or four divided doses for 1 or 2 days prior to surgery, with the last dose being given with a minimum of water approximately 3 to 4 hours before scheduled surgery. Adjustment can usually be made within the recommended dosage range to avoid incapacitation (weakness, drowsiness, etc.) or excessive gastrointestinal irritation (nausea and/or vomiting). See also the package insert for dantrolene sodium capsules. Post Crisis Follow-Up Dantrolene sodium capsules, 4 to 8 mg/kg/day, in four divided doses should be administered for 1 to 3 days following a malignant hyperthermia crisis to prevent recurrence of the manifestations of malignant hyperthermia. Intravenous dantrolene sodium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when oral dantrolene sodium administration is not practical. The i.v. dose of dantrolene sodium in the postoperative period must be individualized, starting with 1 mg/kg or more as the clinical situation dictates.

Cromolyn Sodium 20 MG/ML Oral Solution

Generic Name: CROMOLYN SODIUM

Brand Name: Gastrocrom

Substance Name(s):
CROMOLYN SODIUM

WARNINGS

: The recommended dosage should be decreased in patients with decreased renal or hepatic function. Severe anaphylactic reactions may occur rarely in association with cromolyn sodium administration.

DRUG INTERACTIONS

Drug Interaction During Pregnancy: In pregnant mice, cromolyn sodium alone did not cause significant increases in resorptions or major malformations at subcutaneous doses up to 540 mg/kg (approximately equal to the maximum recommended daily oral dose in adults on a mg/m2 basis). Isoproterenol alone increased both resorptions and major malformations (primarily cleft palate) at a subcutaneous dose of 2.7 mg/kg (approximately 7 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). The incidence of major malformations increased further when cromolyn sodium at a subcutaneous dose of 540 mg/kg was added to isoproterenol at a subcutaneous dose of 2.7 mg/kg. No such interaction was observed in rats or rabbits.

DESCRIPTION

: Each 5 mL ampule of GASTROCROM contains 100 mg cromolyn sodium, USP, in purified water. Cromolyn sodium is a hygroscopic, white powder having little odor. It may leave a slightly bitter aftertaste. GASTROCROM (cromolyn sodium, USP) Oral Concentrate is clear, colorless, and sterile. It is intended for oral use. Chemically, cromolyn sodium is disodium 5,5’-[(2-hydroxytrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxylate]. The empirical formula is C23H14Na2O11; the molecular weight is 512.34. Its chemical structure is: Pharmacologic Category: Mast cell stabilizer Therapeutic Category: Antiallergic ChemicalStructure

CLINICAL STUDIES

: Four randomized, controlled clinical trials were conducted with GASTROCROM in patients with either cutaneous or systemic mastocytosis; two of which utilized a placebo-controlled crossover design, one utilized an active-controlled (chlorpheniramine plus cimetidine) crossover design, and one utilized a placebo-controlled parallel group design. Due to the rare nature of this disease, only 36 patients qualified for study entry, of whom 32 were considered evaluable. Consequently, formal statistical analyses were not performed. Clinically significant improvement in gastrointestinal symptoms (diarrhea, abdominal pain) were seen in the majority of patients with some improvement also seen for cutaneous manifestations (urticaria, pruritus, flushing) and cognitive function. The benefit seen with GASTROCROM 200 mg QID was similar to chlorpheniramine (4 mg QID) plus cimetidine (300 mg QID) for both cutaneous and systemic symptoms of mastocytosis. Clinical improvement occurred within 2-6 weeks of treatment initiation and persisted for 2-3 weeks after treatment withdrawal. GASTROCROM did not affect urinary histamine levels or peripheral eosinophilia, although neither of these variables appeared to correlate with disease severity. Positive clinical benefits were also reported for 37 of 51 patients who received GASTROCROM in United States and foreign humanitarian programs.

HOW SUPPLIED

: GASTROCROM Oral Concentrate is an unpreserved, colorless solution supplied in a low density polyethylene plastic unit dose ampule with 8 ampules per foil pouch. Each 5 mL ampule contains 100 mg cromolyn sodium, USP, in purified water. NDC 0037-0678-08 8 ampules x 5 mL NDC 0037-0678-96 96 ampules x 5 mL GASTROCROM Oral Concentrate should be stored between 15°-30°C (59°-86°F) and protected from light. Do not use if it contains a precipitate or becomes discolored. Keep out of the reach of children. Store ampules in foil pouch until ready for use. Distributed by: Meda Pharmaceuticals® Somerset, New Jersey 08873-4120 MEDA PHARMACEUTICALS and GASTROCROM are registered trademarks of Meda AB or a related entity. © 2013 Meda Pharmaceuticals Inc. Rev. 4/2013 STW-ME7096-642R00 IN-0678-01

GERIATRIC USE

Geriatric Use: Clinical studies of GASTROCROM 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.

INDICATIONS AND USAGE

: GASTROCROM is indicated in the management of patients with mastocytosis. Use of this product has been associated with improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching in some patients.

PEDIATRIC USE

Pediatric Use: In adult rats no adverse effects of cromolyn sodium were observed at oral doses up to 6144 mg/kg (approximately 25 times the maximum recommended daily oral dose in adults on a mg/m2 basis). In neonatal rats, cromolyn sodium increased mortality at oral doses of 1000 mg/kg or greater (approximately 9 times the maximum recommended daily oral dose in infants on a mg/m2 basis) but not at doses of 300 mg/kg or less (approximately 3 times the maximum recommended daily oral dose in infants on a mg/m2 basis). Plasma and kidney concentrations of cromolyn after oral administration to neonatal rats were up to 20 times greater than those in older rats. In term infants up to six months of age, available clinical data suggest that the dose should not exceed 20 mg/kg/day. The use of this product in pediatric patients less than two years of age should be reserved for patients with severe disease in which the potential benefits clearly outweigh the risks.

PREGNANCY

Pregnancy: Pregnancy Category B. In reproductive studies in pregnant mice, rats, and rabbits, cromolyn sodium produced no evidence of fetal malformations at subcutaneous doses up to 540 mg/kg in mice (approximately equal to the maximum recommended daily oral dose in adults on a mg/m2 basis) and 164 mg/kg in rats (less than the maximum recommended daily oral dose in adults on a mg/m2 basis) or at intravenous doses up to 485 mg/kg in rabbits (approximately 4 times the maximum recommended daily oral dose in adults on a mg/m2 basis). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GASTROCROM is administered to a nursing woman.

DOSAGE AND ADMINISTRATION

: NOT FOR INHALATION OR INJECTION. SEE DIRECTIONS FOR USE. The usual starting dose is as follows: Adults and Adolescents (13 Years and Older): Two ampules four times daily, taken one-half hour before meals and at bedtime. Children 2-12 Years: One ampule four times daily, taken one-half hour before meals and at bedtime. Pediatric Patients Under 2 Years: Not recommended. If satisfactory control of symptoms is not achieved within two to three weeks, the dosage may be increased but should not exceed 40 mg/kg/day. Patients should be advised that the effect of GASTROCROM therapy is dependent upon its administration at regular intervals, as directed. Maintenance Dose: Once a therapeutic response has been achieved, the dose may be reduced to the minimum required to maintain the patient with a lower degree of symptomatology. To prevent relapses, the dosage should be maintained. Administration: GASTROCROM should be administered as a solution at least 1/2 hour before meals and at bedtime after preparation according to the following directions: Break open ampule(s) and squeeze liquid contents of ampule(s) into a glass of water. Stir solution. Drink all of the liquid.

Spironolactone 50 MG Oral Tablet

Generic Name: SPIRONOLACTONE

Brand Name: Spironolactone

Substance Name(s):
SPIRONOLACTONE

WARNINGS

Potassium supplementation. Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with spironolactone therapy. Excessive potassium intake may cause hyperkalemia in patients receiving spironolactone (see Precautions: General). Spironolactone should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when spironolactone is given concomitantly with these drugs. Hyperkalemia in patients with severe heart failure. Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving spironolactone. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. The Randomized Spironolactone Evaluation Study excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of spironolactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See CLINICAL STUDIES, Severe heart failure, and DOSAGE AND ADMINISTRATION, Severe heart failure.) Spironolactone should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics (see Precautions: Drug Interactions).

OVERDOSAGE

The oral LD50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, spironolactone should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

DESCRIPTION

Spironolactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ- lactone acetate, which has the following structural formula: Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, croscarmellose sodium, flavor, hypromellose, iron oxide magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, polyvinyl alcohol, povidone, talc, titanium dioxide, and triacetin. The 50 mg tablet also contains D&C yellow # 10 and FD&C yellow # 6. 9943249f-figure-01

CLINICAL STUDIES

Severe heart failure: A Randomized Spironolactone Evaluation Study was conducted. The Randomized Spironolactone Evaluation Study was a multinational, double-blind study in patients with an ejection fraction of ≤ 35%, a history of New York Heart Association (NYHA) class IV heart failure within 6 months, and class III-IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of > 2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of > 5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Follow-up visits and laboratory measurements (including serum potassium and creatinine) were performed every four weeks for the first 12 weeks, then every 3 months for the first year, and then every 6 months thereafter. Dosing could be withheld for serious hyperkalemia or if the serum creatinine increased to >4.0 mg/dL. Patients who were intolerant of the initial dosage regimen had their dose decreased to one tablet every other day at one to four weeks. Patients who were tolerant of one tablet daily at 8 weeks may have had their dose increased to two tablets daily at the discretion of the investigator. The Randomized Spironolactone Evaluation Study enrolled 1,663 patients (3% U.S.) at 195 centers in 15 countries between March 24, 1995, and December 31, 1996. The study population was primarily white (87%, with 7% black, 2% Asian, and 4% other), male (73%), and elderly (median age 67). The median ejection fraction was 0.26. Seventy percent were NYHA class III and 29% class IV. The presumed etiology of heart failure was ischemic in 55%, and non-ischemic in 45%. There was a history of myocardial infarction in 28%, of hypertension in 24%, and of diabetes in 22%. The median baseline serum creatinine was 1.2 mg/dL and the median baseline creatinine clearance was 57 mL/min. The mean daily dose at study end for the patients randomized to spironolactone was 26 mg. Concomitant medications included a loop diuretic in 100% of patients and an ACE inhibitor in 97%. Other medications used at any time during the study included digoxin (78%), anticoagulants (58%), aspirin (43%), and beta-blockers (15%). The primary endpoint for the Randomized Spironolactone Evaluation Study was time to all-cause mortality. The study was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. The survival curves by treatment group are shown in Figure 1. Figure 1. Survival by Treatment Group in the Randomized Spironolactone Evaluation Study Spironolactone reduced the risk of death by 30% compared to placebo (p < 0.001; 95% confidence interval 18% to 40%). Spironolactone reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure by 31% compared to placebo (p < 0.001; 95% confidence interval 18% to 42%). Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias or myocardial infarction) by 30% (p < 0.001 95% confidence interval 18% to 41%). Changes in NYHA class were more favorable with spironolactone: In the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (P <0.001). Mortality hazard ratios for some subgroups are shown in Figure 2. The favorable effect of spironolactone on mortality appeared similar for both genders and all age groups except patients younger than 55; there were too few non-whites enrolled in the Randomized Spironolactone Evaluation Study to draw any conclusions about differential effects by race. Spironolactone’s benefit appeared greater in patients with low baseline serum potassium levels and less in patients with ejection fractions <0.2. These subgroup analyses must be interpreted cautiously. Figure 2. Hazard Ratios of All-Cause Mortality by Subgroup the Randomized Spironolactone Evaluation Study Figure 2: The size of each box is proportional to the sample size as well as the event rate. ACEI denotes angiotensin-converting enzyme inhibitor, LVEF denotes left ventricular ejection fraction, Cr Clearance denotes creatinine clearance and Ser Creatinine denotes serum creatinine. 9943249f-figure-02 9943249f-figure-03

HOW SUPPLIED

Spironolactone Tablets, USP 25 mg are white, film-coated, round tablets, debossed “AN” above “511” on one side and plain on other side. Supplied in: Boxes of 10×10 UD 100 NDC 63739-544-10 Spironolactone Tablets, USP 50 mg are yellow, film-coated, round tablets, debossed “AN” bisect “514” on one side and plain on other side. Supplied in: Boxes of 10×10 UD 100 NDC 63739-545-10 Store at 20° to 25°C (68° to 77°F) (see USP Controlled Room Temperature). Dispense in a tight, light-resistant container. Manufactured by: Amneal Pharmaceuticals Hauppauge, NY 11788 Distributed by: McKesson Packaging Services a business unit of McKesson Corporation 7101 Weddington Rd., Concord, NC 28027 Issued March 2011 IS-4010694

INDICATIONS AND USAGE

Spironolactone is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial. Short-term preoperative treatment of patients with primary hyperaldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). Edematous conditions for patients with: Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. Spironolactone is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate. Cirrhosis of the liver accompanied by edema and/or ascites: Spironolactone levels may be exceptionally high in this condition. Spironolactone is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium. The nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response. Essential hypertension Usually in combination with other drugs, spironolactone is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. Spironolactone is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate. Severe heart failure (NYHA class III – IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy. Usage in Pregnancy The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Spironolactone is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

BOXED WARNING

WARNING Spironolactone Tablets have been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Spironolactone Tablets should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided.

DOSAGE AND ADMINISTRATION

Primary hyperaldosteronism. Spironolactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets. Long test: Spironolactone is administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Short test: Spironolactone is administered at a daily dosage of 400 mg for four days. If serum potassium increases during spironolactone administration but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, spironolactone may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient. Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). An initial daily dosage of 100 mg of spironolactone administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, spionolactone should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to spironolactone has not occurred, a second diuretic which acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of spironolactone when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of spironolactone should remain unchanged when other diuretic therapy is added. Essential hypertension. For adults, an initial daily dosage of 50 to 100 mg of spironolactone administered in either single or divided doses is recommended. Spironolactone may also be given with diuretics which act more proximally in the renal tubule or with other antihypertensive agents. Treatment with spironolactone should be continued for at least two weeks, since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient. Hypokalemia. Spironolactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate. Severe heart failure (NYHA class III – IV). Treatment should be initiated with spironolactone 25 mg once daily if the patient’s serum potassium is ≤5.0 mEq/L and the patient’s serum creatinine is ≤ 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once-daily dose may have their dosage reduced to 25 mg every other day. SEE WARNINGS: Hyperkalemia in patients with severe heart failure for advice on monitoring serum potassium and serum creatinine.

potassium chloride 600 MG Extended Release Oral Capsule

Generic Name: POTASSIUM CHLORIDE

Brand Name: Potassium Chloride

Substance Name(s):
POTASSIUM CHLORIDE

WARNINGS

: (see ) Hyperkalemia OVERDOSAGE In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustments. Interaction with Potassium-Sparing Diuretics Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (e.g., spironolactone, triamterene, or amiloride), since the simultaneous administration of these agents can produce severe hyperkalemia. Interaction with Angiotensin Converting Enzyme Inhibitors Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring. Gastrointestinal Lesions Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric coated preparations of potassium chloride are associated with an increased frequency of small bowel lesions (40 – 50 per 100,000 patient years) compared to sustained-release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric coated products is not available. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are microencapsulated capsules formulated to provide a controlled rate of release of microencapsulated potassium chloride and thus to minimize the possibility of high local concentration of potassium near the gastrointestinal wall. Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid oral potassium chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (i.e., 96 mEq per day in divided doses of potassium chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these findings to the usual conditions (i.e., non-fasting, no anticholinergic agent, smaller doses) under which controlled-release potassium chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq should be discontinued immediately and the possibility of ulceration, obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occur. Metabolic Acidosis Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

DRUG INTERACTIONS

Potassium-sparing diuretics, angiotensin converting enzyme inhibitors (see ). Drug Interactions WARNINGS

OVERDOSAGE

: The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see and ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of ST segment, and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L). CONTRAINDICATIONS WARNINGS Treatment measures for hyperkalemia include the following: (1) elimination of foods and medications containing potassium and of any agents with potassium-sparing properties; (2) intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10 to 20 units of crystalline insulin per 1,000 mL; (3) correction of acidosis, if present, with intravenous sodium bicarbonate; (4) use of exchange resins, hemodialysis, or peritoneal dialysis. In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity. The extended release feature means that absorption and toxic effects may be delayed for hours. Consider standard measures to remove any unabsorbed drug.

DESCRIPTION

: Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are oral dosage forms of microencapsulated potassium chloride containing 600 and 750 mg, respectively, of potassium chloride USP equivalent to 8 and 10 mEq of potassium. Dispersibility of potassium chloride (KCI) is accomplished by microencapsulation and a dispersing agent. The resultant flow characteristics of the KCI microcapsules and the controlled release of K+ ions by the microcapsular membrane are intended to avoid the possibility that excessive amounts of KCI can be localized at any point on the mucosa of the gastrointestinal tract. Each crystal of KCI is microencapsulated by a process with an insoluble polymeric coating which functions as a semi-permeable membrane; it allows for the controlled release of potassium and chloride ions over an eight-to-ten-hour period. Fluids pass through the membrane and gradually dissolve the potassium chloride within the micro-capsules. The resulting potassium chloride solution slowly diffuses outward through the membrane. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are electrolyte replenishers. The chemical name of the active ingredient is potassium chloride and the structural formula is KCI. Potassium chloride USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol. The inactive ingredients are, ethylcellulose, FD&C blue #1, FD&C red # 40, gelatin, sodium lauryl sulfate, titanium oxide and triacetin.

HOW SUPPLIED

: NDC:68151-0609-0 in a PACKAGE of 1 CAPSULE, EXTENDED RELEASES

GERIATRIC USE

Clinical studies of Potassium Chloride Extended-release Capsules 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. Geriatric Use This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

INDICATIONS AND USAGE

: BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxications, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop e.g., digitalized patients or patients with significant cardiac arrhythmias, hepatic cirrhosis with ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, and certain diarrheal states. The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

PEDIATRIC USE

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

PREGNANCY

Animal reproduction studies have not been conducted with Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity. Pregnancy: Teratogenic Effects: Category C

NUSRING MOTHERS

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of potassium chloride supplementation should have little or no effect on the level in human milk. Nursing Mothers

INFORMATION FOR PATIENTS

Information For Patients Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other suitable liquid. To take each dose without crushing, chewing, or sucking the capsules. To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations. To check with the physician if there is trouble swallowing capsules or if the capsules seem to stick in the throat. To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

DOSAGE AND ADMINISTRATION

: The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store. Dosage must be adjusted to the individual needs of each patients. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40 to 100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose. Because of the potential for gastric irritation (see ), Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq should be taken with meals and with a full glass of water or other liquid. WARNINGS Patients who have difficulty swallowing capsules may sprinkle the contents of the capsule onto a spoonful of soft food. The soft food, such as applesauce or pudding, should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the microcapsules. The food used should not be hot and should be soft enough to be swallowed without chewing. Any microcapsule/food mixture should be used immediately and not stored for future use.

trametinib 0.5 MG (as trametinib dimethyl sulfoxide 0.5635 MG) Oral Tablet

Generic Name: TRAMETINIB

Brand Name: Mekinist

Substance Name(s):
TRAMETINIB DIMETHYL SULFOXIDE

DRUG INTERACTIONS

7 No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

DESCRIPTION

11 Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C26H23FIN5O4•C2H6OS with a molecular mass of 693.53. Trametinib dimethyl sulfoxide has the following chemical structure: Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media. MEKINIST (trametinib) tablets are supplied as 0.5 mg and 2 mg tablets for oral administration. Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. The inactive ingredients of MEKINIST tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), titanium dioxide. Trametinib chemical structure

CLINICAL STUDIES

14 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST as a Single Agent The safety and efficacy of MEKINIST were evaluated in an international, multicenter, randomized (2:1), open-label, active-controlled trial (Trial 1) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay. The median age for randomized patients was 54 years, 54% were male, greater than 99% were White, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (less than 1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST. Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with MEKINIST. Table 7 and Figure 1 summarize the PFS results. Table 7. Investigator-Assessed Progression-Free Survival and Confirmed Objective Response Results in Trial 1 †CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. aPike estimator. Investigator-Assessed Endpoints† MEKINIST N = 214 Chemotherapy N = 108 Progression-Free Survival Number of Events (%) 117 (55%) 77 (71%) Progressive Disease 107 (50%) 70 (65%) Death 10 (5%) 7 (6%) Median, months (95% CI) 4.8 (4.3, 4.9) 1.5 (1.4, 2.7) HRa (95% CI) 0.47 (0.34, 0.65) P value (log-rank test) P<0.0001 Confirmed Tumor Responses Objective Response Rate 22% 8% (95% CI) (17, 28) (4, 15) CR, n (%) 4 (2%) 0 PR, n (%) 43 (20%) 9 (8%) Duration of Response Median, months (95% CI) 5.5 (4.1, 5.9) NR (3.5, NR) Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in Trial 1 In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis. MEKINIST with Dabrafenib The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (Trial 2). Trial 2 compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level (greater than the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR). In Trial 2, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, >99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma. Trial 2 demonstrated statistically significant improvements in PFS and OS (see Table 8 and Figure 2). Table 8. Efficacy Results in Trial 2 † CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. a PFS and ORR were assessed by investigator. bBased on stratified log-rank test Endpoint† MEKINIST plus Dabrafenib N=211 Dabrafenib plus Placebo N=212 Progression-Free Survival (PFS) a Number of events (%) 102 (48%) 109 (51%) Median, months (95% CI) 9.3 (7.7, 11.1) 8.8 (5.9, 10.9) HR (95% CI) 0.75 (0.57, 0.99) P valueb 0.035 Overall Survival Number of deaths (%) 99 (47% ) 123 (58%) Median, months (95% CI) 25.1 (19.2, NR) 18.7 (15.2, 23.1) HR (95% CI) 0.71 (0.55, 0.92) P valueb 0.01 Overall Response Rate (ORR) a ORR, % (95% CI) 66 (60, 73) 51 (44, 58) P value <0.001 CR, % 10 8 PR, % 56 42 Median duration of response, months (95% CI) 9.2 (7.4, NR) 10.2 (7.5, NR) Figure 2. Kaplan Meier Curves of Overall Survival in Trial 2 Kaplan-Meier Chart Figure 2 14.2 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multicenter, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 63% were male, all were White, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient achieved a confirmed partial or complete response as determined by the clinical investigators.

HOW SUPPLIED

16 /STORAGE AND HANDLING 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0078-0666-15). 2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0078-0668-15). Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes.

RECENT MAJOR CHANGES

Warnings and Precautions (5.3) 2/2017

GERIATRIC USE

8.5 Geriatric Use Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Of the 559 patients randomized to receive MEKINIST plus dabrafenib in clinical trials, 24% were aged 65 years and older and 6% patients aged 75 years and older. No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in elderly patients as compared to younger patients. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in elderly patients as compared to younger patients.

DOSAGE FORMS AND STRENGTHS

3 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face. Tablets: 0.5 mg and 2 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo. Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

INDICATIONS AND USAGE

1 MEKINIST® is indicated, as a single agent or in combination with dabrafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Clinical Studies (14.1)]. Limitation of use: MEKINIST is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy [see Clinical Studies (14.2)]. MEKINIST is a kinase inhibitor indicated, as a single agent or in combination with dabrafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. (1, 14.1) Limitation of use: MEKINIST is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy. (1)

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been established in pediatric patients. Juvenile Animal Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.

PREGNANCY

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose [see Data]. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Review the Full Prescribing Information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib. New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy while on therapy, and following discontinuation of treatment. (5.1, 2.3) Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. (5.2, 2.3) Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. (5.3). Venous thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST. (5.4, 2.3). Cardiomyopathy: Assess LVEF before treatment, after one month of treatment, then every 2 to 3 months thereafter. (5.5, 2.3) Ocular toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. (5.6, 2.3). Interstitial lung disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.3) Serious febrile reactions: Can occur when MEKINIST is used with dabrafenib. (5.8, 2.3) Serious skin toxicity: Monitor for skin toxicities and for secondary infections. Discontinue MEKINIST for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. (5.9, 2.3) Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. (5.10, 2.3) Embryo-fetal toxicity: MEKINIST can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.11, 8.1, 8.3) 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is administered with dabrafenib. Cutaneous Malignancies In Trial 2, the incidence of basal cell carcinoma in patients receiving MEKINIST and dabrafenib was 3.3% (7/209) compared with 6% (13/211) in patients receiving single-agent dabrafenib. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the MEKINIST plus dabrafenib arm and was 4.4 months (range: 29 days to 16.5 months) in the dabrafenib arm. Among the 7 patients receiving MEKINIST with dabrafenib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3). Cutaneous squamous cell carcinomas (cuSCC) and keratoacanthoma occurred in 3% of patients receiving MEKINIST and dabrafenib and 10% of patients receiving single-agent dabrafenib. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the MEKINIST plus dabrafenib arm and was 2 months (range: 9 days to 20.9 months) in the dabrafenib arm. New primary melanoma occurred in 0.5% (1/209) of patients receiving MEKINIST and dabrafenib and in 1.9% (4/211) of patients receiving dabrafenib alone. Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST are recommended in patients who develop new primary cutaneous malignancies. Non-Cutaneous Malignancies Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving MEKINIST plus dabrafenib and in 2.8% (6/211) of patients receiving single-agent dabrafenib. Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies [see Dosage and Administration (2.3)]. 5.2 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. In Trial 2, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib was 19% (40/209) compared with 15% (32/211) of patients receiving dabrafenib alone. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving MEKINIST in combination with dabrafenib compared with 2.8% (6/211) of patients receiving single-agent dabrafenib. In Trial 2, 1.4% (3/209) of patients receiving MEKINIST and dabrafenib developed fatal intracranial hemorrhage compared with none of the patients receiving single-agent dabrafenib alone. Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level. 5.3 Colitis and Gastrointestinal Perforation Colitis and gastrointestinal perforation can occur with MEKINIST. Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking MEKINIST as a single-agent and when administered with dabrafenib. Across clinical trials of MEKINIST administered as a single agent (N = 329) and MEKINIST administered with dabrafenib (N = 559), colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients. Monitor patients closely for colitis and gastrointestinal perforations. 5.4 Venous Thromboembolism Venous thromboembolism can occur with MEKINIST. In Trial 2, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% (6/209) of patients receiving MEKINIST and dabrafenib compared with 0.9% (2/211) of patients receiving single-agent dabrafenib. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level [see Dosage and Administration (2.3)]. 5.5 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST. In clinical trials of MEKINIST, all patients were required to have an echocardiogram at baseline to document normal LVEF and repeat echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. In Trial 1, cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/211) of patients receiving MEKINIST; no chemotherapy-treated patient in Trial 1 developed cardiomyopathy. The median time to onset of cardiomyopathy in patients receiving MEKINIST was 2.1 months (range: 16 days to 5.1 months); cardiomyopathy was identified within the first month of receiving MEKINIST in five of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/211) and/or dose reduction (7/211) of MEKINIST. Cardiomyopathy resolved in 10 of these 14 (71%) patients. Across clinical trials of MEKINIST as a single agent (N = 329), 11% of patients developed evidence of cardiomyopathy [decrease in LVEF below institutional lower limits of normal (LLN) with an absolute decrease in LVEF ≥10% below baseline] and 5% demonstrated a decrease in LVEF below institutional LLN with an absolute decrease in LVEF of ≥20% below baseline. In Trial 2, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline) occurred in 6% (12/206) of patients receiving MEKINIST and dabrafenib and in 2.9% (6/207) of patients receiving single-agent dabrafenib. The median time to onset of cardiomyopathy in patients receiving MEKINIST and dabrafenib was 8.2 months (range: 28 days to 24.9 months); cardiomyopathy was identified within the first month of receiving MEKINIST and dabrafenib in 2 of these 12 patients. In patients receiving MEKINIST and dabrafenib, cardiomyopathy resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Cardiomyopathy resolved in 10 of 12 patients receiving MEKINIST and dabrafenib. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold MEKINIST for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction of >20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST [see Dosage and Administration (2.3)]. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO) Across all clinical trials with MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO [see Dosage and Administration (2.3)]. Retinal Pigment Epithelial Detachment (RPED) Retinal pigment epithelial detachment (RPED) can occur with MEKINIST administration. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In Trial 1 and Trial 2, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown. Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks [see Dosage and Administration (2.3)]. 5.7 Interstitial Lung Disease In clinical trials of single-agent MEKINIST (N = 329), ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2.4% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 5.3 months (range: 2 to 5.7 months). In Trial 2, 1.0% (2/209) of patients receiving MEKINIST and dabrafenib developed pneumonitis compared with none of the patients receiving single-agent dabrafenib. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis [see Dosage and Administration (2.3)]. 5.8 Serious Febrile Reactions Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib. Fever (serious and non-serious) occurred in 57% (119/209) of patients receiving MEKINIST and dabrafenib and in 33% (69/211) of patients receiving dabrafenib alone. The median time to initial onset of fever was 1.2 months (range: 1 day to 23.5 months) with a median duration of fever of 3 days (range: 1 day to 1.7 months) on the MEKINIST plus dabrafenib arm compared with a median time to initial onset of fever of 20 days (range: 1 day to 22.9 months) and median duration of fever of 3 days (range: 1 day to 1.9 months) on the dabrafenib arm. Approximately one-half of the patients who received MEKINIST and dabrafenib and experienced pyrexia had three or more discrete episodes. Across clinical trials of MEKINIST administered with dabrafenib, serious febrile reactions or fever of any severity complicated by severe rigors/chills hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving MEKINIST and dabrafenib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients. Withhold MEKINIST for fever higher than 104ºF or for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension renal failure, or severe chills/rigors, and there is no evidence of active infection. 5.9 Serious Skin Toxicity Serious skin toxicity can occur with MEKINIST. In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients receiving MEKINIST and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with MEKINIST. Skin toxicity requiring hospitalization occurred in 6% of patients treated with MEKINIST, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to initial onset of skin toxicity in patients treated with MEKINIST was 15 days (range: 1 day to 7.3 months) and median time to resolution of skin toxicity was 1.6 months (range: 1 day to 9.3 months). Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was required in 1% of patients with skin toxicity. In Trial 2, the overall incidence of any skin toxicity was 55% for patients receiving MEKINIST and dabrafenib compared with 55% for patients receiving single-agent dabrafenib. No serious or severe cases of skin toxicity occurred in patients treated with MEKINIST and dabrafenib. The median time to initial onset of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.9 months (range: 1 day to 22.1 months) and median time to resolution of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.2 months (range: 1 day to 24.4 months). Reductions in the dose of MEKINIST were required in 5% of patients receiving MEKINIST and dabrafenib and no patients required permanent discontinuation of MEKINIST for skin toxicity. Across clinical trials of MEKINIST administered with dabrafenib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients. Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)]. 5.10 Hyperglycemia Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy can occur when MEKINIST is administered with dabrafenib. In Trial 2, 27% (4/15) of patients with a history of diabetes who received MEKINIST and dabrafenib and 13% (2/16) of patients with a history of diabetes who received single-agent dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients receiving MEKINIST and dabrafenib, respectively, compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent dabrafenib. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia. 5.11 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1, 8.3)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the following: Confirmation of BRAF V600E or V600K mutation Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary to identify patients for whom treatment with MEKINIST is indicated [see Dosage and Administration (2.1)]. New cutaneous and non-cutaneous malignancies MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. Hemorrhage MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)]. Colitis and gastrointestinal perforation MEKINIST can cause colitis and gastrointestinal perforation. Advise patients to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)]. Venous thrombosis MEKINIST administered with dabrafenib increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. Cardiomyopathy MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. Retinal Pigment Epithelial Detachment MEKINIST can cause severe visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. Interstitial lung disease MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.7)]. Serious febrile reactions MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)]. Serious skin toxicities MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.9)]. Hypertension MEKINIST can cause hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. Diarrhea MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. Embryo-fetal Toxicity MEKINIST can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Females and males of reproductive potential Instruct females of reproductive potential to use highly effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Lactation Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)]. Instructions for taking MEKINIST MEKINIST should be taken at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.2)].

DOSAGE AND ADMINISTRATION

2 Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST. (2.1) The recommended dosage regimen of MEKINIST is 2 mg orally once daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal. (2.2) 2.1 Patient Selection Select patients for treatment of unresectable or metastatic melanoma with MEKINIST based on the presence of BRAF V600E or V600K mutation in tumor specimens [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosing The recommended dosage regimen is MEKINIST 2 mg orally taken once daily at the same time each day as a single agent or with dabrafenib. Continue treatment until disease progression or unacceptable toxicity occurs. Take MEKINIST at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. 2.3 Dose Modifications Review the Full Prescribing Information for dabrafenib for recommended dose modifications. Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. For New Primary Cutaneous Malignancies No dose modifications are required. Table 1. Recommended Dose Reductions Dose Reductions for MEKINIST First Dose Reduction 1.5 mg orally once daily Second Dose Reduction 1 mg orally once daily Subsequent Modification Permanently discontinue if unable to tolerate MEKINIST 1 mg orally once daily Table 2. Recommended Dose Modifications for MEKINIST aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. bSee Table 1 for recommended dose reductions of MEKINIST. Severity of Adverse Reactiona MEKINISTb Febrile Drug Reaction •Fever higher than 104°F •Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until fever resolves. Then resume MEKINIST at same or lower dose level. Cutaneous •Intolerable Grade 2 skin toxicity •Grade 3 or 4 skin toxicity Withhold MEKINIST for up to 3 weeks. •If improved, resume at a lower dose level. •If not improved, permanently discontinue. Cardiac •Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and is below institutional lower limits of normal (LLN) from pretreatment value Withhold MEKINIST for up to 4 weeks. •If improved to normal LVEF value, resume at a lower dose level. •If not improved to normal LVEF value, permanently discontinue. •Symptomatic congestive heart failure •Absolute decrease in LVEF of greater than 20% from baseline that is below LLN Permanently discontinue MEKINIST. Venous Thromboembolism •Uncomplicated DVT or PE Withhold MEKINIST for up to 3 weeks. •If improved to Grade 0-1, resume at a lower dose level. •If not improved, permanently discontinue. •Life threatening PE Permanently discontinue MEKINIST. Ocular Toxicities •Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. •If improved, resume MEKINIST at same or lower dose level. •If not improved, discontinue or resume at a lower dose. •Retinal vein occlusion Permanently discontinue MEKINIST. Pulmonary •Interstitial lung disease/pneumonitis Permanently discontinue MEKINIST. Other •Intolerable Grade 2 adverse reactions •Any Grade 3 adverse reactions Withhold MEKINIST •If improved to Grade 0-1, resume at a lower dose level. •If not improved, permanently discontinue. •First occurrence of any Grade 4 adverse reaction •Withhold MEKINIST until adverse reaction improves to Grade 0-1. Then resume at a lower dose level. Or •Permanently discontinue. •Recurrent Grade 4 adverse reaction Permanently discontinue MEKINIST.