Galantamine Hydrobromide

1 INDICATIONS AND USAGE Galantamine hydrobromide extended-release capsules are indicated for the treatment of mild to moderate dementia of the Alzheimer's type. Galantamine hydrobromide is a cholinesterase inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer’s type ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended starting dosage is 8 mg/day in morning; increase to initial maintenance dose of 16 mg/day after a minimum of 4 weeks. Based on clinical benefit and tolerability, dosage may be increased to 24 mg/day after a minimum of 4 weeks at 16 mg/day. ( 2.1 ) Take with food; ensure adequate fluid intake during treatment ( 2.1 ) Hepatic impairment: should not exceed 16 mg/day for moderate hepatic impairment; do not use in patients with severe hepatic impairment ( 2.2 ) Renal impairment: should not exceed 16 mg/day for creatinine clearance 9 to 59 mL/min; do not use in patients with creatinine clearance less than 9 mL/min. ( 2.3 ) Conversion from galantamine tablets to galantamine hydrobromide extended-release capsules should occur at the same daily dosage with the last dose of galantamine tablets taken in evening and starting galantamine hydrobromide extended-release capsules once daily treatment the next morning. (2.5) 2.1 Recommended Dosage and Administration Administer galantamine hydrobromide extended-release capsules once daily in the morning, preferably with food. Ensure adequate fluid intake during treatment. The recommended starting dosage of galantamine hydrobromide extended-release capsules is 8 mg/day. Increase to the initial maintenance dosage of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day may be attempted after a minimum of 4 weeks at 16 mg/day. Increase dosage based upon assessment of clinical benefit and tolerability of the previous dosage. The dosage of galantamine hydrobromide extended-release capsules shown to be effective in a controlled clinical trial is 16 to 24 mg/day. 2.2 Dosage in Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), the dosage should generally not exceed 16 mg/day. The use of galantamine hydrobromide extended-release capsules in patients with severe hepatic impairment (Child-Pugh score of 10 to 15) is not recommended [see Clinical Pharmacology (12.3)]. 2.3 Dosage in Patients with Renal Impairment In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of galantamine hydrobromide extended-release capsules is not recommended [see Clinical Pharmacology (12.3)]. 2.4 Treatment Interruption If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose. The abrupt withdrawal of galantamine hydrobromide extended-release capsules in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. 2.5 Switching to Galantamine Hydrobromide Extended-release Capsules from Galantamine Tablets Patients currently being treated with galantamine tablets can convert to galantamine hydrobromide extended-release capsules by taking their last dose of galantamine tablets in the evening and starting galantamine hydrobromide extended-release capsules once daily treatment the next morning. Converting from galantamine tablets to galantamine hydrobromide extended-release capsules should occur at the same total daily dosage.

6 ADVERSE REACTIONS Serious adverse reactions are discussed in more detail in the following sections of the labeling: Serious Skin Reactions [see Warnings and Precautions ( 5.1 )] Cardiovascular Conditions [see Warnings and Precautions ( 5.3 )] Gastrointestinal Conditions [see Warnings and Precautions ( 5.4 )] Genitourinary Conditions [see Warnings and Precautions ( 5.5 )] Neurological Conditions [see Warnings and Precautions ( 5.6 )] Pulmonary Conditions [see Warnings and Precautions ( 5.7 )] Deaths in Patients with Mild Cognitive Impairment (MCI) [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥5%) in galantamine-treated patients from double-blind clinical trials were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. The most common adverse reactions associated with discontinuation (≥1%) in galantamine-treated patients from double-blind clinical trials were nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%). The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 3,956 galantamine-treated patients who participated in 8 placebo-controlled clinical studies and 1,454 patients in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer’s type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with tablets. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Table 1 lists the adverse reactions reported in ≥1% of galantamine-treated patients in 8 placebo-controlled, double-blind clinical trials. Table 1. Adverse Reactions Reported by ≥1% of Galantamine-Treated Patients in Pooled Placebo-Controlled, Double-Blind Clinical Trials System/Organ Class Adverse Reaction G alantamine (n=3,956) % Placebo (n=2,546) % Metabolism and Nutrition Disorders Decreased appetite 7.4 2.1 Psychiatric Disorders Depression 3.6 2.3 Nervous System Disorders Headache 7.1 5.5 Dizziness 7.5 3.4 Tremor 1.6 0.7 Somnolence 1.5 0.8 Syncope 1.4 0.6 Lethargy 1.3 0.4 Cardiac Disorders Bradycardia 1.0 0.3 Gastrointestinal Disorders Nausea 20.7 5.5 Vomiting 10.5 2.3 Diarrhea 7.4 4.9 Abdominal discomfort 2.1 0.7 Abdominal pain 3.8 2.0 Dyspepsia 1.5 1.0 Musculoskeletal and Connective Tissue Disorders Muscle spasms 1.2 0.5 General Disorders and Administration Site Conditions Fatigue 3.5 1.8 Asthenia 2.0 1.5 Malaise 1.1 0.5 Investigations Decreased weight 4.7 1.5 Injury, Poisoning and Procedural Complications Fall 3.9 3.0 Laceration 1.1 0.5 The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5 to 7 days. Other Adverse Reactions Observed in Clinical Trials of Galantamine The following adverse reactions occurred in <1% of all galantamine-treated patients (N=3,956) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in patients (N=1,454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below: Metabolism and Nutrition Disorders: Dehydration Nervous System Disorders: Dysgeusia, Hypersomnia, Paresthesia Eye Disorders: Blurred vision Cardiac Disorders: First degree atrioventricular block, Palpitations, Sinus bradycardia, Supraventricular extrasystoles Vascular Disorders: Flushing, Hypotension Gastrointestinal Disorders: Retching Skin and Subcutaneous Tissue Disorders: Hyperhidrosis Musculoskeletal and Connective Tissue Disorders: Muscular weakness Discontinuations Due to Adverse Reactions In the 8 placebo-controlled studies of adults, 418 (10.6%) galantamine-treated patients (N=3,956) and 56 (2.2%) placebo patients (N=2,546) discontinued due to an adverse reaction. Those events with an incidence of ≥0.5% in the galantamine-treated patients included nausea (245, 6.2%), vomiting (129, 3.3%), decreased appetite (60, 1.5%), dizziness (50, 1.3%), diarrhea (31, 0.8%), headache (29, 0.7%), and decreased weight (26, 0.7%). The only event with an incidence of ≥0.5% in placebo patients was nausea (17, 0.7%). In the 5 open-label studies, 103 (7.1%) patients (N=1,454) discontinued due to an adverse reaction. Those events with an incidence of ≥0.5% included nausea (43, 3.0%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), decreased weight (9, 0.6%), dizziness (8, 0.6%), and diarrhea (7, 0.5%). 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of galantamine hydrobromide extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Immune System Disorders: Hypersensitivity Psychiatric Disorders: Hallucinations Nervous System Disorders: Seizures, extrapyramidal disorder [see Warnings and Precautions (5.6)] Ear and Labyrinth Disorders: Tinnitus Cardiac Disorders: Complete atrioventricular block Vascular Disorders: Hypertension Hepatobiliary Disorders: Hepatitis, increased hepatic enzyme Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, Erythema multiforme

12.2 Pharmacokinetics The pharmacokinetics of galantamine are linear over a dose range of 8 to 32 mg/day. Absorption and Distribution Galantamine is absorbed with time to peak concentration of about 1 hour. The absolute bioavailability of galantamine is about 90%. Food did not affect the AUC of galantamine, but C max was decreased by 25% and T max was delayed by 1.5 hours, when galantamine was administered with food. The mean volume of distribution of galantamine is 175 L. The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2. Metabolism and Elimination Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity. In studies of oral 3 H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39 to 77% of the total radioactivity in the plasma, and galantamine glucuronide for 14 to 24%. By 7 days, 93 to 99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average. After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20 to 25% of the total plasma clearance of about 300 mL/min. Galantamine has a terminal half-life of about 7 hours. Galantamine hydrobromide extended-release capsules 24 mg administered once daily under fasting conditions are bioequivalent to galantamine tablets 12 mg twice daily with respect to AUC 24h and C min . The C max and T max of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with C max about 25% lower and median T max occurring about 4.5 to 5 hours after dosing. Dose-proportionality is observed for galantamine hydrobromide extended-release capsules over the dose range of 8 to 24 mg daily and steady state is achieved within a week. There was no effect of age on the pharmacokinetics of galantamine hydrobromide extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. There are no appreciable differences in pharmacokinetic parameters when galantamine hydrobromide extended-release capsules are given with food compared to when they are given in the fasted state. Specific Populations Elderly Data from clinical trials in patients with Alzheimer’s disease indicate that galantamine concentrations are 30 to 40% higher in those patients than in healthy young subjects. Gender and Race A population pharmacokinetic analysis (on 539 men and 550 women) indicates that galantamine clearance is about 20% lower in women than in men (which is explained by a lower body weight in women) and that race (n=1,029 White, 24 Black, 13 Asian and 23 other) did not affect the clearance of galantamine. Hepatic Impairment Following a single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n=8; Child-Pugh score of 5 to 6) were similar to the pharmacokinetics of galantamine in healthy subjects. In patients with moderate hepatic impairment (n=8; Child Pugh score of 7 to 9), galantamine clearance was decreased by about 25% compared to galantamine clearance in normal volunteers. Exposure to galantamine would be expected to increase further with increasing degree of hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)] . Renal Impairment Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in patients with moderate and severe renal impairment, respectively, compared with normal volunteers [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)] . Drug-Drug Interactions Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine so no single pathway appears predominant. Based on in vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of galantamine. CYP2D6 was involved in the formation of O-desmethyl-galantamine, whereas CYP3A4 mediated the formation of galantamine-N-oxide. Galantamine is also glucuronidated and excreted unchanged in urine. Effect of Other Drugs on Galantamine CYP3A4 Inhibitors: Ketoconazole Ketoconazole, a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6, when administered at a dose of 200 mg two times a day for 4 days, increased the AUC of galantamine by 30%. Erythromycin Erythromycin, a moderate inhibitor of CYP3A4, when administered at a dose of 500 mg four times a day for 4 days, affected the AUC of galantamine minimally (10% increase). CYP2D6 Inhibitors: A population pharmacokinetics analysis on a database of 852 patients with Alzheimer’s disease showed that the clearance of galantamine was reduced about 25-33% by the concurrent administration of amitriptyline (n=17), fluoxetine (n=48), fluvoxamine (n=14), and quinidine (n=7), all of which are known inhibitors of CYP2D6. Paroxetine Paroxetine, a strong inhibitor of CYP2D6, when administered at a dose of 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%. H2 Antagonists Galantamine was administered as a single dose of 4 mg on Day 2 of a 3-day treatment with either cimetidine (800 mg daily) or ranitidine (300 mg daily). Cimetidine increased the bioavailability of galantamine by approximately 16%. Ranitidine had no effect on the pharmacokinetics of galantamine. Memantine Memantine, an N-methyl-D-aspartate receptor antagonist, when administered at a dose of 10 mg two times a day, had no effect on the pharmacokinetics of galantamine (16 mg/day) at steady state. Effect of Galantamine on Other Drugs In Vitro Studies In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 or CYP2E1. This indicates that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. In Vivo Studies Warfarin Multiple doses of galantamine at 24 mg/day had no effect on the pharmacokinetics of R- and S-warfarin (administered in a single dose of 25 mg) or on the increased prothrombin time induced by warfarin. The protein binding of warfarin was unaffected by galantamine. Digoxin Multiple doses of galantamine at 24 mg/day had no effect on the steady-state pharmacokinetics of digoxin (at a dose of 0.375 mg once daily) when those two drugs were coadministered. In that study, however, one healthy subject was hospitalized on account of 2nd and 3rd degree heart block and bradycardia.