Galantamine

1 INDICATIONS AND USAGE Galantamine extended-release capsules are indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. Galantamine extended-release capsules are 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 extended-release capsules should occur at the same daily dosage with the last dose of galantamine tablets taken in evening and starting galantamine extended-release capsules once daily treatment the next morning. ( 2.5 ) 2.1 Recommended Dosage and Administration Administer galantamine extended-release capsules once daily in the morning, preferably with food. Ensure adequate fluid intake during treatment. The recommended starting dosage of galantamine 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 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 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 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 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 Extended-Release Capsules from Galantamine Tablets Patients currently being treated with galantamine tablets can convert to galantamine extended-release capsules by taking their last dose of galantamine tablets in the evening and starting galantamine extended-release capsules once daily treatment the next morning. Converting from galantamine tablets to galantamine extended-release capsules should occur at the same total daily dosage.

3 DOSAGE FORMS AND STRENGTHS Galantamine extended-release capsules contain white to off-white mini tablets and are available in the following strengths: 8 mg are white opaque size “1” hard gelatin capsule with inscription “A” over the cap & “8” over the body containing white to off-white, round, biconvex, single mini tablet. 16 mg are pink opaque size “1” hard gelatin capsule with inscription “A” over the cap & “16” over the body containing white to off-white, round, biconvex, two mini tablets. 24 mg are caramel opaque size “1” hard gelatin capsule with inscription “A” over the cap & “24” over the body containing white to off-white, round, biconvex, three mini tablets. Extended-release capsules: 8 mg, 16 mg, 24 mg (3)

4 CONTRAINDICATIONS Galantamine extended-release capsules are contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation. Known hypersensitivity to galantamine hydrobromide or any excipients (4)

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 in galantamine-treated patients from double-blind clinical trials (≥5%) 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 3956 galantamine-treated patients who participated in 8 placebo-controlled clinical studies and 1454 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 Galantamine (n=3956) % Placebo (n=2546) % Metabolism and Nutrition Disorders Decreased appetite 7.4 2.1 Psychiatric Disorders Depression 3.6 2.3 Nervous System Disorders Dizziness 7.5 3.4 Headache 7.1 5.5 Tremor 1.6 0.7 Somnolence 1.5 0.8 Syncope 1.4 0.6 Lethargy 1.3 0.4 Cardiac Disorders Bradycardia 1 0.3 Gastrointestinal Disorders Nausea 20.7 5.5 Vomiting 10.5 2.3 Diarrhea 7.4 4.9 Abdominal pain 3.8 2 Abdominal discomfort 2.1 0.7 Dyspepsia 1.5 1 Musculoskeletal and Connective Tissue Disorders Muscle spasms 1.2 0.5 General Disorders and Administration Site Conditions Fatigue 3.5 1.8 Asthenia 2 1.5 Malaise 1.1 0.5 Investigations Decreased weight 4.7 1.5 Injury, Poisoning and Procedural Complications Fall 3.9 3 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=3956) 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=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below: Metabolism and Nutrition Disorders: Dehydrat …

7 DRUG INTERACTIONS Potential to interfere with the activity of anticholinergic medications (7.1) Synergistic effect expected when given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents, or cholinergic agonists (7.2) 7.1 Use with Anticholinergics Galantamine has the potential to interfere with the activity of anticholinergic medications [see Clinical Pharmacology (12.3) ] . 7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of galantamine extended-release capsules or galantamine tablets in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data In rats, administration of galantamine (oral doses of 2, 8, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses, which were associated with maternal toxicity. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD) of 24 mg/day on a body surface area (mg/m 2 ) basis. When galantamine (oral doses of 4, 12, 28, or 40 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose which was associated with maternal toxicity. The no‐effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m 2 basis. In a study in which pregnant rats were orally dosed with galantamine (2, 8, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre- and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of galantamine in human milk, the effects on the breastfed infant, or the effects of galantamine extended-release capsules on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for galantamine extended-release capsules and any potential adverse effects on the breastfed infant from galantamine extended-release capsules or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Eight double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 6519 patients have investigated galantamine extended-release capsules and galantamine tablets in the treatment of mild to moderate dementia of the Alzheimer’s type [see Adverse Reactions (6.1) and Clinical Studies (14) ] . The mean age of patients enrolled in these clinical studies was 75 years; 78% of these patients were between 65 and 84 years of age, and 10% of patients were 85 years of age or older. 8.6 Hepatic Impairment In patients with moderate hepatic impairment, a dosage adjustment is recommended. The use of galantamine extended-release capsules in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.2 ) and Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment In patients with a creatinine clearance of 9 to 59 mL/min, a dosage adjustment is recommended. The use of galantamine extended-release capsules in patients with creatinine clearance less than 9 mL/min is not recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] .

12.1 Mechanism of Action Although the etiology of cognitive impairment in Alzheimer’s disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer’s disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer’s disease). Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine’s action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process.

11 DESCRIPTION Galantamine extended-release capsules USP contain galantamine, a reversible, competitive acetylcholinesterase inhibitor, as the hydrobromide salt. Galantamine hydrobromide is known chemically as (4a S ,6 R ,8a S )-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6 H -benzofuro[3a, 3,2- ef ][2]benzazepin-6-ol hydrobromide. It has a molecular formula of C 17 H 21 NO 3 •HBr and a molecular weight of 368.27. Galantamine hydrobromide USP is a white to almost white powder and is sparingly soluble in water. The structural formula for galantamine hydrobromide is: Galantamine extended-release capsules USP contain 8 mg, 16 mg, and 24 mg galantamine as 10.25 mg, 20.50 mg, and 30.76 mg of galantamine hydrobromide USP, respectively. Inactive ingredients include colloidal silicon dioxide, gelatin, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, and titanium dioxide. The 16 mg capsule also contains iron oxide red. The 24 mg capsule also contains iron oxide red and iron oxide yellow. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. Meets USP Dissolution Test 6. Chemical Strucutre

10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized. Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the following signs of cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for galantamine extended-release capsules overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1 mg intravenous with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics. It is not known whether galantamine and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included hypoactivity, tremors, clonic convulsions, salivation, lacrimation, chromodacryorrhea, mucoid feces, and dyspnea. In one postmarketing report, one patient who had been taking 4 mg of galantamine daily for a week inadvertently ingested eight 4 mg tablets (32 mg total) on a single day. Subsequently, she developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness for which she required hospital treatment. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalization. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Galantamine extended-release capsules USP are supplied as follows: Galantamine Extended-Release Capsules USP, 8 mg are white opaque size “1” hard gelatin capsule with inscription “A” over the cap & “8” over the body containing white to off-white, round, biconvex, single mini tablet. Bottles of 30 NDC 65862-744-30 Bottles of 90 NDC 65862-744-90 Bottles of 100 NDC 65862-744-01 Bottles of 500 NDC 65862-744-05 Bottles of 1,000 NDC 65862-744-99 Galantamine Extended-Release Capsules USP, 16 mg are pink opaque size “1” hard gelatin capsule with inscription “A” over the cap & “16” over the body containing white to off-white, round, biconvex, two mini tablets. Bottles of 30 NDC 65862-745-30 Bottles of 90 NDC 65862-745-90 Bottles of 100 NDC 65862-745-01 Bottles of 500 NDC 65862-745-05 Bottles of 1,000 NDC 65862-745-99 Galantamine Extended-Release Capsules USP, 24 mg are caramel opaque size “1” hard gelatin capsule with inscription “A” over the cap & “24” over the body containing white to off-white, round, biconvex, three mini tablets. Bottles of 30 NDC 65862-746-30 Bottles of 90 NDC 65862-746-90 Bottles of 100 NDC 65862-746-01 Bottles of 500 NDC 65862-746-05 Bottles of 1,000 NDC 65862-746-99 Storage and Handling Galantamine extended-release capsules USP should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep out of reach of children.