PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - 12 mg Tablet Label

60 TABLETS

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** NDC**24979-724-04

Galantamine Tablets USP

12 mg

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RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Warnings and Precautions (5.6) 8/2021

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DESCRIPTION SECTION

11 DESCRIPTION

Galantamine Tablets USP contain galantamine, a reversible, competitive acetylcholinesterase inhibitor, as the hydrobromide salt. Galantamine hydrobromide is known chemically as
(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide. It has an empirical formula of C 17H 21NO 3 •HBr and a molecular weight of 368.27. Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water. The structural formula for galantamine hydrobromide is:

Galantamine Tablets USP contain 4 mg, 8 mg, and 12 mg galantamine as 5.126, 10.253 and 15.379 mg of galantamine hydrobromide, respectively. Inactive ingredients include colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and titanium dioxide. The 4 mg tablets contain polyethylene glycol and polysorbate 80. The 8 mg tablets contain D&C red #27, FD&C blue #1, and triacetin. The 12 mg tablets contain FD&C yellow # 6, iron oxide yellow, and triethyl citrate.

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INDICATIONS & USAGE SECTION

Highlight: Galantamine Tables are a cholinesterase inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer’s type ( 1)

1 INDICATIONS AND USAGE

Galantamine tablets are indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

DOSAGE & ADMINISTRATION SECTION

Highlight: * Galantamine tablets: Recommended starting dosage is 4 mg twice daily; increase to initial maintenance dosage of 8 mg twice daily after a minimum of 4 weeks. Based on clinical benefit and tolerability, dosage may be increased to 12 mg twice daily after a minimum of 4 weeks at 8 mg twice daily. ( 2.2)

• Take with meals; ensure adequate fluid intake during treatment ( 2.2)
• Hepatic impairment: should not exceed 16 mg/day for moderate hepatic impairment; do not use in patients with severe hepatic impairment ( 2.3)
• 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 ( 2.4)

2 DOSAGE AND ADMINISTRATION

2.2 Galantamine Immediate-Release Tablets

The dosage of galantamine tablets shown to be effective in controlled clinical trials is 16 - 32 mg/day given as twice daily dosing. As the dosage of 32 mg/day is less well tolerated than lower dosages and does not provide increased effectiveness, the recommended dosage range is 16 - 24 mg/day given twice daily. The dosage of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dosage of 24 mg of galantamine tablets might provide additional benefit for some patients.

The recommended starting dosage of galantamine tablets is 4 mg twice a day (8 mg/day). The dosage should be increased to the initial maintenance dosage of 8 mg twice a day (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice a day (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice a day (16 mg/day).

Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

Galantamine tablets should be administered twice a day, preferably with morning and evening meals.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. 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 tablets 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. The beneficial effects of galantamine tablets are lost, however, when the drug is discontinued.

2.3 Dosage in Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7 - 9), the dosage should generally not exceed 16 mg/day. The use of galantamine tablets in patients with severe hepatic impairment (Child-Pugh score of 10 - 15) is not recommended [see Clinical Pharmacology (12.3)] .

2.4 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 tablets is not recommended [see Clinical Pharmacology (12.3)] .

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * Tablets – 4 mg, 8 mg, 12 mg ( 3)

3 DOSAGE FORMS AND STRENGTHS

Galantamine Tablets USP contain 4 mg, 8 mg, and 12 mg galantamine as 5.126 mg, 10.253 mg, and 15.379 mg of galantamine hydrobromide, respectively. Galantamine Tablets USP are available in the following strengths:

4 mg white color film coated, round, biconvex tablet, debossed “YB” on one side and “111” on the other side.

8 mg purple color film coated, round, biconvex tablet, debossed “YB” on one side and “112” on the other side.

12 mg peach color film coated, round, biconvex tablet, debossed “YB” on one side and “113” on the other side.

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CONTRAINDICATIONS SECTION

Highlight: Known hypersensitivity to galantamine hydrobromide or any excipients ( 4)

4 CONTRAINDICATIONS

Galantamine tablets are contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation.

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Serious skin reactions: discontinue at first appearance of skin rash ( 5.1)

• All patients should be considered at risk for adverse effects on cardiac conduction, including bradycardia and AV block, due to vagotonic effects on sinoatrial and atrioventricular nodes ( 5.3)
• Active or occult gastrointestinal bleeding: monitor, especially those with an increased risk for developing ulcers ( 5.4)
• Cholinomimetics may cause bladder outflow obstruction ( 5.5)
• Monitor for respiratory adverse events in patients with a history of severe asthma or obstructive pulmonary disease ( 5.7)

5 WARNINGS AND PRECAUTIONS

5.1 Serious Skin Reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving galantamine tablets. Inform patients and caregivers that the use of galantamine tablets should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed and alternative therapy should be considered.

5.2 Anesthesia

Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.

5.3 Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities [see Adverse Reaction (6.1) (6.2)]. Therefore, all patients should be considered at risk for adverse effects on cardiac conduction.

Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]).

5.4 Gastrointestinal Conditions

Through their primary action, cholinomimetics may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers, e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Clinical studies of galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss. During therapy, the patient’s weight should be monitored.

5.5 Genitourinary Conditions

Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction.

5.6 Neurological Conditions

Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions [see Adverse Reactions (6.2)] . Seizure activity may also be a manifestation of Alzheimer's disease. Patients with Alzheimer's disease should be monitored closely for seizures while taking galantamine.

An increase in cholinergic tone may worsen symptoms related to extrapyramidal disorders [see Adverse Reactions (6.2)].

5.7 Pulmonary Conditions

Because of its cholinomimetic action, galantamine should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease. Respiratory function should be monitored closely for the occurrence of respiratory adverse effects.

5.8 Deaths in Subjects with Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in patients with mild cognitive impairment (MCI), a total of 13 patients on galantamine (n=1026) and 1 patient on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death).

Although the difference in mortality between galantamine- and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of galantamine. Specifically, in these two MCI studies, the mortality rate in the placebo-treated patients was markedly lower than the rate in placebo-treated patients in trials of galantamine in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the mortality rate in the galantamine-treated MCI patients was also lower than that observed in galantamine-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no patients in the placebo group died after 6 months, a highly unexpected finding in this population.

Individuals with mild cognitive impairment demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy: Based on animal data may cause fetal harm. ( 8.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no adequate data on the developmental risk associated with the use of 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 2-4% and 15-20%, 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 Luctation

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 tablets on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for galantamine tablets and any potential adverse effects on the breastfed infant from galantamine tablets 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 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 tablets in patients with severe hepatic impairment is not recommended. [see Dosage and Administration (2.3) 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 tablets in patients with creatinine clearance less than 9 mL/min is not recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

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ADVERSE REACTIONS SECTION

Highlight: The most common adverse reactions (≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, decreased appetite, and weight decreased ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.

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 subjects with mild cognitive impairment (MCI) [see Warnings and Precautions (5.8)]

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 subjects 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

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 5-7 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: 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=3956) and 56 (2.2%) placebo patients (N=2546) 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=1454) 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 tablets. 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

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OVERDOSAGE SECTION

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 tablets overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1.0 mg i.v. 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.

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