Galantamine

Mylan Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use galantamine tablets safely and effectively. See full prescribing information for galantamine tablets. GALANTAMINE tablets, USP for oral useInitial U.S. Approval: 2001INDICATIONS AND USAGEGalantamine hydrobromide is a cholinesterase inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. (1)DOSAGE AND ADMINISTRATION •Recommended starting dosage for galantamine tablets is 4 mg twice daily; increase dose to initial maintenance dosage of 8 mg twice daily after a minimum of 4 weeks. Based upon assessment of 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 galantamine tablets with meals. Ensure adequate fluid intake during treatment. (2.2) DOSAGE FORMS AND STRENGTHS •Tablets – 4 mg, 8 mg, and 12 mg (3) CONTRAINDICATIONSKnown hypersensitivity to galantamine hydrobromide or any excipients. (4)WARNINGS AND PRECAUTIONS •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. (5.2) •Active or occult gastrointestinal bleeding: monitor, especially those with an increased risk for developing ulcers. (5.3) •Cholinomimetics may cause bladder outflow obstruction. (5.4) •Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. Patients with Alzheimer’s disease should be monitored closely for seizures while taking galantamine. (5.5) •Monitor for respiratory adverse events in patients with a history of severe asthma or obstructive pulmonary disease. (5.6) Side EffectsThe most common adverse reactions (≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, decreased appetite, and weight decreased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. toll free at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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) USE IN SPECIFIC POPULATIONS •Pregnancy: Based on animal data may cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 GALANTAMINE INDICATIONS AND USAGE
• 2 GALANTAMINE DOSAGE AND ADMINISTRATION
  • 2.2 Galantamine Tablets
  • 2.3 Hepatic Impairment
  • 2.4 Renal Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 GALANTAMINE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Anesthesia
  • 5.2 Cardiovascular Conditions
  • 5.3 Gastrointestinal Conditions
  • 5.4 Genitourinary Conditions
  • 5.5 Neurological Conditions
  • 5.6 Pulmonary Conditions
  • 5.7 Deaths in Subjects with Mild Cognitive Impairment (MCI)
• 6 GALANTAMINE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Use with Anticholinergics
  • 7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors
  • 7.3 Effect of Other Drugs on Galantamine
  • 7.4 Effect of Galantamine on Other Drugs
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 10 OVERDOSAGE
• 11 GALANTAMINE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NON-CLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Study Outcome Measures
  • 14.2 Immediate-release Tablets
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.2 Galantamine 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 Hepatic Impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment. In patients with moderately impaired hepatic function (Child-Pugh score of 7 to 9), the total daily dosage should generally not exceed 16 mg/day. The use of galantamine tablets in patients with severe hepatic impairment (Child-Pugh score of 10 to 15) is not recommended.

2.4 Renal Impairment

For patients with moderate renal impairment the dosage should generally not exceed 16 mg/day. In patients with severe renal impairment (creatinine clearance < 9 mL/min), the use of galantamine tablets is not recommended.

3 DOSAGE FORMS AND STRENGTHS

Galantamine tablets are available in the following strengths:

The 4 mg tablet is a blue film-coated, round tablet debossed with M on one side of the tablet and G21 on the other side.

The 8 mg tablet is a blue film-coated, round tablet debossed with M on one side of the tablet and G22 on the other side.

The 12 mg tablet is a blue film-coated, round tablet debossed with M on one side of the tablet and G23 on the other side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Anesthesia

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

5.2 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. 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 BID 0.4% [3/692]; 8 mg BID 1.3% [7/552]; 12 mg BID 2.2% [6/273]).

5.3 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 [see Adverse Reactions (6.1)].

5.4 Genitourinary Conditions

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

5.5 Neurological Conditions

Seizures

Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. However, seizure activity may also be a manifestation of Alzheimer’s disease. In clinical trials, there was no increase in the incidence of convulsions with galantamine compared to placebo. Patients with Alzheimer’s disease should be monitored closely for seizures while taking galantamine.

5.6 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.

5.7 Deaths in Subjects with Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in subjects with mild cognitive impairment (MCI), a total of 13 subjects on galantamine (n = 1,026) and one subject on placebo (n = 1,022) 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 subjects was markedly lower than the rate in placebo-treated patients in trials of galantamine in Alzheimer’s disease or other dementias (0.7 per 1,000 person years compared to 22 to 61 per 1,000 person years, respectively). Although the mortality rate in the galantamine-treated MCI subjects was also lower than that observed in galantamine-treated patients in Alzheimer’s disease and other dementia trials (10.2 per 1,000 person years compared to 23 to 31 per 1,000 person years, respectively), the relative difference was much less. When the Alzheimer’s disease and other dementia studies were pooled (n = 6,000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no subjects 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.

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• •Anesthesia [see Warnings and Precautions (5.1)]
• •Cardiovascular conditions [see Warnings and Precautions (5.2)]
• •Gastrointestinal conditions [see Warnings and Precautions (5.3)]
• •Genitourinary conditions [see Warnings and Precautions (5.4)]
• •Neurological conditions [see Warnings and Precautions (5.5)]
• •Pulmonary conditions [see Warnings and Precautions (5.6)]
• •Deaths in subjects with mild cognitive impairment (MCI) [see Warnings and Precautions (5.7)]

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 subjects from double-blind clinical trials (≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, decreased appetite, and weight decreased.

The most common adverse reactions associated with discontinuation (≥ 1%) in galantamine-treated subjects from double-blind clinical trials were nausea (7.7%), vomiting (4.1%), decreased appetite (1.9%), and dizziness (1.6%).

The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 2,932 galantamine-treated subjects who participated in seven placebo-controlled clinical studies and 1,454 subjects in five 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.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of galantamine based on the comprehensive assessment of the available adverse event information. A causal relationship with galantamine cannot be reliably established in individual cases.

Commonly-Observed Side Effects in Double-Blind, Placebo-Controlled Clinical Trials

Table 1 lists the adverse drug reactions reported in ≥ 1% of galantamine-treated subjects in seven placebo-controlled, double-blind clinical trials.

The majority of these adverse events occurred during the dose-escalation period. In those patients who experienced the most frequent adverse event, nausea, the median duration of the nausea was 5 to 7 days.

Administration of galantamine with food, the use of anti-emetic medication, and ensuring adequate fluid intake may reduce the impact of these events [see Dosage and Administration (2) and Patient Counseling Information (17)].

Other Side Effects Observed in Clinical Trials of Galantamine

The following adverse reactions occurred in < 1% of all galantamine-treated subjects (N = 2,932) 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 subjects (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: Vision blurred

Cardiac Disorders: Atrioventricular block first degree, Palpitations, Sinus bradycardia, Supraventricular extrasystoles

Vascular Disorders: Flushing, Hypotension Gastrointestinal Disorders: Retching

Musculoskeletal and Connective Tissue Disorders: Muscular weakness

Injury, Poisoning and Procedural Complications: Fall

Discontinuations Due to Side Effects

In the seven placebo-controlled studies of adults, 379 (12.9%) galantamine-treated patients (N = 2,932) and 42 (2.8%) placebo patients (N = 1,525) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% in the galantamine-treated patients included nausea (225, 7.7%), vomiting (119, 4.1%), decreased appetite (56, 1.9%), dizziness (48, 1.6%), diarrhea (27, 0.9%), headache (26, 0.9%) weight decreased (24, 0.8%), and abdominal pain (15, 0.5%). Those events with an incidence of ≥ 0.5% in placebo patients included nausea (14, 0.9%) and dizziness (8, 0.5%).

In the five 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%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), weight decreased (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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Immune System Disorders: Hypersensitivity

Psychiatric Disorders: Hallucination, Hallucination visual, Hallucination auditory

Ear and Labyrinth Disorders: Tinnitus

Vascular Disorders: Hypertension

Hepatobiliary Disorders: Hepatitis, Hepatic enzyme increased

7 DRUG INTERACTIONS

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)].

7.3 Effect of Other Drugs on Galantamine

In vitro

CYP3A4 and CYP2D6 are the major enzymes involved in the metabolism of galantamine. CYP3A4 mediates the formation of galantamine-N-oxide; CYP2D6 leads to the formation of O-desmethyl-galantamine. Because galantamine is also glucuronidated and excreted unchanged, no single pathway appears predominant [see Clinical Pharmacology (12.3)].

In vivo

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.

Ketoconazole, a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6, at a dose of 200 mg BID for 4 days, increased the AUC of galantamine by 30%.

Erythromycin, a moderate inhibitor of CYP3A4 at a dose of 500 mg QID for 4 days, affected the AUC of galantamine minimally (10% increase).

Paroxetine, a strong inhibitor of CYP2D6, at 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%.

Memantine, an N-methyl-D-aspartate receptor antagonist, at a dose of 10 mg BID, had no effect on the pharmacokinetics of galantamine (16 mg/day) at steady state.

7.4 Effect of Galantamine on Other Drugs

In vitro

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 [see Clinical Pharmacology (12.3)].

In vivo

Galantamine at 24 mg/day had no effect on the pharmacokinetics of R- and S-warfarin (25 mg single dose) or on the prothrombin time. The protein binding of warfarin was unaffected by galantamine.

Galantamine at 24 mg/day had no effect on the steady-state pharmacokinetics of digoxin (0.375 mg once daily) when they were coadministered. In this study, however, one healthy subject was hospitalized for 2nd and 3rd degree heart block and bradycardia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C

There are no adequate and well-controlled studies 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. Galantamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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. 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/m²) basis. When galantamine (oral doses of 4, 12, 28, or 48 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. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m² 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/m² basis.

8.3 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 galantamine is administered to a nursing woman.

8.4 Pediatric Use

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

8.5 Geriatric Use

Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age. Seven double-blind, placebo-controlled clinical trials and five open-label trials in a total of 4,474 patients have investigated galantamine 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 11% of patients were 85 years of age or older.

8.6 Hepatic Impairment

In patients with moderately impaired hepatic function, dose titration should proceed cautiously [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)]. The use of galantamine in patients with severe hepatic impairment is not recommended.

8.7 Renal Impairment

In patients with moderately impaired renal function, dose titration should proceed cautiously [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4)]. In patients with severely impaired renal function (CL_cr < 9 mL/min) the use of galantamine is not recommended.

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 overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 mg to 1 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 coadministered 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 2 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.

11 DESCRIPTION

Galantamine hydrobromide is a reversible, competitive acetylcholinesterase inhibitor. 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 a molecular formula of C₁₇H₂₁NO₃•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: