Galantamine: Package Insert and Label Information

GALANTAMINE- galantamine hydrobromide capsule, extended release
Actavis Pharma, Inc.

1 INDICATIONS AND USAGE

Galantamine extended-release capsules are indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

2 DOSAGE AND ADMINISTRATION

2.1 Galantamine Extended-Release Capsules

Galantamine extended-release capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of galantamine extended-release capsules is 8 mg/day. The dosage should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

The dosage of galantamine extended-release capsules shown to be effective in a controlled clinical trial is 16 to 24 mg/day.

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.

2.3 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)].

2.4 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 extended-release capsules is not recommended [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Galantamine Extended-release Capsules, USP contain 8 mg, 16 mg, and 24 mg galantamine as 10.24 mg, 20.48 mg, and 30.72 mg of galantamine hydrobromide, respectively. Galantamine Extended-release Capsules, USP contain white to off-white matrix tablets and are available in the following strengths:

8 mg white opaque cap and body, size 1 hard gelatin capsules with inscription “WPI 3496”

16 mg pink opaque cap and white opaque body, size 1 hard gelatin capsules with the inscription “WPI 3497”

24 mg pink opaque cap and body, size 1 hard gelatin capsules with the inscription “WPI 3498”

4 CONTRAINDICATIONS

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

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 extended-release capsules. Inform patients and caregivers that the use of galantamine extended-release capsules 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 Reactions (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.

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 to 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 to 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.

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

Galantamine

Placebo

System/Organ Class

(n=3956)

(n=2546)

Adverse Reaction

%

%

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=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%).

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