Galantamine Hydrobromide

GALANTAMINE HYDROBROMIDE — galantamine hydrobromide capsule, extended release
Sun Pharmaceutical Industries, Inc.

1 INDICATIONS AND USAGE

Galantamine hydrobromide 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 Hydrobromide Extended-Release Capsules


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

The recommended starting dosage of galantamine hydrobromide 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 hydrobromide extended-release capsules shown to be effective in a controlled clinical trial is 16 to 24 mg/day.
Patients currently being treated with galantamine hydrobromide tablets can convert to galantamine hydrobromide extended-release capsules by taking their last dose of galantamine hydrobromide tablets in the evening and starting galantamine hydrobromide extended-release capsules once daily treatment the next morning. Converting from galantamine hydrobromide tablets to galantamine hydrobromide extended-release capsules should occur at the same total daily dosage.
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 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. The beneficial effects of galantamine hydrobromide extended-release capsules 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 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)].

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

3 DOSAGE FORMS AND STRENGTHS

Galantamine hydrobromide extended-release capsules contain 8 mg, 16 mg, and 24 mg galantamine as 10.25 mg, 20.51 mg, and 30.76 mg of galantamine hydrobromide, USP, respectively. Galantamine hydrobromide extended-release capsules are available in the following strengths:

8 mg (Size 2 white opaque/white opaque capsules imprinted ‘835’ with black ink on cap and body filled with white color capsule shaped uncoated tablet plain on both sides)

16 mg (Size 2 pink opaque/pink opaque capsules imprinted ‘836’ with black ink on cap and body filled with pink color capsule shaped uncoated tablet plain on both sides)

24 mg (Size 2 caramel opaque/caramel opaque capsules imprinted ‘837’ with black ink on cap and body filled with caramel color capsule shaped uncoated tablet plain on both sides)

4 CONTRAINDICATIONS

Galantamine hydrobromide 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. Inform patients and caregivers that the use of galantamine 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.
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=1,026) and 1 patient 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 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 1,000 person years compared to 22 to 61 per 1,000 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 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 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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