galantamine hydrobromide

Administer GALANTAMINE ER extended-release capsules once daily in the morning, preferably with food. Ensure adequate fluid intake during treatment.

The recommended starting dosage of GALANTAMINE ER 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 ER shown to be effective in a controlled clinical trial is 16–24 mg/day.

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 ER in patients with severe hepatic impairment (Child-Pugh score of 10–15) is not recommended [see Clinical Pharmacology (12.3)] .

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

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 ER 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.

Patients currently being treated with galantamine tablets can convert to GALANTAMINE ER (extended-release capsules) by taking their last dose of galantamine tablets in the evening and starting GALANTAMINE ER once daily treatment the next morning. Converting from galantamine tablets to GALANTAMINE ER should occur at the same total daily dosage.

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving GALANTAMINE ER and galantamine tablets. Inform patients and caregivers that the use of GALANTAMINE ER 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.

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

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]).

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 with GALANTAMINE ER, the patient's weight should be monitored.

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

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 ER.

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

Because of its cholinomimetic action, GALANTAMINE ER 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.

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.

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 (≥5%) in galantamine-treated patients from double-blind clinical trials 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.

The following additional adverse reactions have been identified during post-approval use of GALANTAMINE ER or 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

Galantamine has the potential to interfere with the activity of anticholinergic medications [see Clinical Pharmacology (12.3)] .

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)] .

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 ER on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GALANTAMINE ER and any potential adverse effects on the breastfed infant from GALANTAMINE ER or from the underlying maternal condition.

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

Eight double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 6519 patients have investigated GALANTAMINE ER 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.

In patients with moderate hepatic impairment, a dosage adjustment is recommended. The use of GALANTAMINE ER in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] .

In patients with a creatinine clearance of 9 to 59 mL/min, a dosage adjustment is recommended. The use of GALANTAMINE ER in patients with creatinine clearance less than 9 mL/min is not recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] .

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.

The pharmacokinetics of galantamine are linear over a dose range of 8–32 mg/day.

In each study, the primary effectiveness of galantamine was evaluated using a dual outcome assessment strategy as measured by the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Impression of Change that required the use of caregiver information (CIBIC-plus).

The ability of galantamine to improve cognitive performance was assessed with the cognitive sub-scale of the Alzheimer's Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The patients recruited as participants in each study using the tablet formulation had mean scores on ADAS-cog of approximately 27 units, with a range from 5 to 69. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggests that they gain 6 to 12 units a year on the ADAS-cog. Lesser degrees of change, however, are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in galantamine trials was approximately 4.5 units per year.

The ability of galantamine to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-plus evaluations from other clinical trials. The CIBIC-plus used in the trials was a semi-structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of 4 major areas of patient function: general, cognitive, behavioral and activities of daily living. It represents the assessment of a skilled clinician based on his/her observation at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "marked worsening." The CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

The efficacy of galantamine extended-release capsules was studied in a randomized, double-blind, placebo-controlled trial which was 6 months in duration and had an initial 4-week dose-escalation phase. In this trial, patients were assigned to one of 3 treatment groups: Galantamine extended-release capsules in a flexible dose of 16 to 24 mg once daily; galantamine tablets in a flexible dose of 8 to 12 mg twice daily; and placebo. The primary efficacy measures in this study were the ADAS-cog and CIBIC-plus. On the protocol-specified primary efficacy analysis at Month 6, a statistically significant improvement favoring galantamine extended-release capsules over placebo was seen for the ADAS-cog, but not for the CIBIC-plus. Galantamine extended-release capsules showed a statistically significant improvement when compared with placebo on the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, a measure of function, and a secondary efficacy measure in this study. The effects of both galantamine extended-release capsules and galantamine tablets on the ADAS-cog, CIBIC-plus, and ADCS-ADL were similar in this study.

How Supplied

GALANTAMINE ER (galantamine extended-release capsules) are supplied as follows:

8 mg white opaque, size 4 hard gelatin capsules with the inscription "GAL 8" – bottles of 30 (NDC 10147-0891-3)

16 mg pink opaque, size 2 hard gelatin capsules with the inscription "GAL 16" – bottles of 30 (NDC 10147-0892-3)

24 mg caramel opaque, size 1 hard gelatin capsules with the inscription "GAL 24" – bottles of 30 (NDC 10147-0893-3)

Storage and Handling

GALANTAMINE ER extended-release capsules should be stored at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Serious Skin Reactions

Advise patients and caregivers to discontinue GALANTAMINE ER and seek immediate medical attention at the first appearance of skin rash [see Warnings and Precautions (5.1)] .

General Dosing Guidance

Instruct caregivers about the recommended dosage and administration of GALANTAMINE ER. GALANTAMINE ER extended-release capsules should be administered once daily in the morning, preferably with food. Dose escalation (dose increases) should follow a minimum of four weeks at prior dose. If therapy has been interrupted for more than three days, the patient should be restarted with the lowest dose and then re-titrated to an appropriate dosage [see Dosage and Administration (2)] .

Advise patients and caregivers to ensure adequate fluid intake during treatment [see Dosage and Administration (2)] .

Advise patients and caregivers that the most frequent adverse events associated with use of the drug can be minimized by following the recommended dosage and administration.