Galantamine Information
Galantamine () Description
Galantamine () is a reversible, competitive acetylcholinesterase inhibitor. Galantamine () hydrobromide is known chemically as (4a,6,8a)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6-benzofuro[3a,3,2-][2]benzazepin-6-ol hydrobromide. 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 for oral use are available in round, biconvex, film-coated tablets of 4 mg (yellow), 8 mg (dark pink), and 12 mg (red). Each 4, 8, and 12 mg (base equivalent) tablet contains 5.126, 10.253, and 15.379 mg of Galantamine () hydrobromide, respectively.
Inactive ingredients are: hypromellose, mannitol, polyethylene glycol, polysorbate 80, sodium stearyl fumarate, sodium starch glycolate, talc and titanium dioxide.
In addition: the 4 mg also contains D&C yellow no. 10 aluminum lake and FD&C yellow no. 6/Sunset yellow FCF.
The 8 mg also contains D&C red no. 30/Helendon pink aluminum lake and FD&C blue no. 2/Indigo carmine aluminum lake.
The 12 mg strength also contains FD&C red no. 40/Allura red AC aluminum lake.
Tablets meet USP Dissolution Test 2.
Galantamine () Clinical Pharmacology
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.
Galantamine () is well absorbed with absolute oral bioavailability of about 90%. It has a terminal elimination half-life of about 7 hours and pharmacokinetics are linear over the range of 8 to 32 mg/day.
The maximum inhibition of acetylcholinesterase activity of about 40% was achieved about one hour after a single oral dose of 8 mg Galantamine () in healthy male subjects.
(see also )
Multiple metabolic pathways and renal excretion are involved in the elimination of Galantamine () so no single pathway appears predominant. Based on studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of Galantamine () . CYP2D6 was involved in the formation of O-desmethyl-Galantamine () , whereas CYP3A4 mediated the formation of Galantamine () -N-oxide. Galantamine () is also glucuronidated and excreted unchanged in urine.
Galantamine ()
Galantamine () Indications And Usage
Galantamine () Tablets USP are indicated for the treatment of mild to moderate dementia of the Alzheimer's type.
Galantamine () Contraindications
Galantamine () Tablets are contraindicated in patients with known hypersensitivity to Galantamine () hydrobromide or to any excipients used in the formulation.
Galantamine () Warnings
Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. These actions may be particularly important to patients with supraventricular cardiac conduction disorders or to patients taking other drugs concomitantly that significantly slow heart rate. Postmarketing surveillance of marketed anticholinesterase inhibitors has shown, however, that 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.
In randomized controlled trials, bradycardia was reported more frequently in Galantamine () -treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation. The overall frequency of this event was 2 to 3% for Galantamine () doses up to 24 mg/day compared with
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]).
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 (see ).
Galantamine () Precautions
Caregivers should be instructed about the recommended dosage and administration of Galantamine () . Galantamine () tablets should be administered twice per day, preferably with the morning and evening meals. Dose escalation (dose increases) should follow a minimum of four weeks at prior dose.
Patients and caregivers should be advised that the most frequent adverse events associated with use of the drug can be minimized by following the recommended dosage and administration.
Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for several days or longer, the patient should be restarted at the lowest dose and the dose escalated to the current dose.
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=1026) and 1 subject on placebo (n=1022) died. The deaths were due to a 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 1000 person years compared to 22 to 61 per 1000 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 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 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.
In a 24-month oral carcinogenicity study in rats, a slight increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the Maximum Recommended Human Dose [MRHD] on a mg/mbasis or 6 times on an exposure [AUC] basis) and 30 mg/kg/day (12 times MRHD on a mg/mbasis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/mbasis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/mand AUC basis).
Galantamine () was not carcinogenic in a 6-month oral carcinogenicity study in transgenic (P 53-deficient) mice up to 20 mg/kg/day, or in a 24-month oral carcinogenicity study in male and female mice up to 10 mg/kg/day (2 times the MRHD on a mg/mbasis and equivalent on an AUC basis).
Galantamine () produced no evidence of genotoxic potential when evaluated in the Ames or reverse mutation assay, mouse lymphoma assay, micronucleus test in mice, or chromosome aberration assay in Chinese hamster ovary cells.
No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/mbasis) for 14 days prior to mating in females and for 60 days prior to mating in males.
Galantamine () Adverse Reactions
Other adverse events from post-approval controlled and uncontrolled clinical trials and post-marketing experience observed in patients treated with Galantamine () include:
Body as a Whole - General Disorders
Psychiatric Disorders
Gastrointestinal System Disorders
Metabolic & Nutritional Disorders
These adverse events may or may not be causally related to the drug.
Galantamine () 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 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 a post-marketing 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.
Galantamine () Dosage And Administration
The dosage of Galantamine () Tablets shown to be effective in controlled clinical trials is 16 to 32 mg/day given as twice daily dosing. As the dose of 32 mg/day is less well tolerated than lower doses and does not provide increased effectiveness, the recommended dose range is 16 to 24 mg/day given in a BID regimen. The dose of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dose of 24 mg of Galantamine () Tablets might provide additional benefit for some patients.
The recommended starting dose of Galantamine () Tablets is 4 mg twice a day (8 mg/day). The dose should be increased to the initial maintenance dose 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). Dose 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 several days or longer, the patient should be restarted at the lowest dose and the dose escalated to the current dose.
The abrupt withdrawal of Galantamine () Tablets in those patients who had been receiving doses in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same doses of that drug. The beneficial effects of Galantamine () Tablets are lost, however, when the drug is discontinued.
Galantamine () How Supplied
Galantamine () Tablets USP are available as follows:
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from light and moisture.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
Sellersville, PA 18960
Iss. 7/2010
Galantamine () Principal Display Panel
Galantamine ()
Tablets USP
4 mg*
Rx only
60 TABLETS
TEVA
Galantamine () Principal Display Panel
Galantamine ()
Tablets USP
8 mg*
Rx only
60 TABLETS
TEVA
Galantamine () Principal Display Panel
Galantamine ()
Tablets USP
12 mg*
Rx only
60 TABLETS
TEVA
