Vol. IV, No. 4
   July/August 2001

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 Pharmacotherapy
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Galantamine
Did You Know...

Galantamine (Reminyl^®; Janssen), is a tertiary alkaloid isolated from the bulbs of the daffodil and is a competitive and reversible inhibitor of acetylcholinesterase. It is FDA-approved for the treatment of mild-to-moderate dementia of the Alzheimer's type. The exact mechanism of galantamine's action is unknown, however, it is thought to exert its therapeutic effect by enhancing cholinergic function and thereby increasing the concentration of acetylcholine.

Peak levels of galantamine are reached about 1 hour after oral administration. It is well absorbed orally (90% bioavailability) and plasma protein binding is 18%. The volume of distribution of galantamine is 175 L. The elimination half-life is approximately 1 hour, while the terminal elimination half-life is approximately 7 hours. About 20 to 50% of the galantamine dose is excreted unchanged in the urine and two metabolites, epigalantamine and galanthamione, have been detected in plasma and urine.

Galantamine is metabolized by the cytochrome P-450 2D6 and 3A4; therefore, agents that inhibit or induce these isozymes may impact the hepatic clearance of galantamine. The clearance of galantamine is decreased when given with amitriptyline, fluoxetine, fluvoxamine, and quinidine. Potent inhibitors (e.g., ketoconazole, paroxetine, and erythromycin) may increase the AUC of galantamine. Galantamine has no effect on the pharmacokinetics of warfarin or digoxin.

Adverse effects of galantamine include nausea, vomiting, diarrhea, anorexia, and weight loss. Administration with food, use of anti-emetics, and ensuring adequate fluid intake may reduce the severity or occurrence of nausea and vomiting. Other adverse events that occurred in at least 2% of treated patients include fatigue, syncope, dizziness, headache, tremor, abdominal pain, dyspepsia, bradycardia, depression, insomnia, somnolence, anemia, rhinitis, urinary tract infection, and hematuria.

The recommended starting dose (See table 2) of galantamine is 8 mg/day, administered in two divided doses preferably with the morning and evening meal. If this dose is well tolerated after a minimum of four weeks, the dose should be increased to 16 mg/day (8 mg twice daily). A further increase to 24 mg/day (12 mg twice daily) should be attempted only after a minimum of four weeks at the previous dose. In clinical trials, galantamine was shown to be effective at doses of 16 to 32 mg/day. The dose of galantamine should not exceed 16 mg/day in patients with moderate hepatic impairment, and it should not be administered in patients with severe hepatic or renal impairment.

Galantamine, approved February 2001, is indicated for mild-to-moderate dementia of the Alzheimer's type. It is available as a 4-, 8-, and 12 mg tablet (See Table 3). The initial dose of galantamine is 4 mg twice daily and may be increased to a maximum dose of 24 mg/day. Gastrointestinal effects appear to be the most common adverse effects, however, by taking the recommended dose and taking galantamine with food, these adverse effects may be diminished.