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3/26/2001

FDA Approves Galantamine for Alzheimer's Disease

Cheryl A. Thompson

Galantamine hydrobromide, synthesized from an alkaloid found in daffodil bulbs, has been cleared for marketing as a treatment for mild to moderate Alzheimer's disease. Janssen Pharmaceutica and Ortho-McNeil Pharmaceutical will market the cholinesterase inhibitor under the brand name Reminyl (PDF).

The ability of galantamine to improve or stabilize the symptoms of Alzheimer's disease was assessed in four randomized, double-blind, placebo-controlled trials involving 2653 patients who probably had the dementia. Investigators diagnosed the patients by relying on criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and on scores from the Mini-Mental State Examination. Drug effectiveness was evaluated with the cognitive subscale of the Alzheimer's Disease Assessment Scale, which is a standardized instrument, and the version of the Clinician's Interview Based Impression of Change that incorporates information from a caregiver familiar with the patient’s behavior.

In three of the studies, patients assigned to galantamine groups initially received 4 mg twice daily for one week. This dosage was increased each week by 8 mg/day, in divided doses, until patients were receiving 24 or 32 mg of galantamine per day, depending on the study's design. In the fourth study, the 8-mg/day increase for two of the three galantamine groups occurred every four weeks until patients received their assigned dosage of 16 or 24 mg/day, in divided doses; the dosage for the third group did not change from 8 mg/day. The maintenance phase for the four studies lasted 10 to 23 weeks. For all of the studies, the 16-, 24-, and 32-mg/day galantamine groups had significantly better scores than the 8-mg/day and placebo groups.

Galantamine undergoes metabolism by the cytochrome P-450 enzyme system, primarily isoenzymes 2D6 and 3A4, or by conjugation with glucuronic acid. About 32% of a dose is excreted unchanged in the urine. Less than 20% of galantamine is bound to plasma proteins.

As a cholinesterase inhibitor, galantamine would be expected to exaggerate the neuromuscular blocking effects of succinylcholine and similar agents used during anesthesia. The drug may adversely affect cardiac conduction as a result of vagotonic effects on the sinoatrial and atrioventricular nodes, increase gastric acid secretion, interfere with normal bladder outflow, and aggravate severe asthma or obstructive pulmonary disease. Atropine may be used as an antidote to galantamine overdosage.

During the four major clinical studies, 24% of the galantamine-treated patients had nausea, usually during the initial weeks of dosage increases and commonly lasting five to seven days. Also reported more frequently in the galantamine-treated patients than in the placebo groups were vomiting (13%), dizziness (9%), diarrhea (9%), anorexia (9%), headache (8%), weight loss (7%), and depression (7%).

Metabolic pathways catalyzed by cytochrome P-450 isoenzymes 1A2, 2A6, 3A4, 4A, 2C, 2D6, and 2E1 are not inhibited in vitro by galantamine. Paroxetine and cimetidine, but not ranitidine, increase the oral bioavailability of galantamine above its usual 90%. Exposure to galantamine is increased 30% by ketoconazole and 10% by erythromycin.

The recommended starting dosage of galantamine is 4 mg twice daily. Increases of 8 mg/day, in two divided doses, may be made after at least four weeks at a given dosage. A maintenance dosage of 16–24 mg/day, in two divided doses, has been found to be effective and reasonably tolerated; however, the 24-mg/day dosage may not benefit patients much more than the 16-mg/day regimen. Patients with moderately impaired hepatic or renal function should not receive more than 16 mg of galantamine per day; those with severe hepatic or renal impairment should not receive the drug. Use of an antiemetic medication, administration of doses with the morning and evening meals, and adequate fluid intake may reduce the occurrence of nausea.

Reminyl, available starting in May, will be supplied as film-coated tablets in three strengths: 4 mg (off-white), 8 mg (pink), and 12 mg (orange-brown).