Galantamine: A New Agent for the Treatment of AD

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved the fourth acetylcholineasterase (AchE) inhibitor for the treatment of Alzheimer’s disease (AD). Galantamine, a reversible competitive inhibitor of AchE, is an alkaloid that was originally extracted from bulbs of the daffodil. It has been in use in several other countries for decades.1 Galantamine is marketed by Janssen Pharmaceutica as Reminyl.

Indications

Galantamine is indicated for the treatment of mild-to-moderate dementia of the Alzheimer’s type.

Dosage

The recommended starting dose is 4 mg twice daily for a minimum of 4 weeks. If the dose is tolerated, the dose should be increased to 8 mg twice daily. After a minimum of 4 weeks, an increase to 12 mg twice daily should be attempted.2 Doses should be administered with morning and evening meals to reduce gastrointestinal side effects. In the clinical trials, the dose of 24 mg was not statistically superior to 16 mg, but some patients may gain additional benefit. The 32-mg dose is less tolerated and does not appear to offer additional benefit. In patients with moderate hepatic or renal impairment, the dose should not exceed 16 mg/d. The use of galantamine is not recommended in patients with severe hepatic or renal impairment.2

Galantamine is supplied as 4-mg, 8-mg, and 12-mg tablets.

Potential Advantages

Galantamine appears to have a low potential for interacting with the major cytochrome P450 isoenzymes.2 In addition to inhibition of AchE, galantamine interacts with the nicotinic acetylcholine receptors. This action is believed to enhance the action of acetylcholine on the receptors resulting in the release of acetylcholine and other neurotransmitters such as glutamate.3,4 This "additional" mechanism has yet to be demonstrated clinically. The FDA has not allowed a claim of dual mechanism of action in the product labeling.

Potential Disadvantages

Galantamine requires at least 8 weeks to reach the target dose of 24 mg/d. Most common side effects compared to placebo are gastrointestinal, nausea (24% vs 9%), and vomiting (13% vs 4%).2 Paroxetine increases the oral bioavailability of galantamine by 40%.2 Galantamine requires twice-daily dosing.

Comments

The efficacy of galantamine in mild-to-moderate Alzheimer’s disease was reported in 3 large 5- or 6-month studies, of which 2 were from the United States and 1 was international.5-7 There were 653 subjects in the international trial, 978 in the 5-month US study, and 636 in the 6-month US study. Diagnosis of probable AD was based on the National Institute of Neurologic and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorder Association (NINCDS-ADRDA), a score of 10 or more and 24 or less on the Mini Mental State Examination score (MMSE), and a score of 12 or more on the standard 11-item cognitive subscale of the Alzheimer’s Assessment Scale (ADAS-cog). The primary efficacy measures were the ADAS-cog and the Clinician’s Interview Based Impression of Change plus Caregiver Input (CIBIC-plus). Patients were escalated to a maintenance dose of 8-32 mg/d. Measures were analyzed on an intent-to-treat as well as on an observed case basis. Observed cases are those with postbaseline data using last-observation-carried-forward (LOCF). Galantamine showed a difference in ADAS-cog between placebo in intent-to-treat analysis of 3.1 for 16 mg/d, 0.1-3.1 for 24 mg/d, and 3.2-3.4 for the 32 mg/d. On the observed case basis, the results were 3.3, 3.2-3.9, and 3.8-4.1, respectively. Roughly 1/3 of patients achieved clinically meaningful improvement of 4 units or greater compared to 15-20% on placebo. About 2/3 (64-70%) of subjects showed improvement in the CIBIC-plus compared to about half (47-55%) on placebo.

Galantamine has been reported to reduce the time caregivers spent assisting patients with activity of daily living of 15-38 min/d compared to an increase of 23 min in the placebo group.3,8

Clinical Implications

Currently, there are no direct comparisons among the available AchE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—however, it appears that their effects on ADAS-cog are similar in magnitude. Their potential secondary pharmacologic actions may differ.

Rivastigmine inhibits butrylcholinesterase while galantamine is a modulator of the nicotinic receptors. The importance of these secondary mechanisms have not been established. Until there is more comparative information, donepezil may be preferred because of its convenient once-daily dosing and it generally does not require dose titration. Rivastigmine, donepezil, and galantamine are priced similarly.

References

1. Grutzendler J, Morris JC. Drugs. 2001;61(1):41-52.

2. Reminyl Product Information. Janssen Pharmaceutica. March 2001.

3. Scott LJ, Goa KL. Drugs. 2000;60(5):1095-1122.

4. Albuquerque EX, et al. J Pharmacol Exp Ther. 1997; 280:1117-1136.

5. Raskind MA, et al. Neurology. 2000;54(12):2261-2268.

6. Tariot PN, et al. Neurology. 2000;54(12):2269-2276.

7. Wilcock GK, et al. BMJ. 2000;321:1-7.

8. Wilcock G, et al. Seventh World Alzheimer Congress; July 9-18, 2000: Washington, DC (poster).