Pharmacology Update

Memantine Hydrochloride Tablets (Namenda)

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

The FDA has approved the first drug for the treatment of moderate-to-severe Alzheimer’s disease (AD). Memantine, a noncompetitive inhibitor of the N-methyl-D-aspartate (NMDA) receptor, has been available outside of the United States since 1982. It is licensed from Merz Pharmaceuticals in Germany and is marketed by Forest Pharmaceuticals as Namenda.

Indications

Memantine is indicated for the treatment of moderate-to-severe dementia of the Alzheimer’s type.1

Dosage

The starting dose is 5 mg once daily with a target dose of 20 mg daily. The dose should be increased in 5-mg increments at one-week intervals as follows; 5 mg twice daily, 5 mg and 10 mg as separate doses, and 10 mg twice daily.1 The drug may be taken without regard to meals. Dose reduction show is considered in patients with moderate renal impairment.1

Memantine is available as 5-mg and 10-mg tablets.

Potential Advantages

Memantine is the first drug approved for the treatment of moderate-to-severe AD. Results from clinical trials indicated that patients randomized to memantine or memantine plus donepezil were more likely to show a slower deterioration of disease compared to placebo or donepezil plus placebo.1-4 Less caregiver time was needed for patients who received memantine compared to placebo.2,5 Memantine is well tolerated and is not likely to interact with drugs metabolized by the cytochrome P450 isoenzymes.1

Potential Disadvantages

The most common side effects associated with memantine were dizziness (7% vs 5% for placebo), headache (6% vs 3%), and confusion (6% vs 5%). Twenty three percent of patients discontinued memantine in the clinical trial that compared memantine with placebo.2 Memantine may interact with other NMDA inhibitors such as amantadine, ketamine, and dextromethorphan, and food or drugs that increase of pH of the urine may lead to accumulation of the drug in the body. There is currently no evidence that the drug affects the underlying neurodegeneration of AD.1

Comments

Memantine is the first noncholinesterase inhibitor approved for the treatment of AD. In contrast, memantine acts on the glutamatergic system, as stimulation of the NMDA receptor by glutamate has been speculated to have a role in the disease.6 Memantine showed a better outcome than placebo as assessed by Alzheimer’s Disease Cooperative Study Activity of Daily Living inventory (ADCS-ADL) (0-54 scale) and the Severe Impairment Battery (SIB). ADCS-ADL measured 19 items of functional capacity such as ability to eat, dress, bathe, telephone, shop, travel, and performing household chores. SIB (0-100 scale) measured 9 areas of cognitive performance including attention, orientation, language, memory, visuospatial ability, construction praxis, and social interaction. These patients all had difficulties with self-care functions such as dressing, bathing, and toilet use at baseline. In a 28-week study (n = 252), a mean difference of 3.4 units in ADCS-ADL and 5.7 units in SIB was seen with memantine compared to placebo.1,2 Similarly, in a 24-week study (n = 404), patients on memantine plus donepezil showed a difference of 1.6 units in ADCS-ADL and 3.3 units in SIB compared to donepezil and placebo.1  

Analyses were based on intent to treat and last observation carried forward. A difference in caregiver time of about 50 hours per month was reported for the memantine group.2,5 A favorable trend in favor of memantine was reported in the time to institutionalization.5 While memantine showed measurable differences in some quantitative scales, there is no evidence that memantine slows the underlying neurodegeneration of the disease.1 No significant difference was seen with the Mini-Mental State Examination score, Global Deterioration Scale stage, or Neuropsychiatric Inventory score.2 These measure cognitive function, overall cognitive and functional capacity, and neuropsychiatric disturbance respectively. Memantine appears to be well tolerated, and the frequency of side effects was not significantly different than placebo.1 Significant cognitive benefit also been reported in patients with mild-to-moderate vascular dementia, but the global Clinician’s Interview Based Impression of Change (CIBIC-plus) did not reach statistical significance.7 Memantine is expected to be available in January 2004. The wholesale cost of memantine was not available at the time of this review.

Clinical Implications

AD is believed to affect about 4.5 million Americans, increasing as the population ages. Currently, 4 cholinesterase inhibitors (tacrine, donepezil, galantamine, and rivastigmine) are available for the treatment of mild-to-moderate disease. Memantine is the only drug approved for moderate-to-severe disease and has shown measurable difference in certain quantitative measures of disease symptoms at 24-28 weeks. The effect of the drugs has been characterized by the FDA’s Peripheral & Central Nervous System Drugs Advisory Committee as "small but consistent."8 The role of memantine in less-severe disease and the role of a combination with a cholinesterase inhibitor remains to be determined by clinical trials.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.

References

1. Namenda Product Information. Forest Pharmaceuticals, Inc. October 2003.

2. Reisberg B, et al. N Engl J Med. 2003;348(14): 1333-1341.

3. Tariot P, et al. J Am Geriatr Soc. 2003; 51(suppl 4):S225-S226.

4. Ferris SH, et al. J Am Geriatr Soc. 2003; 51(suppl 4):S77-S78.

5. Wimo A, et al. Pharmacoeconomics. 2003;21(5): 327-240.

6. Doggrell S. Expert Opin Pharmacother. 2003;4(10):1857-1860.

7. Orgogozo JM, et al. Stroke. 2002;33:1834-1839.

8. FDC Report. The Pink Sheet. 2003;65(39):23-24.