Vol. VII, No. 3
  May/June 2004

  Shannon Just, Pharm.D.*

 Return to
 Pharmacotherapy
 Update Index

Namenda™ (Memantine) for
Moderate-to-Severe Alzheimer's Disease

Introduction: Alzheimer's disease (AD) is a progressive, neurodegenerative disease that involves the disruption of multiple neurochemical pathways. Currently, over 4 million people in the United States (U.S.) are estimated to have AD with a projected rise to 7.7 million people by the year 2030.¹ It is the most common cause of dementia in people age 65 years or older, with 360,000 new cases diagnosed yearly. Approximately 100,000 people die of the disease annually, with the average patient living 8-10 years after diagnosis.¹

Degenerative changes in a variety of neurotransmitter systems lead to disruptions in glutamate, acetylcholine, norepinephrine, dopamine, and serotonin pathways, which eventually contribute to the severe cognitive and functional impairment observed in AD patients.^2,3 Although the exact cause of AD or which mechanisms cause the neurotransmitter systems to change is unknown, many theories exist.^2-4 One hypothesis involves acetylcholine deficiency and currently, the approved therapies by the Food and Drug Administration (FDA) only target this deficiency. Four acetylcholinesterase (AchE) inhibitors are approved by the FDA and are considered the mainstay of symptomatic therapy for AD.⁵ These agents include tacrine (Cognex®), donepezil (Aricept®), galantamine (Reminyl®), and rivastigmine (Exelon®). Unfortunately, these medications are only FDA-approved for the treatment of mild-to-moderate AD. Mild AD is considered the beginning stage when a patient is easily confused or disoriented and experiences minor memory loss. The moderate stage of AD is characterized by the emergence of major gaps in memory, deficits in cognitive function, and a true need for help with activities of daily living. Severe AD is when patients can no longer respond appropriately to the world around them and become completely dependent on others for activities of daily living.

AD is often assessed by using the Mini Mental State Exam (MMSE). The MMSE is a 30-point scale measuring cognitive function, with higher scores indicating better function.⁶ When using the MMSE as an assessment tool, a score of 10-26 indicates mild-to-moderate AD, whereas a score less than 10 is classified as severe AD.

Another hypothesis involves changes in the brain that lead to an increase in extracellular glutamate.² Glutamate is the principle excitatory neurotransmitter in the brain and increased levels lead to persistent activation of the central nervous system, specifically N-methyl-D-aspartate (NMDA) receptors. The NMDA receptor has been implicated in memory processes, dementia, and the pathogenesis of AD.⁶ Excessive stimulation of glutamate receptors, particularly the NMDA receptor, results in the death of cholinergic neurons, also known as excitotoxicity, and precipitates the cognitive deficits in AD patients.^2,3,5 NMDA antagonists include ketamine, an anesthetic not commonly used anymore; amantadine (Symmetrel®), sometimes used for Parkinson's disease; dextromethorphan, an antitussive agent; and, recently, memantine (Namenda™). Other agents also used for the treatment of symptoms associated with AD include benzodiazepines, antidepressants, and antipsychotics.

AD is the third most costly disease in the U.S., behind heart disease and cancer.¹ Each year, the U.S. spends at least $100 billion on the disease, since most insurance plans do not cover the long-term care necessary for most patients.¹ The majority of these costs come from caring for patients with severe AD, which previously had no approved treatment by the FDA. Memantine (Namenda™;Forest Pharmaceuticals, Inc) has been used clinically in Europe for many years for the treatment of various forms and stages of dementia, and it is now FDA-approved for the treatment of moderate-to-severe dementia of the Alzheimer's type.^2,7

Pharmacology: Memantine is a noncompetitive, low-to-moderate affinity NMDA receptor antagonist.^2-4,8 Due to its affinity for the receptor, it is not associated with the impaired learning or psychomimetic effects of agents with a high affinity for the receptor, such as ketamine.³ Memantine exerts its therapeutic effect by preferentially binding NMDA receptor-operated cation channels. By binding to these channels, memantine decreases the effects of glutamate.^4,7

Memantine has low-to-negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, in addition to voltage-dependent Ca²⁺, Na⁺, and K⁺ channels.⁷ Memantine also has antagonistic effects at the 5HT₃ receptor similar to its potency for the NMDA receptor and blocks nicotinic acetylcholine receptors with one-sixth to one-tenth of the potency; the clinical significance of this is unknown.⁷

Pharmacokinetics: Memantine is well absorbed following oral administration and appears to have linear pharmacokinetics over the therapeutic dosage range, with peak concentrations reached in about 3-7 hours.^7,9 Food has no effect on its absorption. The mean volume of distribution of memantine is 9-11 L/kg, and the plasma protein binding is low (45%).^7,9 It appears to concentrate in the brain and cerebrospinal fluid.⁹ Memantine undergoes little metabolism, with the majority (57-82%) of an administered dose excreted unchanged in urine; the remainder is converted primarily to three polar metabolites: the N-gludantan conjugate, 6-hydroxymemantine, and 1-nitrosodeaminated memantine.⁷ These metabolites possess minimal NMDA receptor antagonist activity. The hepatic microsomal cytochrome P450 (CYP) enzyme system does not play a significant role in the metabolism of memantine.⁷ Its terminal elimination half-life is about 60-80 hours.^7,9 Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption.

The pharmacokinetics of memantine can be significantly affected by high or low urine pH values.^7,10 Alkaline urine pH results in reduced renal excretion and renal clearance, while acidic urine pH may result in increased renal clearance of memantine.¹⁰

Clinical Studies: Four clinical studies have examined the use of memantine in patients suffering from dementia and evaluated its effects on patients' overall function and cognition (See Table 1). There were numerous tests used as outcome measures in these clinical trials. In addition to the MMSE, other tests include the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) which assesses the effect of medication on overall clinical status, while the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev) assesses functional capacity. The Severe Impairment Battery (SIB) is a performance based measure of cognition. The Clinical Global Impression of Change (CGI-C) measures overall illness severity and response to treatment. The Neuropsychiatric Inventory (NPI) assesses disturbances based on caregiver information regarding the patient's behavior and the associated distress felt by the caregiver. The Behavioral Rating Scale for Geriatric Patients (BGP) measures observable aspects of cognition, function, and behavior. Finally, the Global Deterioration Scale (GDS) is a seven-stage scale assessing a patient's functional capacity based on observation, with higher stages rep-resenting greater impairment (e.g., Stage 5 = moderately severe dementia, Stage 6 = severe dementia, and Stage 7 = very severe dementia).⁶

These studies all showed improved cognitive function, reduced decline in patient functioning, or reduced care dependence with memantine therapy. Additionally, memantine was well-tolerated in patients, with confusion or headache being common adverse effects.

Contraindications/Precautions: Memantine is contraindicated in patients with a known hypersensitivity to it or to any excipients used in the formulation, including lactose.⁷ Memantine has not been thoroughly evaluated in patients with seizure disorders. In clinical trials, seizures occurred in 0.2% of patients treated with memantine and 0.5% of patients treated with placebo.⁷

Conditions that raise urine pH (e.g., renal tubular acidosis and severe infections of the urinary tract) may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine.^7,10 The pharmacokinetics of memantine in patients with hepatic impairment have not been investigated, but would be expected to be only modestly affected since the agent undergoes minimal hepatic metabolism.⁷ There are inadequate data evaluating memantine in patients with mild, moderate, or severe renal impairment, but it is likely that patients with moderate renal impairment will have higher serum concentrations than normal subjects; dose reduction in these patients should be considered.⁷ The use of memantine in patients with severe renal impairment is not recommended.⁷

Adverse Reactions: In general, memantine seems to be well tolerated. Adverse events that were reported in controlled clinical trials in at least 2% of patients receiving memantine, and at a higher frequency than patients treated with placebo, include fatigue, somnolence, dizziness, confusion, hallucinations, headache, pain, hypertension, dyspnea, cough, constipation, and vomiting.⁷ Other adverse events in at least 2% of patients receiving memantine, but at an equal or lower frequency than patients treated with placebo, include depression, agitation, insomnia, anxiety, abnormal gait, falls, inflicted injury, urinary incontinence , urinary tract infection, diarrhea, nausea, anorexia, influenza-like symptoms, bronchitis, upper respiratory tract infection, peripheral edema, and arthralgia.⁷ There were no clinically significant changes from baseline in vital signs, laboratory values, or ECG parameters in patients treated with memantine.⁷ The most common side effects reported across clinical trials were dizziness, headache, urinary incontinence, insomnia, urinary tract infection, agitation, and diarrhea.^3,4

Drug-Drug Interactions: In vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes (i.e., CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4).⁷ Since memantine undergoes minimal metabolism, with the majority of the dose excreted unchanged in the urine, an interaction between memantine and drugs that are inhibitors of CYP450 enzymes is unlikely. The clearance of memantine was reduced by about 80% under alkaline urine conditions at a pH of 8.⁷ Alterations of urine pH toward the alkaline state may lead to an accumulation of memantine, with a possible increase in adverse effects. Drugs (e.g., carbonic anhydrase inhibitors and sodium bicarbonate) or clinical states (e.g., renal tubular acidosis and severe infections of the urinary tract) that alkalinize the urine would be expected to reduce the renal elimination of memantine.⁷ Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin (Coumadin®) and digoxin (Lanoxin®), is unlikely.⁷ The combined use of memantine with other NMDA antagonists (e.g., amantadine [Symmetrel®], ketamine, and dextromethorphan) has not been thoroughly evaluated, but caution should be used if administered together.⁷ Coadministration of memantine with the AchE inhibitor donepezil (Aricept®) did not affect the pharmacokinetics of either compound.⁷

Pregnancy and Lactation: Memantine is classified as a pregnancy risk category B. A pregnancy risk category B drug has either not demonstrated fetal risk in animal-reproduction studies and has no controlled studies in pregnant women, or animal studies have shown an adverse effect but the adverse effect in the first trimester has not been confirmed in controlled studies in women and there is no risk in later trimesters. It is unknown whether memantine is excreted in breast milk. Caution should be used in pregnant or nursing females.⁷

Dosing and Administration: The dosage of memantine shown to be effective in controlled-clinical trials is 20 mg/day. The recommended starting dose of memantine is 5 mg once daily, with a target dose of 20 mg/day.⁷ The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice a day), with a minimum of one week between each dose titration.⁷

Memantine can be taken with or without food. Adequate information on the effect of renal impairment on the pharmacokinetics of memantine is not available. However, since the major route of elimination is renal, it is very likely that subjects with moderate and severe renal impairment will have a lower drug clearance than normal subjects.⁷ Dose reduction is suggested in patients with moderate renal impairment, and use in patients with severe renal impairment is not recommended. There are no dose adjustments required based on gender, age, or hepatic impairment.⁷

Patients should be monitored for improvement in the clinical signs and symptoms of Alzheimer's disease, such as memory, activities of daily living, or orientation to surroundings.⁹

Investigational Uses: Some evidence suggests NMDA receptor involvement in pain due to nerve injury. Two studies have examined the use of memantine for diabetic neuropathy, postherpetic neuralgia, or neuropathic pain due to amputation or surgery. Both studies concluded that memantine showed no significant improvement in pain.^13,14 Other studies have investigated the use of memantine in mild-to-moderate vascular dementia. It appears that memantine shows improvement in cognition of these patients compared to placebo.^15,16 An abstract of a study done in Argentina suggests memantine may have some beneficial effects in Parkinson's disease.¹⁷

Cost: Memantine is available in both 5- and 10-mg tablets. The average wholesale price (AWP) for 60 tablets of either strength is approximately $136. It is also available as a Titration Pak containing 28 of the 5 mg tablets and 21 of the 10 mg tablets. Its AWP is approximately $111.¹⁸ A study reviewing the cost analysis of memantine in patients with moderate-to-severe AD suggested memantine treatment offers cost savings from a societal perspective examining caregiver productivity and patient nonmedical costs, such as adult day care or home health care.¹⁹

Formulary Status: Memantine is on the CCF Formulary of Accepted Drugs, along with 3 of the 4 FDA-approved AchE inhibitors, donepezil (Aricept®), galantamine (Reminyl®), and rivastigmine (Exelon®).

Conclusion: Memantine is the first of a new class of drugs (NMDA antagonists) for AD and the first FDA-approved treatment for moderate-to-severe AD. Memantine has shown improvement in cognitive and functional status in clinical trials of moderate-to-severe AD and has been well tolerated with minimal concerns regarding drug interactions. It appears to be effective as monotherapy or in combination with an AchE inhibitor for moderate-to-severe AD. Memantine offers symptomatic improvement in AD patients, but there is no evidence that it prevents or slows neurodegeneration.

Memantine is on the CCF Formulary of Accepted Drugs, along with 3 of the 4 FDA-approved acetylcholinesterase inhibitors, donepezil (Aricept®), galantamine (Reminyl®), and rivastigmine (Exelon®).

References:

1. Key Statistics at a Glance. Available at: www.namenda.com. Accessed: 10/24/03.
2. Wenk GL. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry 2003;64:7-10.
3. Mintzer JE. The search for better noncholinergic treatment options for Alzheimer's disease. J Clin Psychiatry 2003;64:18-22.
4. Guthrie EW. New drug: memantine. Pharmacist's Letter 2003;19:190715.
5. Alzheimer's disease: emerging noncholinergic treatments. Geriatrics Medicine for Midlife and Beyond 2003:3-15.
6. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ, for the Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333-41.
7. Namenda™ Package Insert. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2003 Oct.
8. Tariot P, Farlow M, Grossberg G, Gergel I, Graham S, Jin J. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. JAMA 2004;291:317-24.
9. Sawaya-Orgeldinger J: Memantine. In: Hutchison TA & Shahan DR (Eds): DRUGDEX® System. MICROMEDEX, Greenwood Village, Colorado (Edition expires 12/2003).
10. Freudenthaler S, Meineke I, Schreeb KH, Boakye E, Remy UG, Gleiter CH. Influence of urine pH and urinary flow on the renal excretion of memantine. Br J Clin Pharmacol 1998;46:541-6.
11. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and Efficacy in Severely Demented Patients During Treatment with Memantine). Int J Geriatr Psychiatry 1999;14:135-46.
12. Ruther E, Glaser A, Bleich S, Degner D, Wiltfang J. A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine. Pharmacopsychiatry 2000;33:103-8.
13. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery. Anesth Analg 2000;91:960-6.
14. Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia. Anesthesiology 2002;96:1053-61.
15. Wilcock G, Mobius HJ, Stoffler A for the MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild-to-moderate vascular dementia. Int Clin Psychopharmacol 2002;17:297-305.
16. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild-to-moderate vascular dementia. Stroke 2002;33:1834-9.
17. Merello M, Nouzeilles MI, Cammarota A, Leiguarda R. Effect of memantine on Parkinson's disease. Clin Neuropharmacol 1999;22:273-6.
18. Namenda™. Cardinal Wholesaler. Accessed April 27, 2004.
19. Wimo A, Winblad B, Stoffler A, Wirth Y, Mobius HJ. Resource utilization and cost analysis of memantine in patients with moderate-to-severe Alzheimer's disease. Pharmacoeconomics 2003;21:327-40.

*At the time of writing, Shannon Just was a Pharm.D. candidate at The Ohio Northern University College of Pharmacy.