Memantine

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Memantine quick reference

Memantine
Memantine general drug information
 Pronunciation meh MAN teen (.wav file)
 Trade Name(s) Namenda
 How Supplied Tablets: 5 mg, 10 mg, 5 and 10 mg titration pack
Oral solution: 10 mg/5 mL
 Generic Availability No generics available
 Patent Expiry Date March 2012
 Classification N-methyl-D-aspartate (NMDA) receptor antagonist, Alzheimer's agent
 Schedule Rx
 Pregnancy Category B
 Breast-feeding Unknown if excreted in breast milk. Use caution when breast-feeding.
Memantine chemical information
 IUPAC Name 1-amino-3,5-dimethyl-adamantane
 Empirical Formula C12H21N•HCl
 Molecular Weight 215.76 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Memantine slows the rate of clinical deterioration in patients with moderate to severe Alzheimer’s disease. This disease causes a progressive dementia leading to a steady decline in cognitive function which adversely affects functional abilities required for activities of daily living. Alzheimer’s disease impacts 15 million people worldwide and there is no cure. Treatment is the only means to slow this devastating disease.[1] Approximately 5% of the population over the age of 65 is affected by Alzheimer’s and the prevalence doubles every 5 years after the age of 65.[2] Memantine is a non-competitive receptor antagonist for the N-methyl-D-asparate (NMDA) receptor.[1] Glutamate is an excitatory neurotransmitter in the brain which stimulates the NMDA receptor. The NMDA receptor is influential for memory, dementia and Alzheimer’s disease. Too much glutamate in the brain leads to neuronal damage via a mechanism which results in excessive calcium in the neurons of the brain. Memantine was approved June 2002 in Europe and October 2003 in the USA.[3] It is derived from amantadine.[4]

Memantine is the only NMDA antagonist on the market to date and is approved for moderate to severe Alzheimer’s disease.[4] The drug demonstrates its efficacy by showing less deterioration when compared with placebo. The deterioration was measured by several scales which demonstrated a statistically significant difference, including The Severe Impairment Battery (p<0.001) and the Functional Assessment Staging Score (p=0.02).[1] Caregivers were noted to spend less time with those patients receiving memantine. The drug is well-tolerated, with more patients in the placebo group discontinuing therapy due to adverse effects.[1]

Mechanism of Action

Memantine is a non-competitive antagonist which blocks the N-methyl-D-asparate (NMDA) receptor. The NMDA receptor, when blocked, prevents excess calcium from entering the neurons, which has been proven to be neuroprotective.[4] Glutamate is the neurotransmitter that physically activates the NMDA receptors. In Alzheimer’s, glutamate causes excitotoxicity, which is thought to be the cause of neuronal cell death. When excitotoxicity occurs, glutamate stimulates the NMDA receptors leading to a rise in intracellular calcium. The excess calcium is toxic to the brain causing the progressive decline in brain function. Memantine binds at the magnesium binding site in the neurons causing a similar action to that of magnesium, though memantine stays in the channel longer. Memantine blocks calcium in a voltage-dependent manner. In rest, memantine blocks the NMDA receptors and in times of pathological over-activation, there is a “tonic increase” in glutamate levels. The drug allows for normal learning by not compromising the brain's synaptic plasticity and because of the pharmacokinetics of the drug, 15-20% of the channels are consistently unblocked and can be physically activated at any point. Via this mechanism, memantine prevents NMDA and glutamate induced neuronal cell death.[1]

Time Required for Therapeutic Response

  • Initial: Steady-state drug concentrations are reached in two weeks.[5]

Pharmacokinetics

Absorption
Memantine is completely absorbed from the gastrointestinal tract with a bioavailability of 100%. Food does not impact the bioavailability.[4] Peak concentrations are reached after 3-7 hours.[5]

Distribution
Memantine exhibits linear pharmacokinetics over the entire the dosage range of 10-40 mg/day. In healthy volunteers the Cmax is 24-29 mcg/L and the tmax is 3.3-6 hours. The AUC is 1716-2498 mcg*hr/L. The drug rapidly passes the blood-brain barrier and is present in the cerebral spinal fluid in less than thirty minutes.[4] The plasma protein binding is 45%.[5]

Metabolism
Memantine is metabolized by glucuronidation, hydroxylation and N-oxidation.[4] The metabolites are not active and include the N-glucuronide conjugate, 6-hydroxymemantine and 1-nitroso-deaminated memantine.[5] Cytochrome P 450 has not been shown to be a factor in the metabolism of memantine.

Excretion
75-90% of memantine and its metabolites are eliminated via the urine with 10-25% of the drug eliminated in the bile and feces.[4] 48% of the drug is excreted unchanged in the urine. 74% of the drug is eliminated as either unchanged drug or the N-glucuronide conjugate.[5] The elimination half-life is about 60-80 hours.[5] Urinary alkalinization appears to decrease the excretion by 7 to 9 fold.[4]

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Special Population Pharmacokinetics

  • Renal insufficiency: When compared to subjects with a creatine clearance (CrCl) of greater than 80 mL/min, the subjects with a CrCl ranging from 50-80 mL/min experienced an AUC increase of 4% and an 18% increase in half life. Those with a CrCl of 30-49 ml/min experienced a 60% increase in the AUC and a 41% increase in half life. Those subjects with a CrCl of 5-29 mL/min experienced an increase in AUC of 115% and a 95% increase in half life. Based on this data, the dosage only needs to be decreased if the patient has an estimated creatinine clearance of 5-29 mL/min.[5]
  • Hepatic insufficiency: No information available. Would expect minimal pharmacokinetic changes given the fact that memantine is only partially metabolized via the liver.
  • Hemodialysis: No information available.
  • Geriatric: The pharmacokinetics in all adult patients is similar.[5]
  • Pediatric: No information available.
  • Gender: Females had a 45% higher exposure when compared with men. This difference was not apparent when the exposure was corrected for body weight.[5]

Indications and Dosages

FDA Approved Indications

Moderate to severe Alzheimer's disease[5]

  • Starting dose:
    • 5 mg PO once daily
  • Maintenance dose:
    • 10 mg PO twice daily
  • Titration schedule: may use Namenda titration pack to facilitate titration. Goal is to increase dose by 5 mg every week as follows:
    • Week 1: 5 mg once daily
    • Week 2: 5 mg twice daily
    • Week 3: 5 mg in the morning, 10 mg in the evening
    • Week 4: 10 mg twice daily

Non-FDA Approved Indications

  • Dementia
  • Nystagmus
  • Huntington's disease
  • Schizophrenia

Dosage Adjustment

Renal insufficiency: For patients with a creatinine clearance between 5-29 mL/min, the target dose is 5 mg twice daily.[5]
Hemodialysis: Data not available.

Dosage Limits

  • Adults: 20 mg daily[5]
  • Elderly: 20 mg daily[5]
  • Adolescents and children: Data not available (not used in this patient population)[5]


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Administration

  • Route: Oral (tablet)
  • Method:
    • Swallow tablet with a drink of water.
    • Tablet should be taken once or twice a day as directed (time should be consistent from day to day) and may be taken without regard to meals.
  • Route: Oral (solution)
  • Method:
    • Solution should be taken once or twice a day as directed (time should be consistent from day to day) and may be taken without regard to meals.
    • Do not mix solution with another liquid.
    • Ensure correct amount of solution is administered at each dose.

Monitoring Parameters

  • Serum creatinine

Contraindications/Precautions

Contraindications

  • Known hypersensitivity to memantine HCl or to any of its excipients.[5]

Precautions

  • Seizure disorders: this drug has not been studied properly in patients who have seizure disorders.
  • Renal insufficiency: dosage adjustment is needed for CrCl of 29 mL/min or less.

Pregnancy indications

Category B

No adequate studies were conducted in pregnant women.

Breast-feeding indications

It is unknown whether or not memantine is secreted into breast milk.[5]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Memantine is generally well-tolerated with a discontinuation rate similar to placebo in three separate clinical trials involving 252, 404 and 166 patients. The most common adverse reactions experienced in clinical trials were headache, constipation, confusion, and coughing.[5]


Memantine Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All None
1-10% CNS Confusion (6%), somnolence (3%), hallucinations (3%)
Cardiovascular Hypertension (4%), cardiac failure (>1%)
Dermatologic Rash (>1%)
GI Constipation (5%), vomiting (3%)
Genitourinary Frequent micturation (>1%)
Neuromuscular/skeletal Back pain (3%)
Respiratory Coughing (4%), dyspnea (2%)
Miscellaneous Fatigue (2%), pain (3%)
<1% All Transient ischemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia, pneumonia, anemia, increased alkaline phosphatase, cataract, conjunctivitis

Overdosage Measures

There is a case report of a patient who consumed 400 mg of memantine. This patient experienced psychosis, hallucinations, and loss of consciousness. The patient recovered without consequence.[5]
Treatment:

  • The patient should be treated based on symptoms.
  • Acidification of the urine may help to hasten the excretion of memantine.
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
5 mg tablet tan oblong FL/5
10 mg tablet grey oblong FL/10
5 (28 count) and 10 (21 count) mg titration pack tan, grey oblong, oblong FL/5, FL/10
10 mg/5 mL solution clear - peppermint flavor
  • Inactive ingredients for tablets: black iron oxide (10 mg tablet only), colloidal silicon dioxide, FD&C Blue No. 2 (5 mg tablet only), FD&C Yellow No. 6 (5 mg tablet only), hypromellose, lactose, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, triacetin
  • Inactive ingredients for solution: citric acid, glycerin, methylparaben, natural peppermint flavor #104, propylene glycol, propylparaben, purified water, sodium citrate, sorbitol solution (70%)

Patient Information

  • Let your prescriber know if you have kidney disease, seizures, or are pregnant or breast-feeding.
  • Memantine can be taken with or without food.
  • This medication should be taken with a drink of water.
  • This medication should be taken at the same time each day.
  • If you are taking the oral solution, it is peppermint-flavored and should not be mixed with any other liquids.
  • Ask your prescriber or pharmacist before you take any medications for cough, cold or allergies.
  • Call your prescriber or pharmacist right away if you experience dizziness, confusion, vomiting, difficulty breathing, rash, or feel fidgety.
  • Some other side effects that you do not have to contact your prescriber or pharmacist for include constipation, drowsiness, difficulty sleeping, nausea, or headache. If these side effects are troublesome, please contact your prescriber or pharmacist.
  • Do not drive until you know how memantine affects you.
  • Keep memantine away from children.
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References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.
  2. ↑ Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129(Pt 11):2840-55.
  3. ↑ Memantine(Namenda®)Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs 2006;66(11):1515-34.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 Namenda® (memantine hydrochloride) package insert. New York, NY; Forest Laboratories; 2005 September.

PUBMED References

Efficacy Trial Articles

  1. Thomas C, Carroll BT, Maley RT, Jayanti K, Koduri A. Memantine and catatonic schizophrenia. Am J Psychiatry 2005;162(3):626.
  2. Cummings JL, Schneider E, Tariot PN, Graham SM, Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006 Jul 11;67(1):57-63.
  3. Dautzenberg PL, Wouters CJ, Bootsma JE. Observations from a 14-week open-label trial with memantine suggest variable response on behavioral symptoms and cognition, depending on former treatment of AD. International Psychogeriatrics. 2006 Mar;18(1):179-81.
  4. Feldman HH, Schmitt FA, Olin JT, Memantine MEM-MD-Study Group, Feldman HH, Schmitt FA, et al. Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Disease & Associated Disorders. 2006 Oct-Dec;20(4):263-8.
  5. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. American Journal of Geriatric Psychiatry. 2006 Aug;14(8):704-15.
  6. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ, et al. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.Archives of Neurology. 2006 Jan;63(1):49-54.
  7. Schmitt FA, van Dyck CH, Wichems CH, Olin JT, for the Memantine MEM-MD-Study Group, Schmitt FA, et al. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Disease & Associated Disorders. 2006 Oct-Dec;20(4):255-62.
  8. Cankurtaran ES, Ozalp E, Soygur H, Cakir A. Clinical experience with risperidone and memantine in the treatment of Huntington's disease. Journal of the National Medical Association. 2006 Aug;98(8):1353-5.
  9. Carpenter SS, Hatchett AD, Fuller MA. Catatonic schizophrenia and the use of memantine. Ann Pharmacother 2006;40(2):344-6.
  10. Thomas C, Carroll BT, Maley RT, Jayanti K, Koduri A. Memantine and catatonic schizophrenia. Am J Psychiatry 2005;162(3):626.
  11. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia.update of Cochrane Database Syst Rev. 2005;(3):CD003154; PMID: 16034889.Cochrane Database of Systematic Reviews. 2006(2):CD003154.
  12. Pasquini M, Biondi M. Memantine augmentation for refractory obsessive-compulsive disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2006 Aug 30;30(6):1173-5.
  13. Schifitto G, Yiannoutsos CT, Simpson DM, Marra CM, Singer EJ, Kolson DL, et al. A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy. Journal of Neurovirology. 2006 Aug;12(4):328-31.
  14. Shery T, Proudlock FA, Sarvananthan N, McLean RJ, Gottlob I. The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. British Journal of Ophthalmology. 2006 Jul;90(7):839-43.
  15. A, Evans SM. Acute effects of memantine in combination with alcohol in moderate drinkers. Psychopharmacology (Berl) 2004;172(1):16-24.
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Therapeutic Class Comparison Articles

  1. Gauthier S, Herrmann N, Ferreri F, Agbokou C, Gauthier S, Herrmann N, et al. Use of memantine to treat Alzheimer's disease. CMAJ Canadian Medical Association Journal. 2006 Aug 29;175(5):501-2.‘’’Full Text Here’’’
  2. Grossberg GT, Edwards KR, Zhao Q. Rationale for combination therapy with galantamine and memantine in Alzheimer's disease. Journal of Clinical Pharmacology. 2006 Jul;46(7 Suppl 1):17S-26S.
  3. Preskorn SH, Borges S, Flockhart D. Clinically relevant pharmacology of neuropsychiatric drugs approved over the last three years: part I. Journal of Psychiatric Practice. 2006 Jul;12(4):244-9.
  4. Rabins PV, Lyketsos CG. Cholinesterase inhibitors and memantine have a role in the treatment of Alzheimer's disease. Nature Clinical Practice Neurology. 2006 Nov;2(11):578-9.
  5. Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs. 2006;66(11):1515-34.

Pharmacokinetics Articles

  1. Rao N, Chou T, et al. Investigation of the pharmacokinetic and pharmacodynamic interactions between memantine and glyburide/metformin in healthy young subjects: a single-center, multiple-dose, open-label study. Clinical Therapeutics. 2005 Oct;27(10):1596-606.
  2. A, Ventura D, Rao N, Abramowitz W. Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 2006;79(1):134-43.
  3. AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother 2004;38(9):1389-94.
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Drug Interaction Articles

  1. No authors listed. Alzheimer's disease: beware of interactions with cholinesterase inhibitors. Prescrire International. 2006 Jun;15(83):103-6.
  2. ED, Vosburg SK, Ward AS, Haney M, Foltin RW. Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans. Pharmacol Biochem Behav 2006;83(1):47-55.

Adverse Effects Articles

  1. Monastero R, Camarda C, Pipia C, Camarda R. Visual hallucinations and agitation in Alzheimer's Disease due to memantine: report of three cases. J Neurol Neurosurg Psychiatry 2006.
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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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