The majority of people with Alzheimer’s disease are 65 years and older. In the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 years old.
No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2.0 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear.
Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.
Memantine hydrochloride USP is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride USP is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:
The molecular formula is C12 H21 N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a fine white to off-white powder and is soluble in water.
Memantine hydrochloride USP is for oral administration as capsule-shaped, film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride. The tablets also contain the following inactive ingredients: microcrystalline cellulose/colloidal silicon dioxide, talc, croscarmellose sodium, and magnesium stearate. In addition the following inactive ingredients are also present as components of the film coat: hypromellose, titanium dioxide, polyethylene glycol 400, FD&C yellow #6 and FD&C blue #2 (5 mg tablets), and hypromellose, titanium dioxide, macrogol/polyethylene glycol 400 and iron oxide black (10 mg tablets).
Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer’s disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer’s disease
Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.
In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.
Following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.
The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours.
The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
Pharmacokinetics in Specific Populations
Following multiple dose administration of memantine hydrochloride 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.
The pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar.
Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50 – 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment [see Dosage and Administration (2)].
Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.
Use with Cholinesterase Inhibitors
Coadministration of memantine with the AChE inhibitor donepezil hydrochloride did not affect the pharmacokinetics of either compound. Furthermore, memantine did not affect AChE inhibition by donepezil. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer’s disease, the adverse event profile observed with a combination of memantine hydrochloride and donepezil was similar to that of donepezil alone.
Effect of Memantine Hydrochloride on the Metabolism of Other Drugs
In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Pharmacokinetic studies evaluated the potential of memantine for interaction with warfarin, and buproprion. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate buproprion or its metabolite hydroxyl-buproprion. Furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin INR.
Effect of Other Drugs on Memantine Hydrochloride
Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of memantine.
Drugs Eliminated via Renal Mechanisms
Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of memantine hydrochloride and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin hydrochloride) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance® , indicating the absence of a pharmacodynamic interaction.
Drugs Highly Bound to Plasma Proteins
Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.
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