7 DRUG INTERACTIONS

7.1 Drugs that Make the Urine Alkaline

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.

7.2 Use with Other N-methyl-D-aspartate (NMDA) Antagonists

The combined use of memantine hydrochloride with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

2 DOSAGE AND ADMINISTRATION

The recommended starting dose of memantine hydrochloride is 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day.

Memantine hydrochloride tablets can be taken with or without food. If a patient misses a single dose of memantine hydrochloride tablets, that patient should not double up on the next dose. The next dose should be taken as scheduled.

If a patient fails to take memantine hydrochloridetablets for several days, dosing may need to be resumed at lower doses and retitrated as described above.

Specific Populations

Renal Impairment

A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min based on the Cockcroft- Gault equation).

Hepatic Impairment

Memantine hydrochloride tablets should be administered with caution to patients with severe hepatic impairment [seeClinical Pharmacology (12.3)].

11 DESCRIPTION

Memantine hydrochloride is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:

The molecular formula is C12H21N•HCl and the molecular weight is 215.76.

Memantine hydrochloride, USP is a white crystalline powder, soluble in water and in methanol, practically insoluble in acetone.

Each memantine hydrochloride tablet, USP intended for oral administration contains 5 mg or 10 mg of memantine hydrochloride. In addition, each film- coated tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hypromellose, microcrystalline cellulose, magnesium stearate, polyethylene glycol, povidone, talc and titanium dioxide**.**

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Absorption

Following oral administration memantine is highly absorbed with peak concentrations reached in about 3 to7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.

Distribution

The mean volume of distribution of memantine is 9 to11 L/kg and the plasma protein binding is low (45%).

Metabolism

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

Elimination

Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half- life of about 60 to 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

Gender

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.

Elderly

The pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar.

Renal Impairment

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50 to 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 to 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 to 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)].

Hepatic Impairment

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 to 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.

Drug-Drug Interactions

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 hydroxy-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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity in a 113 week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (20 and 10 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (9 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

13.2 Animal Toxicology and/or Pharmacology

Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose of 20 mg/day on a mg/m2 basis.

In acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.

The relevance of these findings to humans is unknown.