Memantine

1 INDICATIONS AND USAGE Memantine hydrochloride tablets are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Memantine hydrochloride tablets are an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. (1)

2 DOSAGE AND ADMINISTRATION The recommended starting dose of memantine hydrochloride tablets 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 hydrochloride tablets 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 [see Clinical Pharmacology (12.3) ] . May be taken with or without food. (2) Initial dose is 5 mg once daily. Increase dose in 5 mg increments to a maintenance dose of 10 mg twice daily. A minimum of 1 week of treatment with the previous dose should be observed before increasing the dose. (2) Severe renal impairment: recommended dose is 5 mg twice daily. (2)

6 ADVERSE REACTIONS Most common adverse reactions (≥ 5 % and greater than placebo) are dizziness, headache, confusion and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Memantine hydrochloride was evaluated in eight double-blind placebo-controlled trials involving a total of 1862 dementia (Alzheimer’s disease, vascular dementia) patients (940 patients treated with memantine hydrochloride and 922 patients treated with placebo) for a treatment period up to 28 weeks. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Events Leading to Discontinuation In placebo-controlled trials in which dementia patients received doses of memantine hydrochloride up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the memantine hydrochloride group (10.1%) as in the placebo group (11.5%). No individual adverse reaction was associated with the discontinuation of treatment in 1% or more of memantine hydrochloride-treated patients and at a rate greater than placebo. Most Common Adverse Reactions In double-blind placebo-controlled trials involving dementia patients, the most common adverse reactions (incidence ≥ 5% and higher than placebo) in patients treated with memantine hydrochloride were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred in at least 2% of patients treated with memantine hydrochloride and at an incidence greater than placebo. Table 1: Adverse Reactions Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Memantine Hydrochloride and at a Higher Frequency than Placebo-treated Patients Adverse Reaction Placebo (N = 922) % Memantine Hydrochloride (N = 940) % Body as a Whole Fatigue 1 2 Pain 1 3 Cardiovascular System Hypertension 2 4 Central and Peripheral Nervous System Dizziness 5 7 Headache 3 6 Gastrointestinal System Constipation 3 5 Vomiting 2 3 Musculoskeletal System Back pain 2 3 Psychiatric Disorders Confusion 5 6 Somnolence 2 3 Hallucination 2 3 Respiratory System Coughing 3 4 Dyspnea 1 2 The overall profile of adverse reactions and the incidence rates for individual adverse reactions in the subpopulation of patients with moderate to severe Alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population. Seizures Memantine hydrochloride has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine hydrochloride, seizures occurred in 0.2% of patients treated with memantine hydrochloride and 0.5% of patients treated with placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of memantine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: Blood and Lymphatic System Disorders - agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura. Cardiac Disorders - cardiac failure congestive. Gastrointestinal Disorders - pancreatitis. Hepatobiliary Disorders - hepatitis. Psychiatric Disorders - suicidal ideation. Renal and Urinary Disorders - acute renal failure (including increased creatinine and renal insufficiency). Skin Disorders - Stevens Johnson syndrome.

12.3 Pharmacokinetics Absorption Following oral administration memantine is highly absorbed with peak concentrations reached in about 3 to 7 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 to 11 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 AUC 0-∞ 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 C max 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 Co-administration 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, co-administration 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, co-administration 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, co-administration 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.