MEMANTINE HYDROCHLORIDE

1 INDICATIONS AND USAGE Memantine hydrochloride extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Memantine hydrochloride is a 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 extended-release capsules is 7 mg once daily; the dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily; the minimum recommended interval between dose increases is one week. (2.1) Patients with severe renal impairment: the recommended maintenance dose of memantine hydrochloride extended-release capsules is 14 mg once daily. (2.3) 2.1 Recommended Dosing The dosage of memantine hydrochloride extended-release capsules shown to be effective in a controlled clinical trial is 28 mg once daily. The recommended starting dose of memantine hydrochloride extended-release capsules is 7 mg once daily. The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily. Memantine hydrochloride extended-release capsules can be taken with or without food. Memantine hydrochloride extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each memantine hydrochloride extended-release capsules should be consumed; the dose should not be divided. Except when opened and sprinkled on applesauce, as described above, memantine hydrochloride extended-release capsules should be swallowed whole. Memantine hydrochloride extended-release capsules should not be divided, chewed, or crushed. If a patient misses a single dose of memantine hydrochloride extended-release capsules, 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 extended-release capsules for several days, dosing may need to be resumed at lower doses and retitrated as described above. 2.2 Switching from Memantine Hydrochloride Tablets to Memantine Hydrochloride Extended-Release Capsules Patients treated with memantine hydrochloride tablets may be switched to memantine hydrochloride extended-release capsules as follows: It is recommended that a patient who is on a regimen of 10 mg twice daily of memantine hydrochloride tablets be switched to memantine hydrochloride extended-release capsules 28 mg once daily capsules the day following the last dose of 10 mg memantine hydrochloride tablet. There is no study addressing the comparative efficacy of these 2 regimens. In a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of memantine hydrochloride tablets be switched to memantine hydrochloride extended-release capsules 14 mg once daily capsules the day following the last dose of 5 mg memantine hydrochloride tablet. 2.3 Dosing in Patients with Renal Impairment In patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min, based on the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day [see Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS Each capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine hydrochloride USP. The 7 mg capsules are white to off-white coated pellets filled in the yellow opaque cap/yellow opaque body hard gelatin capsules imprinted with “M 7” on cap with black ink. The 14 mg capsules are white to off-white coated pellets filled in the yellow opaque cap/dark green opaque body hard gelatin capsules imprinted with “M 14” on cap with black ink. The 21 mg capsules are white to off-white coated pellets filled in the white to off-white cap/dark green opaque body hard gelatin capsules imprinted with “M 21” on cap with black ink. The 28 mg capsules are white to off-white coated pellets filled in the dark green opaque cap/dark green opaque body hard gelatin capsules imprinted with “M 28” on cap with white ink. Memantine hydrochloride is available as an extended-release capsule in the following strengths: 7 mg, 14 mg, 21 mg, 28 mg (3)

4 CONTRAINDICATIONS Memantine hydrochloride extended-release capsules are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. Memantine hydrochloride extended-release capsules are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. (4)

6 ADVERSE REACTIONS The most commonly observed adverse reactions occurring at a frequency of at least 5% and greater than placebo with administration of memantine hydrochloride extended-release capsules 28 mg/day were headache, diarrhea and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Memantine hydrochloride extended-release capsules were evaluated in a double-blind placebo-controlled trial in which a total of 676 patients with moderate to severe dementia of the Alzheimer’s type (341 patients on memantine hydrochloride extended-release capsules 28 mg/day and 335 patients on placebo) were treated for up to 24 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 practice. Adverse Reactions Leading to Discontinuation In the placebo-controlled clinical trial of memantine hydrochloride extended-release capsules, the proportion of patients in the memantine hydrochloride extended-release capsules group and the placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively. The most common adverse reaction that led to treatment discontinuation in the memantine hydrochloride extended-release capsules group was dizziness, at a rate of 1.5%. Most Common Adverse Reactions The most commonly observed adverse reactions seen in patients administered memantine hydrochloride extended-release capsules in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride extended-release capsules group and at a frequency higher than placebo, were headache, diarrhea and dizziness. Table 1 lists adverse reactions that were observed at an incidence of ≥ 2% in the memantine hydrochloride extended-release capsules group and occurred at a rate greater than placebo. Table 1: Adverse Reactions Observed with a Frequency of ≥ 2% in the Memantine Hydrochloride Extended-Release Capsules Group and at a Rate Greater than Placebo Adverse Reaction Placebo (n=335) % Memantine Hydrochloride Extended-Release Capsules 28 mg (n=341) % Gastrointestinal Disorders Diarrhea 4 5 Constipation 1 3 Abdominal pain 1 2 Vomiting 1 2 Infections and Infestations Influenza 3 4 Investigations Weight, increased 1 3 Musculoskeletal and Connective Tissue Disorders Back pain 1 3 Nervous System Disorders Headache 5 6 Dizziness 1 5 Somnolence 1 3 Psychiatric Disorders Anxiety 3 4 Depression 1 3 Aggression 1 2 Renal and Urinary Disorders Urinary incontinence 1 2 Vascular Disorders Hypertension 2 4 Hypotension 1 2 Seizure Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% 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.

7 DRUG INTERACTIONS 7.1 Drugs That Make 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 extended-release capsules with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of memantine hydrochloride extended-release capsules in pregnant women. Adverse developmental effects (decreased body weight and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are higher than those used in humans at the maximum recommended daily dose of memantine hydrochloride extended-release capsules [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats during the period of organogenesis resulted in decreased skeletal ossification in fetuses at the highest dose tested. The higher no-effect dose for adverse developmental effects (6 mg/kg) is 2 times the maximum recommended human daily dose (MRHD) of memantine hydrochloride extended-release capsules (28 mg) on a body surface area (mg/m 2 ) basis. Oral administration of memantine to rabbits (0, 3, 10, or 30 mg/kg/day) during the period of organogenesis resulted in no adverse developmental effects. The highest dose tested is approximately 20 times the MRHD of memantine hydrochloride extended-release capsules on a mg/m 2 basis. In rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally prior to and throughout mating and, in females, through the period of organogenesis or continuing throughout lactation to weaning. Decreased skeletal ossification in fetuses and decreased body weight in pups were observed at the highest dose tested. The higher no-effect dose for adverse developmental effects (6 mg/kg/day) is 2 times the MRHD of memantine hydrochloride extended-release capsules on a mg/m 2 basis. Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats from late gestation throughout lactation to weaning, resulted in decreased pup weights at the highest dose tested. The higher no-effect dose (6 mg/kg/day) is approximately 2 times the MRHD of memantine hydrochloride extended-release capsules on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine hydrochloride extended-release capsules on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for memantine hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from memantine hydrochloride extended-release capsules or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6 to 12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder and Pervasive Development Disorder - Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20 to 39 kg, 40 to 59 kg and ≥ 60 kg, respectively. In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-wee …

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.

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 C 12 H 21 N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a white to off-white, colored powder and is slightly soluble in water, soluble in methanol and practically insoluble in acetone. Memantine hydrochloride extended-release capsules are supplied for oral administration as 7 mg, 14 mg, 21 mg, and 28 mg capsules. Each capsule contains extended-release pellets with the labeled amount of memantine hydrochloride USP and the following inactive ingredients: ethylcellulose, hypromellose, polyethylene glycol, sugar spheres [which contains starch (maize) and sucrose] and talc. The hard gelatin capsule shell contains gelatin, iron oxide yellow and titanium dioxide. In addition the 14 mg, 21 mg and 28 mg hard gelatin capsule shell contains FD&C blue 1 and FD&C yellow 6. The 7 mg, 14 mg and 21 mg capsules are imprinted with black ink containing black iron oxide, potassium hydroxide and shellac. The 28 mg capsules are imprinted with white ink containing potassium hydroxide, shellac and titanium dioxide. Chemical Structure

10 OVERDOSAGE Signs and symptoms most often accompanying overdosage with other formulations of memantine 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 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. This patient experienced coma, diplopia, and agitation, but subsequently recovered. One patient participating in a memantine hydrochloride extended-release capsules clinical trial unintentionally took 112 mg of memantine hydrochloride extended-release capsules daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Memantine Hydrochloride Extended-Release Capsules , 7 mg are white to off-white coated pellets filled in the yellow opaque cap/yellow opaque body hard gelatin capsules imprinted with “M 7” on cap with black ink. Bottle of 30 NDC 59651-404-30 Bottle of 90 NDC 59651-404-90 Memantine Hydrochloride Extended-Release Capsules , 14 mg are white to off-white coated pellets filled in the yellow opaque cap/dark green opaque body hard gelatin capsules imprinted with “M 14” on cap with black ink. Bottle of 30 NDC 59651-405-30 Bottle of 90 NDC 59651-405-90 Memantine Hydrochloride Extended-Release Capsules , 21 mg are white to off-white coated pellets filled in the white to off-white cap/dark green opaque body hard gelatin capsules imprinted with “M 21” on cap with black ink. Bottle of 30 NDC 59651-406-30 Bottle of 90 NDC 59651-406-90 Memantine Hydrochloride Extended-Release Capsules , 28 mg are white to off-white coated pellets filled in the dark green opaque cap/dark green opaque body hard gelatin capsules imprinted with “M 28” on cap with white ink. Bottle of 30 NDC 59651-407-30 Bottle of 90 NDC 59651-407-90 Titration Pack Contains 28 capsules (7 x 7 mg, 7 x 14 mg, 7 x 21 mg, 7 x 28 mg) NDC 59651-408-28 Store memantine hydrochloride extended-release capsules at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].