MEMANTINE HCS 20 mg

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) ] .

5 WARNINGS AND PRECAUTIONS Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine. (5.1 , 7.1) 5.1 Genitourinary Conditions Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see Drug Interactions (7.1) ] .

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.