MEMANTINE HYDROCHLORIDE

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 HCl occurs as a fine white to off-white powder and is soluble in water. Memantine HCl is available as tablets or as an oral solution. Memantine HCl is available 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). Memantine HCl oral solution contains memantine hydrochloride in a strength equivalent to 2 mg of memantine hydrochloride in each mL. The oral solution also contains the following inactive ingredients: sorbitol solution (70%), methylparaben, propylparaben, propylene glycol, glycerin, natural peppermint flavor #104, citric acid, sodium citrate, and purified water. Structural Formula

Memantine hydrochloride is indicated for the treatment of moderate to severe dementia of the Alzheimer's type. Memantine HCl is an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer's type. ( 1 )

The recommended starting dose of Memantine HCl 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 HCl can be taken with or without food. If a patient misses a single dose of Memantine HCl, 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 HCl for several days, dosing may need to be resumed at lower doses and retitrated as described above. Do not mix Memantine HCl oral solution with any other liquid. The oral solution is administered with a dosing device that comes with the drug and consists of a syringe, syringe adaptor cap, tubing and other supplies a patient needs to administer the drug. The supplied syringe should be used to withdraw the correct volume of oral solution and the oral solution should be slowly squirted into the corner of the patient's mouth. 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 ) Special Populations Renal Impairment A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min based on the Cockroft-Gault equation). Hepatic Impairment Memantine HCl should be administered with caution to patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

Memantine hydrochloride is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. Memantine HCl is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. ( 4 )

Most common adverse reactions (≥ 5 % and greater than placebo) are dizziness, headache, confusion and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Memantine HCl 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 HCl 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 HCl up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the Memantine HCl 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 HCl-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 HCl were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred in at least 2% of patients treated with Memantine HCl and at an incidence greater than placebo. Table 1: Adverse Reactions Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Memantine HCl and at a Higher Frequency than Placebo-treated Patients Adverse Reaction Placebo (N = 922) % Memantine HCl (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 HCl has not been systematically evaluated in patients with a seizure disorder. In clinical trials of Memantine HCl, seizures occurred in 0.2% of patients treated with Memantine HCl 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.

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 HCl with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.