Memantine Hydrochloride Oral

1. INDICATIONS AND USAGE Memantine hydrochloride is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Memantine hydrochloride is 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 is 5 mg (2.5 mL) once daily. The dose should be increased in 5 mg increments to 10 mg/day (2.5 mL twice daily), 15 mg/day (2.5 mL and 5 mL as separate doses), and 20 mg/day (5 mL 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 (5 mL twice daily). Dosing Titration Schedule Memantine hydrochloride can be taken with or without food. If a patient misses a single dose of memantine hydrochloride, 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 for several days, dosing may need to be resumed at lower doses and retitrated as described above. Do not mix memantine hydrochloride oral solution with any other liquid. Memantine hydrochloride is administered with a dosing device that comes with the drug and consists of a syringe, press in bottle adaptor, 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. Special Populations Renal Impairment A target dose of 5 mg (2.5 mL) 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 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 (2.5 mL) once daily. Increase dose in 5 mg increments to a maintenance dose of 10 mg (5 mL) 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 (2.5 mL) twice daily. (2) dosing-titration-schedule

3. DOSAGE FORMS AND STRENGTHS Memantine hydrochloride 2 mg/mL oral solution: clear colourless, alcohol-free, sugar-free, and peppermint flavored. Oral Solution: 2 mg/mL (3)

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

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)].

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.

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 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 (Alzheimers 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. 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. Table 1 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.

Signs and symptoms most often accompanying memantine overdosage 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 2.0 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered. 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.

8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of memantine in pregnant women. Memantine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m 2 basis.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine hydrochloride is administered to a nursing mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use The majority of people with Alzheimer’s disease are 65 years and older. In the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old.

8.6 Renal Impairment No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)] .

Pregnancy Category B There are no adequate and well-controlled studies of memantine in pregnant women. Memantine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m 2 basis.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine hydrochloride is administered to a nursing mother.

Safety and effectiveness in pediatric patients have not been established.

The majority of people with Alzheimer’s disease are 65 years and older. In the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old.

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 hydrochloride 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, peppermint flavor 0516161, citric acid, sodium citrate, and purified water. memantine-structure

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.

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca 2+ , Na + or K + channels. Memantine also showed antagonistic effects at the 5HT 3 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.

13.1 Carginogenesis, 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/m 2 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/m 2 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/m 2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.