^ Pharmacodynamics
Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3 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.
^ Patient Counseling Information
See FDA-approved patient labeling (Patient Information).
To assure safe and effective use of Memantine Hydrochloride Tablets, the following information and instructions provided in the patient information section should be discussed with patients and caregivers.
Patients/caregivers should be instructed to follow the dose titration schedule provided by their physician or healthcare professional for Memantine Hydrochloride Tablets. They should be warned not to use any Memantine Hydrochloride Tablets that are damaged or show signs of tampering.
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 should not be resumed without consulting that patient's healthcare professional.
^ 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.
^ 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 C12H21N∙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 Tablets are 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: colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose. In addition the following inactive ingredients are also present as components of the film coat: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, iron oxide yellow (5 mg), iron oxide red (5 mg) and iron oxide black (10 mg).
^ Clinical Trials Experience
Memantine 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 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.
^ Hepatic Impairment
No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine Hydrochloride Tablets should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
^ Overdosage
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.
^ 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 is administered to a nursing mother.
^ 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)].
^3 Dosage Forms And Strengths
Memantine Hydrochloride Tablets 5 mg tablet: capsule-shaped, film-coated tablets are tan, with 12 debossed on one side and 832 on the other.
Memantine Hydrochloride Tablets 10 mg tablet: capsule-shaped, film-coated tablets are gray, with 13 debossed on one side and 832 on the other.
^ Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
^4 Contraindications
Memantine Hydrochloride Tablets are contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
^ 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.
^ Animal Toxicology And/or Pharmacology
Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose of 20 mg/day on a mg/m2 basis
In acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.
The relevance of these findings to humans is unknown.
^ How Supplied/storage And Handling
5 mg Tablet:
Tan, capsule-shaped, film-coated tablets with 12 debossed on one side and 832 on the other.
Bottle of 60 NDC #0832-1112-60
10 mg Tablet:
Gray, capsule-shaped, film-coated tablets with 13 debossed on one side and 832 on the other.
Bottle of 60 NDC #0832-1113-60
^ Geriatric Use
The majority of people with Alzheimer's disease are 65 years and older. In the clinical studies of memantine 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.
^ Carcinogenesis, 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/m2 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/m2 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/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
^Principal Display Panel - Mg Bottle Label
NDC 43353-170-18
MemantineHydrochloride Tablets
10 mg
3000 Tablets Rx only
^ Clinical Studies
The effectiveness of memantine as a treatment for patients with moderate to severe Alzheimer's disease was demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States that assessed both cognitive function and day to day function. The mean age of patients participating in these two trials was 76 with a range of 50-93 years. Approximately 66% of patients were female and 91% of patients were Caucasian. A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but did not assess cognitive function as a planned endpoint. Study Outcome Measures: In each U.S. study, the effectiveness of memantine was determined using both an instrument designed to evaluate overall function through caregiver-related assessment, and an instrument that measures cognition. Both studies showed that patients on memantine experienced significant improvement on both measures compared to placebo.
Day-to-day function was assessed in both studies using the modified Alzheimer's disease Cooperative Study - Activities of Daily Living inventory (ADCS-ADL). The ADCS-ADL consists of a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The investigator performs the inventory by interviewing a caregiver familiar with the behavior of the patient. A subset of 19 items, including ratings of the patient's ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores has been validated for the assessment of patients with moderate to severe dementia. This is the modified ADCS-ADL, which has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.
The ability of memantine to improve cognitive performance was assessed in both studies with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
^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.
^Repackaging Information
Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:
Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.
Repackaged by: Cookeville, TN 38506 20170620JH
^1 Indications And Usage
Memantine Hydrochloride Tablets are indicated for the treatment of moderate to severe dementia of the Alzheimer's type.
^ Use With Other N-methyl-d-aspartate (nmda) Antagonists
The combined use of memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
^ 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)].
^ 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.