Each tablet contains memantine HCl.
Pharmacology: The main active ingredient of Memotin tablet is memantine HCl, an N-methyl-D-aspartate (NMDA) receptor antagonist used for the palliative treatment of moderate to severe dementia of the Alzheimer's disease.
Pharmacodynamics: 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, that 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.
Pharmacokinetics: Absorption: Memantine hydrochloride is well absorbed following oral administration, with peak plasma concentrations achieved in about 3-7 hours and has linear pharmacokinetics over the therapeutic dose range. There is no difference in memantine exposure whether the drug is taken with food or on empty stomach. However, Cmax is achieved about 18 hours after administration with food compared with 25 hours after administration on an empty stomach. Memantine may be taken without regard to food.
Distribution: The mean volume of distribution of memantine is 9 to 11 L/kg, and the plasma protein binding is low (45%).
Metabolism/Excretion: Memantine undergoes partial hepatic metabolism; about 48% of administered drug is excreted unchanged in urine. The remainder is converted primarily to 3 polar metabolites, which pose minimal NMDA receptor antagonist activity: N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucoronide conjugate. The hepatic microsomal cytochrome P450 (CYP-450) enzyme system does not play a significant role in the metabolism of memantine. Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption. Memantine has a terminal elimination half-life of about 60 to 80 hours.
Special populations: Renal function impairment: Mean AUC0-∞ increased 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects. The terminal elimination half-life increased 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects.
Hepatic function impairment: Terminal elimination half-life increased by approximately 16% in subjects with moderate hepatic impairment when compared with healthy subjects. The pharmacokinetics of memantine have not been evaluated in patients with severe hepatic impairment.
Gender: Following multiple-dose administration of memantine 20 mg twice daily, women has an approximately 45% higher exposure than men but there was no difference in exposure when body weight was taken into account.
Memantine hydrochloride is indicated for treatment of moderate to severe dementia of the Alzheimer's type.
Recommended Dose: Importance of instructing caregiver regarding proper administration (twice daily for dosages exceeding 5 mg daily) and dosage escalation (minimal interval of 1 week between dosage increases).
The recommended initial adult dosage of memantine hydrochloride is 5 mg once daily. The dosage of memantine hydrochloride shown to be effective in clinical trials and the recommended target dosage is 20 mg daily, given in 2 divided doses (10 mg twice daily). Dosage should be increased to the target dosage in increments of 5 mg daily at intervals of not less than 1 week. Following initiation of therapy at a dosage of 5 mg once daily, dosage should be increased to 10 mg daily (5 mg twice daily), with subsequent increase to 15 mg daily (5 mg and 10 mg as separate doses) and then to 20 mg daily (10 mg twice daily).
Special populations: No dosage adjustment is needed in patients with mild to moderate renal impairment. However, in patients wit severe renal impairment (i.e., creatinine clearance of 5-29 mL/minute), a target dosage of 5 mg twice daily is recommended. Creatinine clearance may be estimated using the following formulas: See equation.
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Where age is in years, weight is in kg, and serum creatinine is in mg/dL.
Mode of Administration: Memantine hydrochloride is administered orally without regard to meals.
Symptoms: Signs and symptoms associated with memantine overdosage in clinical trials and from worldwide marketing experience alone or in combination with other drugs and/or alcohol include agitation, asthenia, bradycardia, coma, confusion, dizziness, electrocardiogram (ECG) changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gate, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 g in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced agitation, coma, and diplopia but subsequently recovered.
One patient participating in a memantine ER clinical trial unintentionally took memantine ER 112 mg daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.
Treatment: Utilize general supportive measures and symptomatic treatment. Elimination of memantine can be enhanced by acidification of urine.
Known hypersensitivity to memantine hydrochloride or any ingredient in the formulation.
Seizures: Memantine has not been systematically evaluated in patient with a seizure disorder. In clinical studies, seizures occurred in 0.2% of patients receiving memantine and in 0.5% of patients receiving placebo.
Urinary Excretion: Conditions that increase urinary pH (e.g., dietary changes [e.g., from a high-protein to a vegetarian diet], concomitant use of drugs that alkalinize urine [e.g., carbonic anhydrase inhibitors, sodium bicarbonate], renal tubular acidosis, severe urinary tract infections) may decrease elimination of memantine, resulting in increased plasma memantine concentrations; use with caution under such conditions.
Hepatic impairment: Although pharmacokinetics have not been evaluated in patients with hepatic impairment, only a modest effect on clearance would be expected.
Renal impairment: Dosage adjustment is recommended in patients with severe renal impairment, but not in those with mild or moderate renal impairment.
Carcinogenicity: There was no evidence of carcinogenicity on 113-week oral study in mice at doses up to 40 mg per kg per day (10 times the maximum recommended human dose (MRHD) on a mg per m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg per kg per day for 71 weeks followed by 20 mg per kg per day (20 times and 10 times the MRHD on a mg per m2 basis, respectively) through 128 weeks.
Mutagenicity: Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium and E. coli reverse mutation assays, the in vitro chromosomal aberration test in human lymphocytes, the in vivo cytogenesis assay for the 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.
Use in Children: Safety and efficacy not established in children.
Use in the Elderly: Clinical studies have been conducted principally in older patients since dementia of Alzheimer's type occurs mainly in an older patient population. Memantine pharmacokinetics were similar in elderly patients and younger adults.
Fertility: No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg per kg per day (9 times the human MRHD on a mg per m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for up to 60 days prior to mating in males.
Pregnancy: Category B. There are no adequate and well-controlled studies of memantine in pregnant woman. Use memantine 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 per kg per day in rats and 30 mg per kg per day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose (MRHD) on a mg per m2 basis). Slight maternal toxicity, decreased pup weight, and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg per kg per 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 per kg, which is 3 times the MRHD on a mg per m2 basis.
Lactation: It is not known whether memantine is excreted in human breast milk. Due to the large volume of distribution, it is unlikely that memantine would transfer to any measurable extent. Because many drugs are excreted in human milk, exercise caution when memantine is administered to a breast-feeding woman.
Adverse reactions (2% or more) and higher frequency than placebo: See table.
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Adverse reaction (2% or more) and at a greater or equal rate as placebo: CNS: Agitation, anxiety, depression, gait abnormal, insomnia.
GI: Diarrhea, nausea.
GU: Urinary incontinence, urinary tract infection.
Respiratory: Bronchitis, upper respiratory tract infection.
Miscellaneous: Anorexia, arthralgia, fall, inflicted injury, influenza-like symptoms, peripheral edema.
Drug Affecting Hepatic Microsomal Enzymes: Inhibitors or inducers of cytochrome P-450 (CYP) system; pharmacokinetic interactions unlikely.
Drug Metabolized by Hepatic Microsomal Enzymes: Minimal inhibition of CYP isoenzymes 1A2, 2A6, 2C9, 2D6, 2E1, or 3A4 by memantine observed in vitro. No induction of CYP isoenzymes 1A2, 2C9, 2E1, or 3A4/5 observed in vitro at concentrations exceeding those associated with therapeutic efficacy. Pharmacokinetic interaction unlikely.
Protein-bound Drugs: Because plasma protein binding of memantine is low (45%), a pharmacokinetic interaction with drugs that are highly protein bound (e.g., digoxin, warfarin) is unlikely.
Drug Secreted by Renal Tubular Cationic Transport: Potential pharmacokinetic interaction (altered plasma concentrations of both drugs) when memantine is used with drugs secreted by same renal cationic system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene). However, concomitant use of memantine with a fixed combination of hydrochlorothiazide and triamterene did not affect bioavailability of either memantine or triamterene, and maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%. In addition, concomitant use of memantine with a fixed combination of glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glyburide, and the hypoglycemic effect of the glyburide-metformin combination were not affected.
Alkalinizing Agents: Potential decreased memantine clearance with resulting increases in adverse effects when the drug is used concomitantly with agents that increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate). Use with caution. Memantine clearance was decreased by approximately 80% at alkaline urine conditions (i.e., pH 8).
Cholinesterase Inhibitors: Concomitant use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either drug or substantially alter acetylcholinesterase inhibitor by donepezil. In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, adverse effects observed with combination therapy with memantine and donepezil were similar to those observed with donepezil alone. In vitro and animal studies indicate that memantine does not affect the reversible inhibition of acetylcholinesterase produced by donepezil, galantamine, or tacrine.
N-Methyl-D-aspartate (NMDA) Antagonists: Concomitant use of memantine hydrochloride with other NMDA antagonist (e.g., amantadine, ketamine, dextromethorphan) has not been systematically evaluated. Use with caution.
N06DX01 - memantine ; Belongs to the class of other anti-dementia drugs.
Memotin film-coated tab 10 mg
2 × 14's
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