Each film-coated tablet contains: Memantine Hydrochloride 10 mg.
Pharmacology: 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.
Pharmacodynamics: Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca, Na or K channels. Memantine also showed antagonistic effects at the 5HT 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.
Pharmacokinetics: Absorption: Following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.
Distribution: The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
Metabolism: Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
Elimination: Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours.
The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitrosodeaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
Pharmacokinetics in Specific Populations: Gender: Following multiple dose administration of memantine hydrochloride 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when bodyweight was taken into account.
Elderly: The pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar.
Renal Impairment: Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50-80 mL/min), 8 subjects with moderate renal impairment (CLcr 30-49 mL/min), 7 subjects with severe renal impairment (CLcr 5-29 mL/min) and 8 healthy subjects (CLcr >80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment.
Hepatic Impairment: Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.
Memantine is indicated for the treatment of moderately severe to severe Alzheimer's disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines. Memantine hydrochloride should be administered once a day and should be taken at the same time every day. It 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 as follows.
Alzheimer's disease: The recommended starting dose of Memantine hydrochloride is 5 mg once daily. The recommended target dose is 20 mg/day. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses) and 20 mg/day (10 mg twice a day). The minimum recommended interval between dose increases is one week.
Children and adolescents under the age of 18 years: Memantine hydrochloride is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Elderly: On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (two 10 mg film-coated tablets once a day) as described previously.
Renal impairment: In patients with mildly impaired renal function (creatinine clearance 50-80 mL/min) no dosage adjustment is required. In patients with moderate renal impairment (creatinine clearance 30-49 mL/min) daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5-29 mL/min) daily dose should be 10 mg per day.
Hepatic impairment: In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dosage adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of Memantine hydrochloride is not recommended in patients with severe hepatic impairment.
Only limited experience with overdose is available from clinical studies and postmarketing experience.
Symptoms: Relatively large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhea or no symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).
In the most extreme case of overdosage, the patient survived the oral intake of a total of 2000 mg memantine with effects on the central nervous system (coma for 10 days, and later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without permanent sequelae.
In another case of a large overdose, the patient also survived and recovered. The patient had received 400 mg memantine orally. The patient experienced central nervous system symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and unconsciousness.
Treatment: In the event of overdosage, treatment should be symptomatic. No specific antidote for intoxication or overdose is available. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, forced diuresis should be used as appropriate.
In case of signs and symptoms of general CNS overstimulation, careful symptomatic clinical treatment should be considered.
Memantine is contraindicated to patients with known hypersensitivity to the active ingredient or any of its components.
Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.
Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse drug reactions (mainly CNS-related) may be more frequent or more pronounced.
Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalizing gastric buffers. Also, urine pH may be elevated by states of renal tubular acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.
In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.
Effects on ability to drive and use machines: Moderate to severe Alzheimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, Memantine has minor or moderate influence on the ability to drive and use machines, such that outpatients should take special care.
No clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels that are identical or slightly higher than at human exposure. The
potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
It is not known whether Memantine is excreted in human breast milk but, taking into consideration the lipophilicity of the substance, this probably occurs. Women taking Memantine should not breast-feed.
In clinical trials in mild to severe dementia, involving 1,784 patients treated with Memantine and 1,595 patients treated with placebo, the overall incidence rate of adverse events with Memantine did not differ from those with placebo; the adverse events were usually mild to moderate in severity. The most frequently occurring adverse events with a higher incidence in the Memantine group than in the placebo group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs 2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%).
The following Adverse Drug Reactions listed in the following table have been accumulated in clinical studies with Memantine and since its introduction in the market. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions are ranked according to system organ class, using the following convention: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). (See table.)
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Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these events have been reported in patients treated with Memantine hydrochloride.
Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur: The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhance by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dosage adjustment may be necessary.
Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan.
There is one published case report on a possible risk also for the combination of memantine and phenytoin.
Other active substances such as such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels.
There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT.
In post-marketing experience isolated cases with INR increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants.
In single dose PK studies in young healthy subjects no relevant drug-drug interaction of memantine with glyburide/metformin or donepezil was observed.
In a clinical study in young healthy volunteers no relevant effect of memantine on the pharmacokinetics of galantamine was observed.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase or sulphation in vitro.
Store at temperatures not exceeding 30°C.
N06DX01 - memantine ; Belongs to the class of other anti-dementia drugs.
FC tab 10 mg (white to off white colored, oblong shaped biconvex, debossed '10' on one side and breakline on other side) x 30's