Each film-coated tablet contains 10 mg memantine hydrochloride.
The tablet can be divided into equal doses.
Excipients/Inactive Ingredients: The ingredients in the tablet core: lactose monohydrate, microcrystalline cellulose, anhydrous colloidal silica, talc and magnesium stearate.
The ingredients in the film coating: methacrylic acid-ethyl acrylate copolymer (1:1), talc, triacetin and simeticone.
Pharmacotherapeutic Group: Other anti dementia drugs. ATC Code: N06DX01.
Pharmacology: Pharmacodynamics: There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
Pharmacokinetics: Absorption: Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.
Distribution: Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5 - 1 μmol) with large interindividual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.
Biotransformation: About 80% of the circulating memantine-related material is present as the parent compound. Main metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. Total clearance (Cltot) amounts to 170 ml/min/1.73 m2 and part of total renal clearance is achieved by tubular secretion.
Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.
Linearity: Memantine has a linear pharmacokinetics in the dose range of 10 to 40 mg.
Pharmacokinetic/pharmacodynamic relationship: At a dose of memantine of 20 mg per day the CSF levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 μmol in frontal cortex.
Treatment of adult patients with moderate to severe Alzheimer's disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia.
Posology: 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. The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines.
Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.
Adults: Dose titration: The maximum daily dose is 20 mg daily. In order to reduce the risk of undesirable effects the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows: Week 1 (day 1-7): The patient should take half a 10 mg film-coated tablet (5 mg) per day for 7 days.
Week 2 (day 8-14): The patient should take one 10 mg film-coated tablet (10 mg) per day for 7 days.
Week 3 (day 15-21): The patient should take one and a half 10 mg film-coated tablets (15 mg) per day for 7 days.
From Week 4 on: The patient should take two 10 mg film-coated tablets (20 mg) once a day.
Maintenance dose: The recommended maintenance dose is 20 mg per day.
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) as described previously.
Renal impairment: In patients with mildly impaired renal function (creatinine clearance 50 - 80 ml/min) no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) daily dose should be 10 mg (one 10 mg film-coated tablet) 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 (one 10 mg film-coated tablet) per day.
Hepatic impairment: In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B), no dose adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of Marixino is not recommended in patients with severe hepatic impairment.
Children and adolescents: Marixino is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Method of administration: Marixino tablets should be administered orally once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food. The tablet can be divided into equal doses.
Only limited experience with overdose is available from clinical studies and post-marketing experience.
Symptoms: Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea 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 overdose, 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 overdose, 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 central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.
Hypersensitivity to the active substance or to any of the excipients.
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 reactions (mainly central nervous system (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 alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.
Only limited data are available for patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension and patients with these conditions should be closely supervised.
Marixino contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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, Marixino has minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.
Pregnancy: There are no or limited amount of data from the use of memantine in pregnant women. Animal studies indicate a potential for reducing intrauterine growth at exposure levels, which 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.
Breast-feeding: 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.
Fertility: No adverse reactions of memantine were noted on male and female fertility.
Tabulated list of adverse reactions:
The following undesirable effects listed in the Table as follows have been observed with memantine.
Undesirable effects are ranked according to system organ class, using the following convention: very common, common, uncommon, rare, very rare, not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)
Click on icon to see table/diagram/image
Alzheimer's disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these reactions have been reported in patients treated with memantine.
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 enhanced 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 dose 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 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.
Isolated cases with international normalized ratio (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.
There has been no relevant active substance-active substance interaction of memantine with glyburide/metformin or donepezil.
There has been no relevant effect of memantine on the pharmacokinetics of galantamine.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase, epoxide hydrolase or sulphation in vitro.
Special Precautions for Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Do not store above 30°C.
Shelf-Life: 4 years.
N06DX01 - memantine ; Belongs to the class of other anti-dementia drugs.
Marixino FC tab 10 mg