- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsDose titrationThe maximum daily dose is 20 mg per day. 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) or one 20 mg film-coated tablet per day.Maintenance doseThe recommended maintenance dose is 20 mg per day.
ElderlyOn 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 or one 20 mg film-coated tablet once a day) as described above.
Paediatric populationMarixino is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Renal impairmentIn 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 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 impairmentIn 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.
Method of administrationMarixino should be administered once a day and should be taken at the same time every day. The film-coated tablets can be taken with or without food.
|Infections and infestations||Uncommon||Fungal infections|
|Immune system disorders||Common||Drug hypersensitivity|
|Not known||Psychotic reactions2|
|Nervous System disorders||Common||Dizziness|
|Cardiac disorders||Uncommon||Cardiac failure|
|Respiratory, thoracic and mediastinal disorders||Common||Dyspnoea|
|Hepatobiliary disorders||Common||Elevated liver function test|
|General disorders and administration site conditions||Common||Headache|
SymptomsRelative 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 2,000 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.
Clinical studiesA pivotal monotherapy study in a population of patients suffering from moderate to severe Alzheimer's disease (mini mental state examination (MMSE) total scores at baseline of 3 - 14) included a total of 252 outpatients. The study showed beneficial effects of memantine treatment in comparison to placebo at 6 months (observed cases analysis for the clinician´s interview based impression of change (CIBIC-plus): p = 0.025; Alzheimer's disease cooperative study activities of daily living (ADCS-ADLsev): p = 0.003; severe impairment battery (SIB): p = 0.002).A pivotal monotherapy study of memantine in the treatment of mild to moderate Alzheimer's disease (MMSE total scores at baseline of 10 to 22) included 403 patients. Memantine-treated patients showed a statistically significantly better effect than placebo-treated patients on the primary endpoints: Alzheimer's disease assessment scale (ADAS-cog) (p = 0.003) and CIBIC-plus (p = 0.004) at week 24 (last observation carried forward (LOCF)). In another monotherapy study in mild to moderate Alzheimer's disease a total of 470 patients (MMSE total scores at baseline of 11 - 23) were randomised. In the prospectively defined primary analysis statistical significance was not reached at the primary efficacy endpoint at week 24.A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total scores < 20) from the six phase III, placebo-controlled, 6-month studies (including monotherapy studies and studies with patients on a stable dose of acetylcholinesterase inhibitors) showed that there was a statistically significant effect in favour of memantine treatment for the cognitive, global, and functional domains. When patients were identified with concurrent worsening in all three domains, results showed a statistically significant effect of memantine in preventing worsening, as twice as many placebo-treated patients as memantine-treated patients showed worsening in all three domains (21 % vs. 11 %, p < 0.0001).
AbsorptionMemantine 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.
DistributionDaily 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.
BiotransformationIn man, about 80 % of the circulating memantine-related material is present as the parent compound. Main human 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 in vitro. In a study using orally administered 14C-memantine, a mean of 84 % of the dose was recovered within 20 days, more than 99 % being excreted renally.
EliminationMemantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, 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 (see section 4.4). 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.
LinearityStudies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.
Pharmacokinetic/pharmacodynamic relationshipAt 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 human frontal cortex.
Tablet coreLactose monohydrateCellulose, microcrystalline E460Silica, colloidal anhydrousTalc E553bMagnesium stearate E572
Film coatingMethacrylic acid-ethyl acrylate copolymer (1:1)Sodyum laurilsulfatePolysorbate 80Talc E553bTriacetinSimeticone
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888