Ebixa

Ebixa

memantine

Manufacturer:

Lundbeck

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Memantine HCl.
Description
Each 10- and 20-mg film-coated tablet contains memantine hydrochloride 10 mg and 20 mg equivalent to memantine free base 8.3 mg and 16.62 mg, respectively.
Each film-coated tablet also contains the following excipients: Tablet-Core: Lactose monohydrate, microcrystalline cellulose, anhydrous colloidal silica, talc and magnesium stearate.
Tablet-Coat: Methacrylic acid + ethyl acrylate copolymer (1:1), sodium lauryl sulfate, polysorbate 80, talc, triacetin, simethicone emulsion.
The 10-mg film-coated tablet can be divided into equal halves.
Action
Pharmacotherapeutic Group: Anti-dementia drugs. ATC Code: N06DX01.
Pharmacology: Pharmacodynamics: There is increasing evidence that malfunctioning of glutamatergic neurotransmission, particularly at N-methyl-D-aspartate (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.
Clinical Studies: A pivotal monotherapy study in a population of patients suffering from moderate to severe Alzheimer's disease [minimental state examination (MMSE) total scores at baseline of 3-14] included a total of 252 outpatients. The study showed the beneficial effects of memantine treatment in comparison to placebo at 6 months [observed cases analysis for 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 10-22) 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 randomized. 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 6 phase III, placebo-controlled, 6-month studies (including monotherapy studies and studies with patients on a stable dose of acetylcholinesterase inhibitors) showed 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 3 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 3 domains (21% vs 11%, p<0.0001).
Pharmacokinetics: Absorption: Memantine has an absolute bioavailability of approximately 100%. The tmax is between 3 hrs and 8 hrs. 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 70-150 ng/mL (0.5-1 micromol) with large interindividual variations. When daily doses of 5-30 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: In 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, >99% being excreted renally.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal half-life of 60-100 hrs. 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 7-9 (see Precautions). Alkalisation of urine may result from drastic changes in diet eg, from a carnivore to a vegetarian diet or from the massive ingestion of alkalising gastric buffers.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10-40 mg.
Pharmacokinetic/Pharmacodynamic Relationship: At a dose of memantine 20 mg/day, the CSF levels match the inhibition constant (ki) value of memantine which is 0.5 micromol in human frontal cortex.
Toxicology: Preclinical Safety Data: In short-term studies in rats, memantine like other NMDA-antagonists has induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to a very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long-term studies in rodents nor in nonrodents, the clinical relevance of these findings is unknown.
Ocular changes were inconsistently observed in repeat-dose toxicity studies in rodents and dogs but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did not disclose any ocular changes.
Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes was observed in rodents. This effect is known from other drugs with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolisation observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.
No genotoxicity has been observed following testing of memantine in standard assays. There was no evidence of any carcinogenicity in life-long studies in mice and rats. Memantine was not teratogenic in rats and rabbits, even at maternally toxic, doses and no adverse effects of memantine were noted on fertility. In rats, foetal growth reduction was noted at exposure levels which are identical or slightly higher than at human exposure.
Indications/Uses
Treatment of patients with moderate to severe Alzheimer's disease.
Dosage/Direction for Use
Adults: Dose Titration: Maximum Daily Dose: 20 mg daily. In order to reduce the risk of side effects, the maintenance dose is achieved by upward-titration of 5 mg weekly over the 1st 3 weeks as follows: Treatment should be started with 5 mg daily (½ of 10-mg tab) for the 1st week (day 1-7), 10 mg daily (one 10-mg tab) for the 2nd week (day 8-14) and 15 mg daily (1½ of 10-mg tab) for the 3rd week (day 15-21). From the 4th week onwards, continue treatment with a maintenance dose of 20 mg daily (one 20-mg tab).
Recommended Maintenance Dose: 20 mg daily.
Elderly: On the basis of the clinical studies, the recommended dose for patients >65 years is 20 mg daily (two 10-mg tab once daily or one 20-mg tab once daily).
Children and Adolescents: Ebixa is not recommended for use in children <18 years due to lack of data on safety and efficacy.
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 daily. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg daily according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5-29 mL/min), daily dose should be 10 mg daily.
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 Ebixa is not recommended in patients with severe hepatic impairment.
Administration: 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 to regularly monitor drug intake by the patient. Diagnosis should be made according to current guidelines.
Ebixa should be administered once daily and should be taken at the same time everyday. The film-coated tablets can be taken with or without food.
Overdosage
Only limited experience with overdosage is available from clinical studies and post-marketing experience.
Symptoms: Relative large overdoses (200 mg and 105 mg daily for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdosage cases <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 memantine 2000 mg 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 overdosage, the patient also survived and recovered. The patient had received memantine 400 mg orally. The patient experienced central nervous system symptoms eg, 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 overdosage is available. Standard clinical procedures to remove active substance material eg, 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 overstimulation, careful symptomatic clinical treatment should be considered.
Contraindications
Hypersensitivity to memantine hydrochloride or to any of the excipients of Ebixa.
Special Precautions
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 eg, 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 (see Interactions).
Some factors that may raise urine pH (see Pharmacokinetics under Actions) may necessitate careful monitoring of the patient. These factors include drastic changes in diet eg, 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.
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 those conditions should be closely supervised.
Excipients: Ebixa contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on the Ability to Drive or Operate Machinery: Moderate to severe Alzheimer's disease usually causes impairment of driving performance and comprises the ability to use machinery. Furthermore, Ebixa has a minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.
Use in pregnancy & lactation: For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels which are identical or slightly higher than at human exposure (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). 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 memantine, this probably occurs. Women taking memantine should not breastfeed.
Use In Pregnancy & Lactation
For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels which are identical or slightly higher than at human exposure (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). 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 memantine, this probably occurs. Women taking memantine should not breastfeed.
Adverse Reactions
In clinical trials in mild to severe dementia involving 1784 patients treated with Ebixa and 1595 patients treated with placebo, the overall incidence rate of adverse events with Ebixa 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 Ebixa 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 reactions listed in the table have been accumulated in clinical studies with Ebixa 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 (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data). (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 events have been reported in patients treated with Ebixa.
Drug Interactions
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 eg, 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 (see Precautions). There is one published case report on a possible risk also for the combination of memantine and phenytoin.
Other drugs eg, 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 international normalized ration (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 pharmacokinetic (PK) studies in young healthy subjects, no relevant effect of memantine on the pharmacokinetics of galantamine was observed.
In a clinical study in young healthy subjects, no relevant effect of memantine on the pharmacokinetics of galantamine was observed.
Memantine did not inhibit CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase and sulphation in vitro.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C.
Shelf-Life: 4 years.
ATC Classification
N06DX01 - memantine ; Belongs to the class of other anti-dementia drugs.
Presentation/Packing
FC tab 10 mg (white to off-white, centrally-tapered, oblong, biconvex with a single breakline on both sides) x 56's. 20 mg (pale red to grey-red, oval-oblong) x 28's.
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