Ebixa 10 mg

The apparent volume of distribution of memantine is approximately 9-11 L/kg and the plasma protein binding is approximately 45%. Memantine rapidly crosses the blood-brain barrier with a CSF/serum ratio of about 0.5.

Orally administered memantine is completely absorbed. Oral bioavailability is almost 100%. Time to maximum plasma concentration (t_max) following single oral doses of 10 to 40 mg memantine ranged between 3 to 8 hours. It has a terminal elimination half-life of about 60-80 hours, with the majority of the dose excreted unchanged in urine. There is no indication that food influences the absorption of memantine.

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg. Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/mL (0.5-1 µM) with large inter-individual variations.

Figure 4 illustrates the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. The mean difference in the SIB change scores for the Ebixa/donepezil treated patients compared to the patients on placebo/donepezil was 3.4 units (p<0.001). Ebixa/donepezil treatment was statistically significantly superior to placebo/donepezil.

The potential efficacy of Ebixa (memantine hydrochloride) as a treatment for the symptomatic management of moderate to severe Alzheimer's disease was demonstrated by the results of 2 randomized, double-blind, placebo-controlled 6-month clinical studies. Both studies were conducted in patients with Alzheimer's disease. The mean age of patients participating in the Ebixa trials was 76 with a range of 50 to 93 years. Approximately 66% of patients were women. Female patients participating in the clinical trials were required to be at least 50 years of age and at least 2 years postmenopausal or surgically sterile. The racial distribution was approximately 91% Caucasian.

Study Outcome Measures: In each study, the effectiveness of Ebixa was determined from instruments evaluating activities of daily living through caregiver-related evaluation, a measure of cognition, and a clinician's global assessment of change.

The ability of Ebixa to improve day-to-day function was assessed in both studies (Study 1 and Study 2) using the modified Alzheimer's Disease Cooperative Study—Activities of Daily Living inventory (ADCS-ADL_sev). The ADCS-ADL_sev consists of a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The inventory is performed by interviewing a caregiver familiar with the behaviour of the patient. The modified ADCS-ADL_sev consists of a subset of 19 items including ratings of the patients' ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores, and has been validated for the assessment of patients with moderate to severe dementia. The modified ADCS-ADL_sev scoring range is from 0 to 54, with lower scores indicating greater functional impairment.

The ability of Ebixa to improve cognitive performance was assessed in both studies (Study 1 and Study 2) with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. Unlike the Alzheimer's Disease Assessment Scale—cognitive subscale (ADAS-cog) the sensitivity of the SIB is not limited by floor effects in patients with advanced dementia. The SIB examines selected aspects of cognitive performance including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment. The SIB has been shown to be a valid and reliable instrument sensitive to longitudinal changes in patients with moderate to severe dementia.

The ability of Ebixa to produce an overall clinical effect was assessed in both studies (Study 1 and Study 2) using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus used in both trials was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioural. It represents the assessment of a skilled clinician using validated scales based on his/her observation at an interview with the patient, in combination with information supplied by a caregiver familiar with the behaviour of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “markedly improved” to a score of 4, indicating “unchanged” to a score of 7, indicating “markedly worse”. The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

In elderly volunteers with normal and reduced renal function (creatinine clearance of 50 to ≤80 mL/min/1.73 m²), a significant correlation was observed between creatinine clearance and total renal clearance of memantine. Following a single 20 mg oral dose of memantine, systemic exposure in geriatric subjects with mild and moderate renal impairment was 14% and 39% greater, respectively, compared to geriatric subjects with normal renal function (see Precautions and Dosage).

The CIBIC-Plus was used as a secondary efficacy measure. The Ebixa-placebo difference of CIBIC-Plus mean rating was 0.25 units (p=0.027). Ebixa/donepezil treatment was statistically significantly superior to placebo/donepezil.

Memantine is metabolized to a minor extent into metabolites with no NMDA-antagonistic activity, and is excreted primarily in an unchanged form by the kidneys. In a study comparing the pharmacokinetics of memantine in subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh B), moderate hepatic impairment did not significantly alter the pharmacokinetics of memantine following administration of a single 20 mg oral dose of memantine (see Precautions and Dosage).

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. Memantine undergoes little metabolism being in majority excreted unchanged in urine (75-90%). The remaining dose is converted primarily to three polar metabolites: the N-gludantan conjugate, 6-hydroxy memantine and 1-nitroso-deaminated memantine. These metabolites possess minimal NMDA receptor antagonist activity. The hepatic microsome CYP450 enzyme system does not play a significant role in the metabolism of memantine.

In volunteers with normal kidney function, total clearance (Cl_tot) 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 resulting in increased plasma levels of memantine (see Warnings, Genitourinary Conditions). 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 alkalizing gastric buffers.

The pharmacokinetics of memantine in young and elderly subjects is similar. No adjustment of dosage on the basis of age is recommended.

There is limited information on the safety of memantine treatment in patients with moderate to severe Alzheimer's disease with serious co-morbidities, as these patients were excluded from clinical trials. The use of Ebixa in Alzheimer's disease patients with chronic illnesses common among the geriatric population should be considered only after a proper risk/benefit assessment. Dose escalation in this patient population should proceed with caution.

The safety and effectiveness of Ebixa in any illness occurring in pediatric patients have not been established. Therefore, Ebixa is not recommended for use in children.

Oral treatment of female rats with memantine once daily during organogenesis produced mild maternal toxicity at doses of 6-18 mg/kg/day (3-9 times the Maximum Recommended Human Dose [MRHD] on a mg/m² basis); however, memantine was not teratogenic at doses up to 18 mg/kg/day (9 times the MRHD on a mg/m² basis), the highest dose tested. In a rat reproduction and fertility study, reduced growth and a developmental delay were observed at 18 mg/kg/day (9 times the MRHD on a mg/m² basis).

Memantine doses of 0, 3, 10 and 30 mg/kg/day were orally administered to pregnant rabbits during the period of organogenesis. At 30 mg/kg/day (30 times the MRHD on a mg/m² basis) maternal toxicity and a slight increase in post-implantation loss were observed. No teratogenic effects were observed in rabbits administered memantine 30 mg/kg/day (30 times the MRHD on a mg/m² basis). The maternal and fetal no observed effect level (NOEL) was 10 mg/kg/day (10 times the MRHD on a mg/m² basis).

In a peri and postnatal study, memantine was orally administered to rats at up to 18 mg/kg/day (9 times the MRHD on a mg/m² basis). At 18 mg/kg/day pups showed reduced mean body weights but there was no effect on their development or behaviour. Animal studies showed no indication of an adverse effect of memantine on labour and delivery.

There are no adequate and well-controlled studies of memantine in pregnant women to establish the safe use of Ebixa for this population. Therefore, Ebixa should not be used in women of childbearing potential, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus.

In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) revealed minimal inhibition of these enzymes by memantine. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.

Ebixa undergoes minimal hepatic metabolism and is excreted primarily in its unchanged form by the kidneys. The pharmacokinetics of memantine have been studied in subjects with moderate hepatic impairment (see Pharmacology, Pharmacokinetics). In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dose adjustment is needed. There are no data available for use of memantine in patients with severe hepatic impairment. Therefore, administration of Ebixa is not recommended in patients with severe hepatic impairment.

In post-marketing experience isolated cases of international normalized ratio (INR) increases have been reported in patients treated concomitantly with memantine and warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advised for patients treated concomitantly with memantine and oral anticoagulants.

Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of memantine.

Use with compounds chemically related to N-methyl-D-aspartate (NMDA) antagonists: As these compounds act at the same receptor system as memantine, adverse drug reactions (mainly CNS-related) may be more frequent or pronounced. Pharmacotoxic psychosis has been reported in the literature in two Parkinson's disease patients who were treated concomitantly with memantine, amantadine, L-dopa and terguride (see Precautions, Drug Interactions, Other Agents). The combined use of Ebixa with other compounds chemically related to NMDA antagonists such as amantadine, ketamine or dextromethorphan has not been systematically evaluated and is therefore not recommended.

Since the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with Ebixa, dosage adjustment of these other agents may be necessary.

In young healthy adult subjects (n=21, age range 19-35 years), co administration of a single 20 mg oral dose of memantine under steady state conditions of glyburide/metformin (1.25 mg glyburide/250 mg metformin) did not affect the pharmacokinetics of memantine, glyburide or metformin. The renal excretion of metformin and memantine, and potential for compromised renal function in elderly patients should be considered when memantine and metformin will be used concomitantly (see Precautions and Dosage).

There are limited data available from clinical trials for patients with mild to moderate renal impairment. In patients with normal to mildly impaired renal function (creatinine clearance >60 mL/min/1.73 m²) no dose reduction is needed. In patients with moderate renal impairment (creatinine clearance 40-60 mL/min/1.73 m²) daily dose should be reduced to 10 mg per day (see Pharmacology, Pharmacokinetics). There are no data available in patients with severe renal impairment (creatinine clearance less than 9 mL/min/1.73 m²), and the use of Ebixa in these patients is not recommended (see Pharmacology and Dosage).

In placebo-controlled clinical studies, the number of patients aged 85 years or older who received memantine at the therapeutic dose of 20 mg/day was 40. There is limited safety information for Ebixa in this patient population.

There was no evidence of carcinogenicity in a 113-week oral study in mice for either sex at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m² basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (19 and 10 times the MRHD on a mg/m² basis, respectively) through 128 weeks.

Memantine did not show any genotoxic potential in assays for gene mutation (bacterial and mammalian cells in vitro) or in clastogenicity assays (human lymphocytes in vitro and mouse bone marrow in vivo).

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (9 times the MRHD on a mg/m² basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions (see Pharmacology and Warnings).

The combined use of Ebixa with other compounds chemically related to NMDA antagonists such as amantadine, ketamine or dextromethorphan has not been systematically evaluated and is therefore not recommended (see Precautions, Concomitant Use with Other Drugs).

It is not known whether memantine is excreted in human breast milk. Therefore Ebixa should not be used in nursing mothers.

In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil or galantamine. In young healthy adult subjects (n=19, age range 18-35 years) under steady-state conditions of the AChE inhibitor donepezil HCl (10 mg/day), co-administration of a single 10 mg oral dose of memantine did not affect the pharmacokinetics of either drug and did not affect donepezil-mediated AChE inhibition. In a 24-week study of patients with moderate to severe Alzheimer’s disease the adverse event profiles were similar for patients treated with a combination of memantine and donepezil or placebo and donepezil.

In a pharmacokinetic study in healthy adult subjects (n=15, age range 21-55 years), co-administration of memantine (10 mg b.i.d.) did not significantly affect the steady state pharmacokinetics of galantamine (16 mg/day). The effect of galantamine on memantine pharmacokinetics was not evaluated. The safety of co-administering memantine and galantamine in patients with Alzheimer’s disease has not been evaluated in clinical trials.

Co-administration of drugs that use the same renal cationic transport system as memantine, such as cimetidine, ranitidine, quinidine, hydrochlorothiazide (HCTZ), triamterene (TA), and nicotine could potentially alter the plasma levels of both agents. Co-administration of Ebixa and hydrochlorothiazide/triamterene (HCTZ/TA) did not affect the bioavailability of either memantine or triamterene, and the bioavailability of HCTZ decreased by 20%. The pharmacokinetics of memantine is similar in smokers and non-smokers, suggesting that nicotine may not affect the disposition of memantine. The potential for compromised renal function in elderly patients should be considered when memantine will be used concomitantly with other drugs eliminated via renal mechanisms (see Precautions and Dosage).

In an open label study where Ebixa was administered to 10 elderly patients at a dose of 20 mg per day for approximately 48 months, memantine concentrations in lacrimal fluid were about 3 fold higher than in plasma and did not show ophthalmologic effects. In another 6-month placebo-controlled trial, no major treatment differences were reported for ocular effects but worsening of the corneal condition was reported for slightly more patients treated with Ebixa than placebo (5.4% memantine vs. 3.3% placebo). Repeat-dose toxicology studies demonstrated corneal and lens histopathological changes in rodents treated with Ebixa. Therefore, periodic monitoring of the patient's ophthalmic condition is recommended.

Seizures: Ebixa (memantine hydrochloride) has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of Ebixa. In clinical trials, seizures occurred in 0.3% of patients treated with Ebixa and 0.4% of patients treated with placebo. Seizure activity may be a manifestation of Alzheimer's disease. The risk/benefit of memantine treatment for patients with a history of seizure disorder or predisposing factors for epilepsy must, therefore, be carefully evaluated.

Conditions that raise urine pH may reduce the urinary elimination of memantine by a factor of 7 to 9, resulting in increased plasma levels of memantine (see Pharmacology). These conditions include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers (see Precautions, Conditions That Make Urine Alkaline). 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), and uncontrolled hypertension were excluded. However, patients such as those with controlled hypertension (DBP <105 mm/Hg), right bundle branch blockage and pacemaker were included. Although cardiovascular adverse events occurred at low frequencies in the two placebo-controlled clinical trials involving patient with moderate to severe Alzheimer's disease, there were increased frequencies of hypertension, chest pain, bradycardia and cardiac failure adverse events in patients who were treated with Ebixa compared to placebo in these trials. Consequently, caution should be observed when memantine is initiated in patients with cardiovascular conditions.

The following adverse events of possible importance, for which there are inadequate data to determine the causal relationship to memantine treatment have been reported to be temporally associated with memantine treatment and are not described elsewhere in labeling: acne, atrioventricular block, bone fracture, carpal tunnel syndrome, cerebral infarction, cholelithiasis, claudication, colitis, depressed level of consciousness (including loss of consciousness and coma), dyskinesia, encephalopathy, gastritis, grand mal convulsions, hepatic failure, hepatitis (including increased ALT and AST), hyperlipidemia, hypoglycemia, ileus, impotence, increased INR, intracranial hemorrhage, lethargy, myoclonus, neuroleptic malignant syndrome, acute pancreatitis, aspiration pneumonia, acute renal failure, otitis media, prolonged QT interval, psychotic reactions, restlessness, sepsis, Stevens-Johnson syndrome, supraventricular tachycardia, tardive dyskinesia, thrombocytopenia.

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.

Frequent: aphasia, ataxia, cerebrovascular disorder, hypokinesia, transient ischemic attack, vertigo. Infrequent: absences, cerebral hemorrhage, coma, convulsions, coordination abnormal, extrapyramidal disorder, hemiparesis, hemiplegia, hyperkinesia, hypertonia, hypoesthesia, muscle contractions involuntary, neuralgia, neuropathy, paralysis, paresthesia, ptosis, speech disorder, stupor, tremor.

Ebixa and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with Ebixa treatment.

In placebo-controlled trials in which dementia patients received doses of Ebixa up to 20 mg/day, 10.8 % (80/738) of the Ebixa-treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 11.2% (81/721). The most frequent adverse event leading to discontinuation was agitation with an observed frequency among patients who discontinued treatment of 1.2% in patients receiving memantine vs. 2.1% in patients administered placebo. None of the other adverse events leading to discontinuation met the criteria for most common adverse events, defined as those occurring at a frequency of at least 2% and at twice the incidence seen in placebo patients.

Frequent: cataract, conjunctivitis, eye abnormality, macula lutea degeneration, vision abnormal. Infrequent: blepharitis, blurred vision, conjunctival hemorrhage, corneal opacity, decreased visual acuity, diplopia, ear ache, ear disorder NOS, eye infection, eye pain, glaucoma, hearing decreased, lacrimation abnormal, myopia, xerophthalmia, retinal detachment, retinal disorder, retinal hemorrhage, tinnitus.

Frequent: hyperglycemia, hypernatremia, hypokalemia, phosphatase alkaline increased, weight decrease. Infrequent: bilirubinemia, BUN increased, dehydration, diabetes mellitus, diabetes mellitus aggravated, gamma-GT increased, gout, hepatic enzymes increased, hepatic function abnormal, hypercholesterolemia, hyperkalemia, hyperuricemia, hyponatremia, NPN increased, polydipsia, AST increased, ALT increased, thirst.

Frequent: bullous eruption, herpes zoster, skin disorder, skin ulceration. Infrequent: alopecia, cellulitis, dermatitis, eczema, pruritus, rash erythematous, seborrhea, skin dry, skin reaction localized, urticaria.

Female: Infrequent: vaginal hemorrhage, moniliasis; Male: Frequent: moniliasis.

Frequent: arthritis, arthrosis, muscle weakness, myalgia. Infrequent: arthritis aggravated, arthritis rheumatoid, bursitis, skeletal pain.

Ebixa and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with Ebixa treatment.

Frequent: asthenia, oedema, leg pain, malaise, sepsis, syncope. Infrequent: abscess, allergic reaction, allergy, chest pain precordial, choking, condition aggravated, ESR increased, flushing, hernia NOS, hot flushes, hypothermia, infection, infection fungal, infection viral, moniliasis, edema peripheral, pallor, rigors, sudden death.

Frequent: purpura. Infrequent: epistaxis, hematoma, leukocytosis, leukopenia, polycythemia.

Infrequent: venous thrombosis/thromboembolism.

Frequent: abdominal pain, dyspepsia, fecal incontinence, hemorrhoids, tooth disorder. Infrequent: diverticulitis, dysphagia, esophageal ulceration, esophagitis, flatulence, gastroenteritis, gastroesophageal reflux, gastrointestinal disorder NOS, GI hemorrhage, gingivitis, hemorrhage rectum, melena, mucositis NOS, oesophagitis, saliva altered, saliva increased, stomatitis ulcerative, tooth ache, tooth caries.

Treatment emergent signs and symptoms that were reported in at least 2% of Ebixa/donepezil treated patients (but less than 9%) and at an equal or lower rate than placebo/donepezil treated patients were abdominal pain, agitation, anorexy, anxiety, asthenia, back pain, bronchitis, dehydration, diarrhea, dizziness, fatigue, fecal incontinence, hallucinations, inflicted injury, insomnia, personality disorder, somnolence, syncope, tremor, upper respiratory tract infection.

Infrequent: basal cell carcinoma, breast neoplasm benign (female), breast neoplasm malignant (female), carcinoma, neoplasm NOS, skin neoplasm malignant.

Frequent: pharyngitis, pneumonia, upper respiratory tract infection, rhinitis. Infrequent: apnea, asthma, bronchospasm, hemoptysis, respiratory disorder, sinusitis.

Ebixa has been administered to approximately 1150 patients with dementia, of whom more than 1000 received the maximum recommended dose of 20 mg/day. Approximately 739 patients received Ebixa for at least 6 months of treatment and 387 patients were treated for approximately a year or more.

All adverse events occurring in at least two patients are included, except for those already listed in Table 1 and Table 2, WHO terms too general to be informative, or events unlikely to be caused by the drug. Also included are the adverse events observed in the placebo-controlled trial in patients who had been previously treated with donepezil prior to Ebixa treatment. Events are classified by body system and listed using the following definitions: frequent—those occurring on one or more occasions in at least 1/100 patients; infrequent—those occurring in less than 1/100 patients but at least in 1/1000 patients. These adverse events are not necessarily related to Ebixa treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Infrequent: sweating increased, mouth dry.

Frequent: cystitis, dysuria. Infrequent: hematuria, micturition disorder, polyuria, pyuria, renal function abnormal, urinary retention.

Frequent: aggressive reaction, apathy, cognitive disorder, delusion, nervousness. Infrequent: amnesia, appetite increased, concentration impaired, crying abnormal, delirium, depersonalization, emotional lability, libido increased, neurosis, paranoid reaction, paroniria, personality disorder, psychosis, sleep disorder, suicide attempt, thinking abnormal.

Ebixa and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Ebixa treatment.

Frequent: angina pectoris, bradycardia, cardiac failure, cardiac failure left, heart murmur, oedema dependent. Infrequent: aneurysm, arrhythmia, cardiac arrest, embolism pulmonary, fibrillation atrial, heart block, heart disorder, hypertension aggravated, hypotension, hypotension postural, myocardial infarction, palpitation, phlebitis, pulmonary oedema, tachychardia, thrombophlebitis, thrombophlebitis deep, vascular disorder.

In a documented case of an overdosage with up to 400 mg memantine, the patient experienced restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor and loss of consciousness. The patient recovered without permanent sequelae.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for Ebixa. Elimination of memantine can be enhanced by acidification of urine.

In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dose adjustment is needed (see Pharmacology, Pharmacokinetics). There are no data available for use of memantine in patients with severe hepatic impairment. Therefore, administration of Ebixa is not recommended in patients with severe hepatic impairment.

On the basis of the clinical studies the recommended dose for patients over the age of 65 years is 20 mg per day (10 mg twice a day) as described above (see Pharmacology, Pharmacokinetics).

The recommended maintenance dose for memantine is 20 mg/day. In order to reduce the risk of side effects the maintenance dose is achieved by upward titration as follows: the usual starting dose is 5 mg/day. The dose should then be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (10 mg and 5 mg as separate doses), and 20 mg/day (10 mg twice a day), depending on the patient's response and tolerability. The minimum recommended interval between dose increases is one week. The recommended dose titration is summarized in the following table.

The tablets can be taken with or without food.

In patients with normal to mildly impaired renal function (creatinine clearance >60 mL/min/1.73 m²) no dose reduction is needed. In patients with moderate renal impairment (creatinine clearance 40-60 mL/min/1.73 m²) daily dose should be reduced to 10 mg per day. In patients with severe renal impairment the use of Ebixa has not been systematically evaluated and is therefore not recommended in these patients (see Pharmacology, Pharmacokinetics and Precautions).