Namenda Information
Namenda ()
Namenda () Description
Namenda () ® (memantine hydrochloride) is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:
The molecular formula is CHN•HCl and the molecular weight is 215.76.
Memantine HCl occurs as a fine white to off-white powder and is soluble in water. Namenda () is available as tablets or as an oral solution. Namenda () is available for oral administration as capsule-shaped, film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride. The tablets also contain the following inactive ingredients: microcrystalline cellulose/colloidal silicon dioxide, talc, croscarmellose sodium, and magnesium stearate. In addition the following inactive ingredients are also present as components of the film coat: hypromellose, titanium dioxide, polyethylene glycol 400, FD&C yellow #6 and FD&C blue #2 (5 mg tablets), and hypromellose, titanium dioxide, macrogol/polyethylene glycol 400 and iron oxide black (10 mg tablets). Namenda () oral solution contains memantine hydrochloride in a strength equivalent to 2 mg of memantine hydrochloride in each mL. The oral solution also contains the following inactive ingredients: sorbitol solution (70%), methyl paraben, propylparaben, propylene glycol, glycerin, natural peppermint flavor #104, citric acid, sodium citrate, and purified water.
Namenda () Clinical Pharmacology
Mechanism of Action and Pharmacodynamics
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.
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.
Pharmacokinetics
Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly in the urine, unchanged, and has a terminal elimination half life of about 60-80 hours.
Absorption and Distribution
Following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. Food has no effect on the absorption of memantine. The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
Metabolism and Elimination
Memantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; 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-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine. Memantine has a terminal elimination half-life of about 60-80 hours. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
Special Populations
No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment (See DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions
Namenda () Clinical Trials
The effectiveness of Namenda () (memantine hydrochloride) as a treatment for patients with moderate to severe Alzheimer's disease was demonstrated in 2 randomized, double-blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States that assessed both cognitive function and day to day function. The mean age of patients participating in these two trials was 76 with a range of 50-93 years. Approximately 66% of patients were female and 91% of patients were Caucasian.
A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but did not assess cognitive function as a planned endpoint.
Study Outcome Measures: In each U.S. study, the effectiveness of Namenda () was determined using both an instrument designed to evaluate overall function through caregiver-related assessment, and an instrument that measures cognition. Both studies showed that patients on Namenda () experienced significant improvement on both measures compared to placebo.
Day-to-day function was assessed in both studies using the modified Alzheimer's disease Cooperative Study - Activities of Daily Living inventory (ADCS-ADL). The ADCS-ADL 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 investigator performs the inventory by interviewing a caregiver familiar with the behavior of the patient. A subset of 19 items, including ratings of the patient's ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores has been validated for the assessment of patients with moderate to severe dementia. This is the modified ADCS-ADL, which has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.
The ability of Namenda () to improve cognitive performance was assessed in both studies 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. 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.
Study 1 (Twenty-Eight-Week Study)
In a study of 28 weeks duration, 252 patients with moderate to severe probable Alzheimer's disease (diagnosed by DSM-IV and NINCDS-ADRDA criteria, with Mini-Mental State Examination scores ≥3 and ≤14 and Global Deterioration Scale Stages 5-6) were randomized to Namenda () or placebo. For patients randomized to Namenda () , treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day).
Effects on the ADCS-ADL:
Figure 1 shows the time course for the change from baseline in the ADCS-ADL score for patients in the two treatment groups completing the 28 weeks of the study. At 28 weeks of treatment, the mean difference in the ADCS-ADL change scores for the Namenda () -treated patients compared to the patients on placebo was 3.4 units. Using an analysis based on all patients and carrying their last study observation forward (LOCF analysis), Namenda () treatment was statistically significantly superior to placebo.
Figure 2 shows the cumulative percentages of patients from each of the treatment groups who had attained at least the change in the ADCS-ADL shown on the X axis.
The curves show that both patients assigned to Namenda () and placebo have a wide range of responses and generally show deterioration (a negative change in ADCS-ADL compared to baseline), but that the Namenda () group is more likely to show a smaller decline or an improvement. (In a cumulative distribution display, a curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.)
Namenda ()
Namenda ()
Namenda ()
Namenda () Indications And Usage
Namenda () (memantine hydrochloride) is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.
Namenda () Contraindications
Namenda () (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
Namenda () Precautions
Neurological Conditions
Seizures: Namenda () has not been systematically evaluated in patients with a seizure disorder. In clinical trials of Namenda () , seizures occurred in 0.2% of patients treated with Namenda () and 0.5% of patients treated with placebo.
Genitourinary Conditions
Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.
Special Populations
Hepatic Impairment
Namenda () undergoes partial hepatic metabolism, with about 48% of administered dose excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate (74%). No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda () should be administered with caution to patients with severe hepatic impairment.
Renal Impairment
No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions
Carcinogenesis, Mutagenesis and Impairment of Fertility
There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m 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 (20 and 10 times the MRHD on a mg/m basis, respectively) through 128 weeks.
Memantine produced no evidence of genotoxic potential when evaluated in the or reverse mutation assay, an chromosomal aberration test in human lymphocytes, an cytogenetics assay for chromosome damage in rats, and the mouse micronucleus assay. The results were equivocal in an gene mutation assay using Chinese hamster V79 cells.
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/m basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
Pregnancy
Pregnancy Category B: Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m basis.
There are no adequate and well-controlled studies of memantine in pregnant women. Memantine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether memantine is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered to a nursing mother.
Pediatric Use
There are no adequate and well-controlled trials documenting the safety and efficacy of memantine in any illness occurring in children.
Namenda () Adverse Reactions
The experience described in this section derives from studies in patients with Alzheimer's disease and vascular dementia.
Other adverse events occurring with an incidence of at least 2% in Namenda () -treated patients but at a greater or equal rate on placebo were agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, depression, upper respiratory tract infection, anxiety, peripheral edema, nausea, anorexia, and arthralgia.
The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate to severe Alzheimer's disease were not different from the profile and incidence rates described above for the overall dementia population.
Other Adverse Events Observed During Clinical Trials
Namenda () has been administered to approximately 1350 patients with dementia, of whom more than 1200 received the maximum recommended dose of 20 mg/day. Patients received Namenda () treatment for periods of up to 884 days, with 862 patients receiving at least 24 weeks of treatment and 387 patients receiving 48 weeks or more of treatment.
Treatment emergent signs and symptoms that occurred during 8 controlled clinical trials and 4 open-label trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using WHO terminology, and event frequencies were calculated across all studies.
All adverse events occurring in at least two patients are included, except for those already listed in Table 1, WHO terms too general to be informative, minor symptoms or events unlikely to be drug-caused, e.g., because they are common in the study population. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Namenda () treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Events Reported Subsequent to the Marketing of Namenda () , both US and Ex-US
Although no causal relationship to memantine treatment has been found, the following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in labeling: aspiration pneumonia, asthenia, atrioventricular block, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, colitis, deep venous thrombosis, depressed level of consciousness (including loss of consciousness and rare reports of coma), dyskinesia, dysphagia, encephalopathy, gastritis, gastroesophageal reflux, grand mal convulsions, intracranial hemorrhage, hepatitis (including increased ALT and AST and hepatic failure), hyperglycemia, hyperlipidemia, hypoglycemia, ileus, increased INR, impotence, lethargy, malaise, myoclonus, neuroleptic malignant syndrome, acute pancreatitis, Parkinsonism, acute renal failure (including increased creatinine and renal insufficiency), prolonged QT interval, restlessness, sepsis, Stevens-Johnson syndrome, suicidal ideation, sudden death, supraventricular tachycardia, tachycardia, tardive dyskinesia, thrombocytopenia, and hallucinations (both visual and auditory).
Namenda () Animal Toxicology
Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose on a mg/m basis.The potential for induction of central neuronal vacuolation and necrosis by NMDA receptor antagonists in humans is unknown.
Namenda () Overdosage
Signs and symptoms associated with memantine overdosage in clinical trials and from worldwide marketing experience include agitation, confusion, ECG changes, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2.0 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered.
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.
As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.
Namenda () Dosage And Administration
The dosage of Namenda () (memantine hydrochloride) shown to be effective in controlled clinical trials is 20 mg/day.
The recommended starting dose of Namenda () 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.
Namenda () can be taken with or without food.
Patients/caregivers should be instructed on how to use the Namenda () Oral Solution dosing device. They should be made aware of the patient instruction sheet that is enclosed with the product. Patients/caregivers should be instructed to address any questions on the usage of the solution to their physician or pharmacist.
Doses in Special Populations
A target dose of 5 mg BID is recommended in patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min based on the Cockroft-Gault equation):
Namenda () How Supplied
The capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other.
The capsule-shaped, film-coated tablets are gray, with the strength (10) debossed on one side and FL on the other.
Repackaged by
Rebel Distributors Corp
Thousand Oaks, CA 91320
Namenda () Principal Display Panel
Namenda () Principal Display Panel
