Professional Information — Namenda

Indications and Usage

Namenda (memantine hydrochloride) is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

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):

For males: CLcr = [140-age (years)]· Weight (kg)/[72 · serum creatinine (mg/dL)]

For females: CLcr = 0.85 · [140-age (years)]· Weight (kg)/[72 · serum creatinine (mg/dL)]

Contraindications

Namenda (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

Adverse Reactions

The experience described in this section derives from studies in patients with Alzheimer's disease and vascular dementia.

Adverse Events Leading to Discontinuation: In placebo-controlled trials in which dementia patients received doses of Namenda up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the Namenda group as in the placebo group. No individual adverse event was associated with the discontinuation of treatment in 1% or more of Namenda-treated patients and at a rate greater than placebo.

Adverse Events Reported in Controlled Trials: The reported adverse events in Namenda (memantine hydrochloride) trials reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ. Table 1 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled dementia trials and for which the rate of occurrence was greater for patients treated with Namenda than for those treated with placebo. No adverse event occurred at a frequency of at least 5% and twice the placebo rate.

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.

Vital Sign Changes: Namenda and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with Namenda. A comparison of supine and standing vital sign measures for Namenda and placebo in elderly normal subjects indicated that Namenda treatment is not associated with orthostatic changes.

Laboratory Changes: Namenda 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 Namenda treatment.

ECG Changes: Namenda 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 Namenda treatment.

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.

Body as a Whole: Frequent: syncope. Infrequent: hypothermia, allergic reaction.

Cardiovascular System: Frequent: cardiac failure. Infrequent: angina pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary embolism, pulmonary edema.

Central and Peripheral Nervous System: Frequent: transient ischemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia. Infrequent: paresthesia, convulsions, extrapyramidal disorder, hypertonia, tremor, aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia, involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ptosis, neuropathy.

Gastrointestinal System: Infrequent: gastroenteritis, diverticulitis, gastrointestinal hemorrhage, melena, esophageal ulceration.

Hemic and Lymphatic Disorders: Frequent: anemia. Infrequent: leukopenia.

Metabolic and Nutritional Disorders: Frequent: increased alkaline phosphatase, decreased weight. Infrequent: dehydration, hyponatremia, aggravated diabetes mellitus.

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

Respiratory System: Frequent: pneumonia. Infrequent: apnea, asthma, hemoptysis.

Skin and Appendages: Frequent: rash. Infrequent: skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria.

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

Urinary System: Frequent: frequent micturition. Infrequent: dysuria, hematuria, urinary retention.

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).

Drug Abuse and Dependence

Controlled Substance Class: Memantine HCl is not a controlled substance.

Physical and Psychological Dependence: Memantine HCl is a low to moderate affinity uncompetitive NMDA antagonist that did not produce any evidence of drug-seeking behavior or withdrawal symptoms upon discontinuation in 2,504 patients who participated in clinical trials at therapeutic doses. Post marketing data, outside the U.S., retrospectively collected, has provided no evidence of drug abuse or dependence.

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.

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 C₁₂H₂₁N•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.

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 Ca²⁺, Na⁺ or K⁺ channels. Memantine also showed antagonistic effects at the 5HT₃ receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

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

Renal Impairment: Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50 – 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC_0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.

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).

Hepatic Impairment: Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on C_max and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.

Elderly: The pharmacokinetics of Namenda in young and elderly subjects are similar.

Gender: Following multiple dose administration of Namenda 20 mg b.i.d., females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.

Drug-Drug Interactions

Substrates of Microsomal Enzymes: In vitro studies indicated that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, CYP2C9, CYP2E1 and CYP3A4/5.  In addition, in vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. These data indicate that no pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Inhibitors of Microsomal Enzymes: Since memantine undergoes minimal metabolism, with the majority of the dose excreted unchanged in urine, an interaction between memantine and drugs that are inhibitors of CYP450 enzymes is unlikely. Coadministration of Namenda with the AChE inhibitor donepezil HCl does not affect the pharmacokinetics of either compound.

Drugs Eliminated via Renal Mechanisms: Memantine is eliminated in part by tubular secretion. In vivo studies have shown that multiple doses of the diuretic hydrochlorothiazide/triamterene (HCTZ/TA) did not affect the AUC of memantine at steady state. Memantine did not affect the bioavailability of TA, and decreased AUC and C_max of HCTZ by about 20%. Coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Memantine did not modify the serum glucose lowering effects of Glucovance®, indicating the absence of a pharmacodynamic interaction.

Drugs that make the urine alkaline: The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline state may lead to an accumulation of the drug with a possible increase in adverse effects. Drugs that alkalinize the urine (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) would be expected to reduce renal elimination of memantine.

Drugs highly bound to plasma proteins: 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.

How Supplied / Storage and Handling

5 mg Tablet:

The capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other.

10 mg Tablet:

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