Data from FDA - Curated by Toby Galbraith - Last updated 16 May 2017

Licensing authority

FDA (Food and Drug Administration, USA)

Indication(s)

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

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Advisory information

contraindications
CONTRAINDICATIONS Namenda (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
Special warnings and precautions

PRECAUTIONS Information for Patients and Caregivers: Caregivers should be instructed in the recommended administration (twice per day for doses above 5 mg) and dose escalation (minimum interval of one week between dose increases).

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 N-methyl-D-aspartate (NMDA) antagonists: The combined use of Namenda with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

Effects of Namenda on substrates of microsomal enzymes: In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, - 2A6, -2 C9, - 2D6, - 2E1, - 3A4) showed minimal inhibition of these enzymes by memantine.

In addition, i n vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, CYP2C9, CYP2E1 and CYP3A4/5.

No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Effects of inhibitors and/or substrates of microsomal enzymes on Namenda: 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.

Acetylcholinesterase (AChE) inhibitors: Coadministration of Namenda with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound.

In a 24-week controlled clinical study in patients with moderate to severe Alzheimer 's disease, the adverse event profile observed with a combination of memantine and donepezil was similar to that of donepezil alone.

Drugs eliminated via renal mechanisms: Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents.

However, coadministration of Namenda and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20 %.

In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide.

Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance®. 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 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.

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 2 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 2 basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in_vitro S. typhimurium or E. coli reverse mutation assay, an in_vitro chromosomal aberration test in human lymphocytes, an in_vivo cytogenetics assay for chromosome damage in rats, and the in_vivo mouse micronucleus assay.

The results were equivocal in an in_vitro 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 2 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 2 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 2 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.

Adverse reactions

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.

Table 1: Adverse Events Reported in Controlled Clinical Trials in at Least 2 % of Patients Receiving Namenda and at a Higher Frequency than Placebo-treated Patients.

Body System Adverse Event Placebo (N = 922) % Namenda (N = 940) % Body as a Whole Fatigue 1 2 Pain 1 3 Cardiovascular System Hypertension 2 4 Central and Peripheral Nervous System Dizziness 5 7 Headache 3 6 Gastrointestinal System Constipation 3 5 Vomiting 2 3 Musculoskeletal System Back pain 2 3 Psychiatric Disorders Confusion 5 6 Somnolence 2 3 Hallucination 2 3 Respiratory System Coughing 3 4 Dyspnea 1 2 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).

Usage information

Dosing and administration

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)]

Pregnancy and lactation
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.

Interactions

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.

More information

Category Value
Authorisation number NDA021487
Orphan designation No
Product NDC 55289-937
Date Last Revised 05-11-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 996561
Marketing authorisation holder PD-Rx Pharmaceuticals, Inc.

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