Prescription Drug Information: Memantine Hydrochloride (Page 2 of 4)

8.2 Lactation

Risk Summary

There are no data on the presence of memantine in human milk, the effects on the breastfed infant, or the effects of memantine hydrochloride on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for memantine hydrochloride and any potential adverse effects on the breastfed infant from memantine hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.
Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder and Pervasive Development Disorder — Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively. In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).

The overall risk profile of memantine in pediatric patients was generally consistent with the known risk profile in adults [see Adverse Reactions (6.1)].

In Study A, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of patients and at least twice the frequency of the placebo group (N=58) are listed in Table 2:

Table 2: Study A Commonly Reported Adverse Reactions with a Frequency ≥ 5% and Twice That of Placebo

Adverse Reaction

Memantine N=56

Placebo N=58

Cough

8.9%

3.4%

Influenza

7.1%

3.4%

Rhinorrhea

5.4%

0%

Agitation

5.4%

1.7%

Discontinuations due to adverse reactionsa

Aggression

3.6%

1.7%

Irritability

1.8%

3.4%

a Reported adverse reactions leading to discontinuation in more than one patient in either treatment group.

The adverse reactions that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in Study B are listed in Table 3:

Table 3: 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions with a Frequency ≥ 5%

Adverse Reaction

Memantine N=903

Headache

8.0%

Nasopharyngitis

6.3%

Pyrexia

5.8%

Irritability

5.4%

Discontinuations due to adverse reactionsa

Irritability

1.2%

Aggression

1.0%

a At least 1% incidence of adverse reactions leading to premature discontinuation.

In the randomized withdrawal study (Study B), the adverse reaction in patients randomized to placebo (n=160) and reported in at least 5% of patients and at twice the frequency of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

Juvenile Animal Study

In a study in which memantine (0, 15, 30 or 45 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days [PND] 14 through 70), delays in sexual maturation were noted in males and females at all but the lowest dose tested, and body weight was reduced at the high dose. In rats orally administered memantine as a single dose (PND 14) or three daily doses (PND 14-16), neuronal lesions were observed in several areas of the brain at all but the lowest dose tested. Adverse neurobehavioral effects (decreased auditory startle habituation) were observed at the high dose. The noeffect dose for developmental toxicity was the lowest dose tested (15 mg/kg/day).

In a second juvenile animal study, memantine (0, 1, 3, 8, 15, 30, and 45 mg/kg/day) was orally administered to male and female rats beginning on PND 7 and continuing for various periods during postnatal development. Because of early memantine-related mortality, the 30 and 45 mg/kg/day groups were terminated without further evaluation. Apoptosis or neuronal degeneration in the brain was observed on PNDs 8-17 at a dose of 15 mg/kg/day. The no-effect dose for apoptosis and neuronal degeneration was 8 mg/kg/day. In animals in which memantine (0, 1, 3, 8, or 15 mg/kg/day) was orally administered on PNDs 7-70, adverse neurobehavioral effects (increased locomotor motor activity, increased auditory startle response and decreased habituation, and deficit in learning and memory) were observed at all but the lowest dose tested. Effects on auditory startle persisted after drug discontinuation.
The no-effect dose for developmental toxicity was the lowest dose tested (1 mg/kg/day).

8.5 Geriatric Use

The majority of people with Alzheimer’s disease are 65 years and older. In the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 years old.

8.6 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 Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, 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. Fatal outcome has been very rarely reported with memantine, and the relationship to memantine was unclear.
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.

11 DESCRIPTION

Memantine hydrochloride USP is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride USP is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:

figure1

The molecular formula is C12 H21 N•HCl and the molecular weight is 215.76. Memantine hydrochloride occurs as a fine white to off-white powder and is soluble in water.
Memantine hydrochloride USP is 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).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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.

RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

Medication Sections

Medication Information by RSS

As a leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. RxDrugLabels.com provides the full prescription-only subset of the FDA's repository. Medication information provided here is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.