Memantine Hydrochloride (Page 2 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of memantine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include:
Blood and Lymphatic System Disorders -agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.
Cardiac Disorders -cardiac failure congestive.

Gastrointestinal Disorders -pancreatitis.

Hepatobiliary Disorders – hepatitis.

Psychiatric Disorders -suicidal ideation.

Renal and Urinary Disorders -acute renal failure (including increased creatinine and renal insufficiency).

Skin Disorders -Stevens Johnson syndrome.

7 DRUG INTERACTIONS

7.1 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.

7.2 Use with Other N-methyl-D-aspartate (NMDA) Antagonists

The combined use of memantine hydrochloride with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of memantine hydrochloride in pregnant women.

Adverse developmental effects (decreased body weight, and skeletal ossification) were observed in the offspring of rats administered memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are higher than those used in humans at the maximum recommended daily dose of memantine hydrochloride [see Data ].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats during the period of organogenesis resulted in decreased skeletal ossification in fetuses at the highest dose tested. The higher no-effect dose for adverse developmental effects (6 mg/kg) is 3 times the maximum recommended human daily dose (MRHD) of memantine hydrochloride (20 mg) on a body surface area (mg/m2) basis.

Oral administration of memantine to rabbits (0, 3, 10, or 30 mg/kg/day) during the period of organogenesis resulted in no adverse developmental effects. The highest dose tested is approximately 30 times the MRHD of memantine hydrochloride on a mg/m2 basis.

In rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally prior to and throughout mating and, in females, through the period of organogenesis or continuing throughout lactation to weaning. Decreased skeletal ossification in fetuses and decreased body weight in pups were observed at the highest dose tested. The higher no-effect dose for adverse developmental effects (6 mg/kg/day) is 3 times the MRHD of memantine hydrochloride on a mg/m2 basis.

Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) to rats from late gestation throughout lactation to weaning, resulted in decreased pup weights at the highest dose tested. The higher no-effect dose (6 mg/kg/day) is approximately 3 times the MRHD of memantine hydrochloride on a mg/m2 basis.

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).

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