Namenda XR (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 NAMENDA XR 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

Pregnancy Category B

There are no adequate and well-controlled studies of memantine in pregnant women. NAMENDA XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 6 and 21 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 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 2 times the MRHD on a mg/m2 basis.

8.3 Nursing Mothers

It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Namenda XR is administered to a nursing mother.

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 safety profile of memantine in pediatric patients was generally consistent with the known safety 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 twice that in 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 in Placebo

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

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 reactions a
Aggression 3.6% 1.7%
Irritability 1.8% 3.4%

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%

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

Adverse Reaction Memantine
N=903
Headache 8.0%
Nasopharyngitis 6.3%
Pyrexia 5.8%
Irritability 5.4%
Discontinuations due to adverse reactions a
Irritability 1.2%
Aggression 1.0%

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 twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-Observed-Adverse-Effect-Level (NOAEL) for this study.

In a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 7 through PND 70. Due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation. Memantine induced apoptosis or neuronal degeneration in several areas of the brain on PND 8, 10, and 17 at a dose of 15 mg/kg/day. The NOAEL for apoptosis and neuronal degeneration was 8 mg/kg/day. Behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation. Therefore, the 1 mg/kg/day dose was considered the NOAEL for the neurobehavioral effect in this study.

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