d 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 memantine is administered to a nursing mother.
8.4 Pediatric Use The safety and effectiveness of memantine 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 treatment emergent adverse events 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 Events With a Frequency ≥ 5% and Twice That in Placebo a Reported adverse events leading to discontinuation in more than one patient in either treatment group.
Adverse Event 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 eventsa
Aggression 3.6% 1.7%
Irritability 1.8% 3.4%
The treatment emergent adverse events 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 Events With a Frequency ≥ 5% a At least 1% incidence of adverse events leading to premature discontinuation.
Adverse Event Memantine
N=903
Headache 8.0%
Nasopharyngitis 6.3%
Pyrexia 5.8%& |
