adverse effects on embryofetal development werereported. The high dose, which was not associated with evidence of maternal toxicity, isapproximately 4 times the MRHD on a mg/m2 basis.
When midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to female ratsduring late gestation and throughout lactation, no clear adverse effects were noted in theoffspring. The high dose, which was not associated with evidence of maternal toxicity, isapproximately 4 times the MRHD on a mg/m2 basis.
In published animal studies, administration of benzodiazepines, including midazolam, orother drugs that enhance GABAergic neurotransmission to neonatal rats has been reported toresult in widespread apoptotic neurodegeneration in the developing brain at plasmaconcentrations relevant for seizure control in humans. The window of vulnerability to these
changes in rats (postnatal days 0-14) includes a period of brain development corresponding tothat taking place during the third trimester of pregnancy in humans.
8.2 Lactation
Risk Summary
Midazolam is excreted in human milk. Studies assessing the effects of midazolam in thebreastfed infant or on milk production/excretion have not been performed. Postmarketingexperience suggests that breastfed infants of mothers taking benzodiazepines, such asNAYZILAM, may have effects of lethargy, somnolence, and poor sucking.
The developmental and health benefits of breastfeeding should be considered along with themother’s clinical need for NAYZILAM and any potential adverse effects on the breastfedinfant from midazolam or from the underlying maternal condition.
8.4 Pediatric Use
Safety and effectiveness of NAYZILAM have been eva luated in the age group 12 to 17years. Use of NAYZILAM in this age group is supported by evidence from an adequate andwell-controlled study of NAYZILAM in adults and adolescents with seizure clusters [seeClinical Studies (14)] and pharmacokinetic and safety data from adult and pediatric patients[see Clinical Pharmacology (12.3)].
Safety and effectiveness in pediatric patients below the age of 12 years have not beenestablished.
8.5 Geriatric Use
Safety and efficacy studies of NAYZILAM did not include sufficient numbers of subjectsaged 65 and over to determine whether they respond differently from younger subjects.
Geriatric patients have longer elimination half-lives for midazolam and its metabolites, whichmay result in prolonged drug exposure. Geriatric patients may have altered drug distribution;diminished hepatic and/or renal function; and subjects over 70 years of age may beparticularly sensitive [see Clinical Pharmacology (12.3)]. Administration of intramuscular(IM) midazolam to elderly patients has been associated with rare reports of death undercircumstances compatible with cardiorespiratory depression [see Warnings and Precautions(5.2)]. In most of these cases, the patients also received other CNS depressants capable ofdepressing respiration, especially narcotics [see Warnings and Precautions (5.1, 5.3)]. Closemonitoring of geriatric patients is recommended.
8.6 Renal Impairment
Based on a population pharmacokinetic analysis of patients administered NAYZILAM,midazolam and 1-OH midazolam pharmacokinetics are expected to be similar in subjects
with mild renal impairment when compared to normal subjects. Safety and efficacy studies ofNAYZILAM did not include patients with severe renal impairment and there were notenough s |
