8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications, including COBENFY, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . Risk Summary There are no available data on COBENFY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.
There are risks to the mother associated with untreated schizophrenia ( see Clinical Considerations ). In animal reproduction studies, oral administration of xanomeline alone or in combination with trospium chloride during the period of organogenesis or during pregnancy and lactation caused maternal toxicities of adverse clinical signs, decreased body weight, weight gain and food consumption, and/or maternal death. At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.
The no observed adverse effect level (NOAEL) of xanomeline or xanomeline/trospium chloride combination for maternal, embryofetal, and/or developmental toxicity is equal to or higher than the xanomeline and trospium chloride dose at the maximum recommended human dose (MRHD) of 250/60 mg xanomeline/trospium chloride, based on mg/m 2 body surface area (BSA) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk There is a risk to the pregnant patient from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide.
Schizophrenia is associated with adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Data Animal Data Pregnant rats were orally treated during the period of organogenesis with 150 mg/kg/day xanomeline alone, 100 mg/kg/day trospium chloride alone, or xanomeline/trospium chloride combination at 30/25, 75/50, and 150/100 mg/kg/day, respectively.
Xanomeline alone and the high dose combination caused maternal toxicities of decreased body weight, weight gain, and food consumption. At these maternally toxic doses, fetal weights were decreased. The NOAEL for maternal and embryofetal toxicity is 75/50 mg/kg/day for the combination, which is approximately 3 and 8 times the xanomeline and trospium chloride dose, respectively, at the MRHD of 250/60 mg xanomeline/trospium chloride, based on BSA.
No fetal malformation was observed. Trospium chloride alone did not cause maternal or embryofetal toxicity. Pregnant rabbits were orally treated during the period of organogenesis with120 mg/kg/day xanomeline alone, 80 mg/kg/day trospium chloride alone, or xanomeline/trospium chloride combination at 30/20, 60/40, and 120/80 mg/kg/day, respectively. Xanomeline alone and the high dose combination caused maternal toxicities of decreased body weight, weight gain, and food consumption, and/or early abortion.
At these maternally toxic doses, decreased fetal weight and decreased fetal viability (increased resorption and post-implantation loss) were observed. The NOAEL for maternal and embryofetal toxicity is 60/40 mg/kg/day for the xanomeline/trospium chloride combination, which is 5 and 13 times the xanomeline and trospium chloride dose, respectively at the MRHD, based on BSA. No fetal malformation was observed. Trospium chloride alone did not cause maternal or embryofetal toxicity.
Rats were orally treated during pregnancy and lactation with 30, 75, and 150 mg/kg/day xanomeline alone, 100 mg/kg/day trospium chloride alone, or xanomeline/trospium chloride combination at 30/25, 75/50, and 150/100 mg/kg/day, respectively. Xanomeline alone at ≥ 75 mg/kg/day or in combination with trospium chloride at ≥ 75/50 mg/kg/day caused maternal toxicity of adverse clinical signs, decreased body weight, weight gain, food consumption, and maternal death.
At these maternally toxic doses, developmental toxicity was observed in the offspring, including growth suppression (decreased body weight and weight gain), delayed developmental landmarks, stillborn pups, and neonatal deaths. No drug effect was observed on the neurobehavioral function, including learning and memory, or the reproductive capacity of the offspring. The NOAEL for maternal and developmental toxicity is 30/25 mg/kg/day for the xanomeline/trospium chloride combination, which is approximately 1 and 4 times the xanomeline and trospium chloride dose, respectively at the MRHD, based on BSA.
Trospium chloride alone did not cause maternal or developmental toxicity. Pregnant rats were treated during the period of organogenesis with trospium chloride at doses up to 200 mg/kg/day. No malformation or fetal toxicity was observed up to 200 mg/kg/day, which is approximately 32 times the trospium chloride dose at the MRHD of 250/60 mg xanomeline/trospium chloride based on BSA. Pregnant rabbits were treated during the period of organogenesis with trospium chloride at doses up to 200 mg/kg/day.
Maternal toxicity (reduced feces, hunched posture, and diarrhea) was observed at 200 mg/kg/day. The NOAEL for maternal toxicity is 20 mg/kg/day, which is approximately 3 times the trospium chloride dose at the MRHD based on BSA. Rats were orally treated during pregnancy and lactation with trospium chloride at doses up to 200 mg/kg/day. Maternal toxicity (death, irregular breathing, increased excitability) and neonatal deaths were observed at 200 mg/kg/day, which is approximately 32 times the MRHD, based on BSA.
The NOAEL for maternal and developmental toxicity is 20 mg/kg/day, which is approximately 3 times the trospium chloride dose at the MRHD, based BSA.
