Diazepam, alcohol, or other CNS-acting drugs may potentiate the orthostatic hypotension observed with olanzapine Anticholinergic drugs Use with caution Olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility Antihypertensive agents Monitor BP and reduce dosage of antihypertensive drug in accordance with its prescribing information Olanzapine/samidorphan may enhance the effects of certain antihypertensive agents Levodopa and dopamine agonists Not recommended Olanzapine/samidorphan may antagonize the effects of levodopa and dopamine agonists Pregnancy No data are available on use of samidorphan or olanzapine/samidorphan in pregnant females to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes Olanzapine Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery Overall published epidemiologic studies of pregnant females exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Pregnancy exposure registry Monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy Encourage patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ Infertility Based on the pharmacologic action of olanzapine (D2 antagonism), an increase in serum prolactin levels may occur, which may lead to a reversible reduction in fertility in females of reproductive potential Clinical considerations Disease-associated maternal and/or embryofetal risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth Unknown if a direct result of the illness or other comorbid factors Fetal or neonatal risks Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including the olanzapine, during the third trimester of pregnancy; symptoms vary in severity Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization Animal data Oral administration of olanzapine and samidorphan to pregnant rats during organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6x and >400x the maximum recommended human dose (MRHD) of olanzapine 20mg/samidorphan 10mg, respectively based on AUC Olanzapine Early resorptions and increased numbers of nonviable fetuses were observed at a dose 9x the MRHD based on mg/m2 body surface area (BSA) and gestation was prolonged at 5x the MRHD based on mg/m2 BSA Fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine, which is 30x the MRHD based on mg/m2 BSA Samidorphan Oral administration of samidorphan to pregnant rats and rabbits during organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248x the human exposure at the MRHD of 10 mg/day based on AUC Oral administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weights at 188x the human exposure at the MRHD based on AUC Lactation Olanzapine Present in human milk There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk There is no information on the effects of olanzapine on milk production Samidorphan There are no data on the presence of samidorphan or olanzapine/samidorphan in human milk, effects on breastfed infants, or effects on milk production When administered to lactating rats, samidorphan and a metabolite were detected in the plasma of nursing pups, likely due to the presence of samidorphan in milk Monitor infants exposed to olanzapine/samidorphan for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) Pregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Olanzapine: May act through combination of dopamine and serotonin type 2 receptor site antagonism Samidorphan: Opioid antagonist; mitigates weight gain associated with olanzapine Absorption Steady-state exposure (olanzapine20 mg/samidorphan 10mg) Peak plasma concentration Olanzapine: 64.6 ng/mL Samidorphan: 45.1 ng/mL Peak plasma time Olanzapine: 4.5-7 hr Samidorphan: 1-2 hr AUC Olanzapine: 1,086 ng⋅hr/mL Samidorphan: 364 ng⋅hr/mL Time to reach steady-state Olanzapine: 7 days Samidorphan: 5 days Accumulation at steady-state Olanzapine: 2-fold Samidorphan: 1.3-fold Effect of food High-fat meal: Meal containing ~900-1000 calories and 50% fat content Olanzapine Cmax ratio: 0.88 AUC ratio: 0.93 Samidorphan Cmax ratio: 0.85 AUC ratio: 1.03 Distribution Protein bound Olanzapine: 93% Samidorphan: 23-33% Blood-to-plasma Olanzapine: Not determined Samidorphan: 0.8 Metabolism Olanzapine Primary pathways: UGT1A4, CYP1A2 Minor pathway: CYP2D6 Metabolites: 10-N-glucuronide and 4′-N-desmethyl-olanzapine; both lack pharmacological activity at therapeutic concentrations Samidorphan Primary pathway: CYP3A4 Minor pathways: CYP3A5, CYP2C19, CYP2C8 Metabolites: N-dealkylated and cis-N-oxide metabolites; neither metabolite contributes to the pharmacological effects of samidorphan Elimination Half-life Olanzapine: 35-52 hr Samidorphan: 7-11 hr Clearance Olanzapine: 15-22 L/hr; clearance was ~40% higher in smokers than in nonsmokers Samidorphan: 35-45 L/hr Excretion Olanzapine: Urine (57% [7% unchanged]); feces (30%) Samidorphan: Urine (67% [18% unchanged]); feces (16%) Oral Administration Take with or without food as a single tablet Do not divide tablets or combine strengths Storage Store at room temperature of 20-25ºC (68-77ºF) in original bottle with desiccant; excursions permitted to 15-30ºC (59-86ºF) Keep bottle tightly closed and protect from moisture No images available for this drug. 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