###  Pregnancy Category C

###  Risk Summary

There are no adequate and well-controlled clinical studies with olanzapine and fluoxetine capsules or their components (olanzapine and fluoxetine) in pregnant women. 

A number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. 

Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine capsules, and other SSRIs and SNRIs late in the third trimester have developed complications arising immediately upon delivery (respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying) requiring prolonged hospitalization, respiratory support, and tube feeding. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture is consistent with serotonin syndrome. Neonates exposed to olanzapine, a component of olanzapine and fluoxetine capsules, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. 

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). 

Olanzapine and fluoxetine capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, taking into account the risk of untreated Bipolar I Depression or Treatment Resistant Depression.

###  Human Data

There are no adequate and well-controlled clinical studies with olanzapine and fluoxetine capsules, olanzapine or fluoxetine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. 

Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine capsules, and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [ see Dosage and Administration ( 2.3) and Warnings and Precautions ( 5.6) ]. 

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association. 

Neonates exposed to antipsychotic drugs (including olanzapine, a component of olanzapine and fluoxetine capsules), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. 

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. 

When treating a pregnant woman with olanzapine and fluoxetine capsules, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [ see Dosage and Administration ( 2.3) ]. 

Olanzapine and fluoxetine capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

###  Animal Data

Olanzapine and fluoxetine capsules — Embryo fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [1 and 0.5 times the maximum recommended human dose (MRHD) for olanzapine (20 mg) and fluoxetine (80 mg), respectively on a mg/m 2 body surface area], and 4 and 8 mg/kg/day (high-dose) [2 and 1 times the MRHD on a mg/m 2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [4 and 1 times the MRHD on a mg/m 2 basis, respectively], and 8 and 8 mg/kg/day (high-dose) [9 and 2 times the MRHD on a mg/m 2 basis, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high-doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination. 

In a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (1 and 0.5 times the MRHD on a mg/m 2 body surface area. An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced bodyweight (approximately 8% in female) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (fluoxetine) mg/kg/day (0.25 and 0.13 times the MRHD on a mg/m 2 body surface area). Among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose. 

Olanzapine — In oral embryo-fetal studies in rats and rabbits, there was no evidence of teratogenicity following administration of olanzapine at doses up to 18 and 30 mg/kg/day, respectively (9 and 30 times the MRHD on a mg/m 2 basis, respectively). In a rat teratology study, early resorptions and increased numbers of dead fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m 2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m 2 basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m 2 basis). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 

Placental transfer of olanzapine occurs in rat pups. 

Fluoxetine — In oral embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg/day on a mg/m 2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis).