Use is not recommended.

US FDA pregnancy category: Not assigned.

Risk summary: Based on animal studies, this drug may cause fetal harm when administered during pregnancy; available clinical data on the use of this drug in pregnant women is insufficient to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-If the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential harm to the fetus.
-Patients of childbearing potential who are planning to become pregnant should use alternative treatment.
---The separate effect of dextromethorphan on developmental toxicity at the recommended clinical dose is unclear.

Animal studies have failed to reveal evidence of fetal harm. In pregnant mice, this drug was administered orally during organogenesis at doses up to 150-68 mg/kg/day (bupropion-dextromethorphan, respectively); administration of this drug did not affect body weight, weight gain, food consumption, or pregnancy at any dose level and did not produce gross pathologic findings or placental or fetal findings at any dose level. The no-effect level for reproductive organ findings in mice was 150-68 mg/kg in both sexes, which is about 3.5/3.7 times the maximum recommended human dose (MRHD) for this drug on a mg/m2 basis. There are no controlled data in human pregnancy.

BUPROPION (alone): Animal studies have revealed evidence of teratogenicity and fetotoxicity. When administered orally to pregnant rabbits during organogenesis, non-dose-related increases in the rate of fetal malformations and skeletal variations were seen at the lowest dose tested (25 mg/kg/day, about 2 times the MRHD on a mg/m2 basis) and greater, and decreased fetal weights were seen at doses of 50 mg/kg/day (about 5 times the MRHD on a mg/m2 basis) and greater; no maternal toxicity was apparent at doses up to 50 mg/kg/day. After oral administration to pregnant rats during organogenesis at doses up to 450 mg/kg/day (about 21 times the MRHD on a mg/m2 basis), fetal malformations were not evident. There are no controlled data in human pregnancy.
-Data from the international bupropion pregnancy registry (675 first trimester exposures) and a retrospective cohort study (1213 first trimester exposures) did not show an increased risk for malformations overall; the registry was not designed/powered to evaluate specific defects but suggested a possible increase in cardiac malformations. No increased risk for cardiovascular malformations overall was seen after bupropion exposure during the first trimester; the prospectively observed rate was 1.3% (which was similar to the background rate of cardiovascular malformations [about 1%]), and the retrospective study had a limited number of exposed cases with cardiovascular malformations, and a case-control study (11,700 infants with cardiovascular malformations and 20,093 infants with non-cardiovascular malformations) of self-reported antidepressant use (including bupropion [n=728]) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) or ventricular septal defect (VSD) were inconsistent and did not allow conclusions regarding a possible association; the retrospective study lacked sufficient power to evaluate the LVOTO association, NBDPS found slightly increased risk for LVOTO after partially accounting for underlying maternal conditions, and an epidemiology case-control study did not find increased risk for LVOTO. The epidemiology study found an increased risk for VSD after first-trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above); the NBDPS and retrospective study did not find an association between first-trimester maternal bupropion exposure and VSD. For LVOTO and VSD findings, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case-control studies.

DEXTROMETHORPHAN-QUINIDINE: Animal studies have revealed evidence of teratogenicity and embryolethality. When administered orally (dextromethorphan-quinidine up to 50-100 mg/kg/day) to pregnant rats during organogenesis, embryofetal deaths were seen at the highest dose tested and reduced skeletal ossification was seen at all doses. After oral administration to pregnant rabbits during organogenesis (up to 50-100 mg/kg/day), an increased rate of fetal malformations was observed at all but the lowest dose tested. When dextromethorphan-quinidine was orally administered (up to 25-50 mg/kg) to male and female rats on postnatal day (PND) 7, the highest dose resulted in neuronal death in brain (thalamus and medulla oblongata); PND 7 in rats corresponds to the third trimester of gestation through the first few months of life (may extend through the first 3 years of life) in humans. There are no controlled data in human pregnancy.

A prospective, longitudinal study followed 201 pregnant women with history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy; the women who discontinued antidepressants during pregnancy were more like to have a relapse of major depression than those who continued antidepressants. The risks to the mother of untreated depression and potential effects on the fetus should be considered when discontinuing/changing antidepressant therapy during pregnancy and postpartum.

To monitor outcomes of pregnant women exposed to antidepressant therapy, a National Pregnancy Registry for Antidepressants has been established. Health care providers are encouraged to register patients. For additional information: https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

Breastfeeding is not recommended during use of this drug and for 5 days after the last dose.

Excreted into human milk: Yes (bupropion and its metabolites); Unknown (dextromethorphan)
Excreted into animal milk: Data not available (dextromethorphan)

Comments:
-The effects in the nursing infant are unknown.
---Postmarketing reports have described seizures in breastfed infants; the relationship between bupropion exposure and these seizures is unclear.

BUPROPION:
Limited information indicates that maternal bupropion doses (up to 300 mg/day) produce low levels in breast milk and would not be expected to cause any adverse effects in breastfed infants; however, there is little reported use in breastfed newborn infants and case reports of possible seizure in partially breastfed 6-month-olds. A safety scoring system finds bupropion use to be possible with caution during breastfeeding. If bupropion is required by a nursing mother, it is not a reason to discontinue breastfeeding; however, an alternate drug may be preferred, particularly while breastfeeding newborn or preterm infants. Infants exposed to bupropion and a selective serotonin reuptake inhibitor (SSRI) through nursing should be closely monitored for vomiting, diarrhea, jitteriness, or sedation, and possibly measurement of serum levels to rule out toxicity if there is a concern.

In a lactation study, 10 women received sustained-release bupropion 150 mg daily for 3 days, then 300 mg daily for 4 days; these women averaged 12.5 months postpartum and did not nurse their infants after starting bupropion. On the 7th day, breast milk levels of the drug and metabolites were measured at a median 2.5 hours (range: 1 to 12 hours) after the last dose; breast milk levels were: bupropion 45.2 mcg/L (range: 4 to 168 mcg/L), hydroxybupropion 104.6 mcg/mL (range: 9 to 242 mcg/L), erythrohydroxybupropion 72.1 mcg/mL (range: 25.4 to 143 mcg/L), and threohydroxybupropion 459 mcg/mL (range: 193 to 1052 mcg/L). According to author estimation, an exclusively breastfed infant would receive an average of 0.2% of the maternal weight-adjusted dose of bupropion and an average of 2% of the maternal weight-adjusted dosage of bupropion plus metabolites with this maternal dosage regimen.

DEXTROMETHORPHAN:
The amounts of dextromethorphan and its active metabolite in breast milk are very low and not expected to affect breastfed infants. Products with a high alcohol content should not be used while nursing.

Dextromethorphan is metabolized to its active metabolite dextrorphan by CYP450 2D6; dextrorphan is further metabolized to dextrorphan glucuronide by UGT2B. Nursing mothers who were extensive metabolizers of CYP450 2D6 (n=20) donated a blood sample and completely emptied 1 breast 2 hours after a single 30 mg oral dose of dextromethorphan; all mothers were at least 3 months postpartum and patients who were poor, intermediate, or ultra-rapid metabolizers were excluded from the study. The milk levels of dextromethorphan and the active metabolite dextrorphan at 2 hours after dosing (presumed peak) averaged 2.5 and 17 mcg/L, respectively; these values translated to average "worst-case" infant dosages of 0.33 and 1.8 mcg/kg/day, and relative infant dosages of 0.07% and 0.41% for dextromethorphan and dextrorphan, respectively. The authors used published values of serum levels after a typical 60 mg twice daily dosage regimen to estimate average steady-state relative infant dosages of 0.04% and 0.07% for dextromethorphan and dextrorphan, respectively; the potential contribution of dextrorphan glucuronide to infant dosage in neonates was not estimated.

See references