Animal studies with nirmatrelvir have failed to reveal evidence of adverse developmental outcomes at systemic exposures (AUC) 3 to 10 times higher than clinical exposure at the approved human dose of this product; in rabbits, reduced fetal body weights were observed at systemic exposures (AUC) about 11 times higher than clinical exposure at the approved human dose of this product. Animal studies with ritonavir have failed to reveal evidence of adverse developmental outcomes at systemic exposures (AUC) 5 (rat) or 8 (rabbit) times higher than clinical exposure at the approved human dose of this product. There are no controlled data in human pregnancy.

Placental transfer of ritonavir to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3). While placental transfer and fetal drug levels are generally low, detectable levels of ritonavir have been found in cord blood samples and neonate hair.

The Antiretroviral Pregnancy Registry has received prospective reports of over 7000 exposures to ritonavir-containing regimens (over 3500 exposed in the first trimester; over 3500 exposed in the second/third trimester) resulting in live births; there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the US reference population. For ritonavir, enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects/live births with first trimester and second/third trimester exposures to ritonavir was 2.4% and 2.9%, respectively.

Coronavirus disease 2019 (COVID-19) is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.

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.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus.

US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of nirmatrelvir in pregnant women to inform a drug-related risk; published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects.

Comments:
-Patients of childbearing potential should use effective contraception during therapy.
-Ritonavir may reduce the efficacy of combined hormonal contraceptives; patients of childbearing potential using these products should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during therapy.

See references

Nirmatrelvir is administered in combination with ritonavir, which enhances its bioavailability. Due to the poor oral bioavailability of nirmatrelvir and small amounts of ritonavir in milk, this product is unlikely to adversely affect nursing infants. In a cross-sectional study of women who had COVID-19 and received this product, 2 women breastfed their infants; no adverse effects were reported in the infants.

RITONAVIR:
Measurable levels of ritonavir are excreted in milk and low levels can be found in the blood of some breastfed infants. No adverse effects have been reported in breastfed infants.

In 1 study, nursing mothers used ritonavir as part of a clinical trial to evaluate maternal-to-child transmission of HIV infection. Doses, dose regimens, and breast milk collection times were not provided. Ritonavir was not detected in any of 60 breast milk samples.

A total of 23 milk samples were obtained (at birth, 1 month, 3 months, and/or 6 months postpartum) from 9 mothers using lopinavir 400 mg plus ritonavir 100 mg twice a day as part of combination antiretroviral therapy. Their breastfed infants had a total of 6 blood samples analyzed at 1 month, 3 months, and/or 6 months postpartum. Milk samples and infant blood samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the previous maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. The ritonavir level in breast milk averaged 79 mcg/L (range: 31 to 193 mcg/L). The ritonavir plasma level in infants averaged 7 mcg/L (range: 0 to 138 mcg/L), which was about 12% (range: 11% to 40%) of the maternal serum level.

Starting at delivery, 30 mothers used zidovudine 300 mg, lamivudine 150 mg, lopinavir 400 mg, and ritonavir 100 mg orally twice a day; they were studied at 6, 12, or 24 weeks postpartum (10 at each time). Infants could breastfeed freely during the study period. On the study day, breast milk samples and maternal and infant plasma samples were collected before the maternal morning dose (about 14.9 hours after the prior evening dose) and 2, 4, and 6 hours after the maternal dose. Detectable quantities (at least 10 mcg/L) of ritonavir were found in 112 of 121 breast milk samples; breast milk level averaged 79 mcg/L over the 6 hours. Ritonavir was undetectable (less than 10 mcg/L) in all of the 115 infant plasma samples.

At 3-hour intervals before cesarean section, 9 women with HIV infection received 3 doses of lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg, lamivudine 50 mg; breast milk samples were collected at about 25 hours postpartum. Milk level averaged 240 mcg/L (range: 98 to 402 mcg/L) for ritonavir in the 8 women where it was quantified.

Ritonavir was measured in 117 breastfed (90% exclusive) infants whose mothers were using lopinavir plus ritonavir for HIV infection during pregnancy and postpartum. At 8 and 12 weeks postpartum, none of the infants had detectable ritonavir plasma levels. At 12 weeks postpartum, ritonavir was detectable in hair samples of 91% of infants; concentration averaged 0.15 ng/mg of hair (range: 0.03 to 0.42 ng/mg). According to author interpretation, infant exposure to ritonavir during breastfeeding is negligible.

Until more data are available, this product should only be used with careful infant monitoring for adverse effects.
---According to some authorities: Breastfeeding is not contraindicated during use of this product.
---According to some authorities: Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Unknown (nirmatrelvir); Yes (ritonavir)
Excreted into animal milk: Unknown (nirmatrelvir)

Comments:
-Minimal information is available on the use of nirmatrelvir during breastfeeding.
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
-The effects in the nursing infant are unknown; potential adverse effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
-Breastfeeding patients with coronavirus disease 2019 (COVID-19) should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

See references