Ritonavir Pregnancy and Breastfeeding Warnings

Brand names: Norvir

Medically reviewed by Drugs.com. Last updated on Aug 10, 2023.

Ritonavir Pregnancy Warnings

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus; use of the oral solution is not recommended.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-The oral solution should not be used during pregnancy due to the ethanol content; it contains about 43% (v/v) ethanol and about 27% (w/v) propylene glycol.
-This drug 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.

Animal studies have failed to reveal evidence of teratogenicity (at doses producing systemic exposures [AUC] equal to about one-third lower than human exposure at the recommended daily dose in rats and rabbits); developmental toxicity was observed in rats (early resorption, decreased fetal body weight, ossification delays, developmental variations) and rabbits (resorptions, decreased litter size, decreased fetal weights) at maternally toxic doses (at an exposure equal to about one-third lower than human exposure at the recommended daily dose and at doses about 1.8 times higher than the recommended daily dose [based on a body surface area conversion factor], respectively). A slight increase in the incidence of cryptorchidism was also observed in rats (at a maternally toxic dose) at an exposure about one-fifth lower than human exposure at the recommended daily dose. There are no controlled data in human pregnancy.

Placental transfer 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 have been found in cord blood samples and neonate hair.

Lower plasma drug levels have been observed during pregnancy compared to postpartum, at doses sufficient for HIV suppression or at a low dose to boost levels of other protease inhibitors; this drug is an effective booster of lopinavir, atazanavir, and darunavir in pregnant women. According to some experts, this drug should be used during pregnancy only as a low-dose booster for other protease inhibitors.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Health care providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 6900 exposures to ritonavir-containing regimens (over 3400 exposed in the first trimester; over 3500 exposed in the second/third trimester) resulting in live births; there was no difference between this drug and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. 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 with first trimester and second/third trimester exposures was 2.3% and 2.9%, respectively.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

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

Ritonavir Breastfeeding Warnings

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

Measurable levels of this drug are excreted in milk and low levels can be found in the blood of some breastfed infants. No side effects in breastfed infants have been reported with this drug.

In 1 study, nursing mothers used this drug 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. This drug 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; over the 6 hours, breast milk level averaged 79 mcg/L. This drug was not detectable (less than 10 mcg/L) in any 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.

This drug 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, 91% had ritonavir detectable in hair samples; concentration averaged 0.15 ng/mg of hair (range: 0.03 to 0.42 ng/mg). According to author interpretation, infant exposure to this drug during breastfeeding is negligible.

See references

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