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

AU TGA pregnancy category: B2
US FDA pregnancy category: Not assigned.

Risk summary: Available data on use of this drug in pregnant women have not identified a drug-related risk after exposure in the second and third trimester; however, insufficient pregnancy data are available to evaluate the risk of drug exposure during the first trimester.

Comments:
-A pregnancy exposure registry is available.
-A study evaluating the pharmacokinetics of this drug during pregnancy showed no clinically relevant differences between pregnant and nonpregnant patients.
-According to some authorities: Patients of childbearing potential should use effective contraception during therapy.
-There are maternal and fetal risks associated with untreated coronavirus disease 2019 (COVID-19) in pregnancy.

Animal studies have failed to reveal evidence of embryofetal toxicity; no adverse effects on embryofetal development (rats and rabbits) were observed at systemic exposures (AUC) of the main circulating metabolite (GS-441524) up to 4 times the exposure in humans at the recommended human dose. There are no controlled data in human pregnancy.

Pharmacokinetics (PKs) and safety of up to 10 days of treatment with this drug were evaluated in a nonrandomized, open-label clinical study in 25 hospitalized pregnant and 28 hospitalized nonpregnant patients of childbearing potential. Of the 25 pregnant patients, gestational age averaged 28 weeks at baseline (range: 22 to 33 weeks) and about half were in each of the second and third trimester of pregnancy. No clinically relevant differences in the PKs of this drug or its metabolites (GS-704277 and GS-441524) were observed between pregnant (n=21) and nonpregnant (n=22) patients; no difference in PKs of this drug or its metabolites is expected between the first and second/third trimesters. The adverse reactions observed were consistent with those observed in clinical trials of this drug in adults; there were no adverse reactions in infants born during the study (n=16).

To monitor the pregnancy outcomes of pregnant women exposed to this drug, a pregnancy registry has been established. Pregnant and recently pregnant patients can enroll at covid-pr.pregistry.com or call 1-800-616-3791 for information about the registry.

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

AU TGA pregnancy category B2: 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 are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

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

Based on limited data, it does not appear that mothers using this drug need to avoid breastfeeding; however, until more data are available, this drug should be used with careful infant monitoring during breastfeeding.
-According to some authorities: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother and the benefit of breastfeeding for the child.

Excreted into human milk: Yes (very low [parent drug and its active metabolite])

Comments:
-Information from 1 patient indicates that milk levels of this drug and its active metabolite are very low.
-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 side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
---Available data from pharmacovigilance reports do not indicate adverse effects on breastfed infants from exposure to this drug and its metabolite through breast milk.

This drug is poorly absorbed orally, and the metabolite is only partially absorbed orally; infants are not likely to absorb clinically significant amounts of the drug from milk. In addition, neonates have received this drug IV for Ebola and for coronavirus disease 2019 (COVID-19) with no serious adverse drug reactions.

The most common side effects reported after IV infusion included elevated aminotransferase levels, elevated bilirubin levels, other liver enzyme elevations, diarrhea, rash, renal dysfunction, and hypotension.

A woman was diagnosed with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 2 days after delivery; she was given 200 mg of this drug on the first day of therapy, then 100 mg once a day for 4 more days (route not provided; presumed IV). Milk was collected on the fifth day of therapy, just before the dose and 1, 3, 6, and 24 hours after the last dose; the parent drug and its metabolite (GS-441524) were measured in milk. Parent drug milk level was 1.29 mcg/L an hour before administration on day 5, but undetectable (less than 0.5 mcg/L) in the other samples; GS-441524 milk levels were 13.5 mcg/L before the fifth dose, 285 mcg/L at 3 hours after the dose, and 64.3 mcg/L at 24 hours after the dose. According to author estimation, the relative infant doses of the parent drug and GS-441524 in breast milk were 0.007% and 1.6%, respectively. The half-life of GS-441524 in milk was 9.3 hours (estimated).

See references