This drug should be used during pregnancy only if the benefit outweighs the risk.

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

Risk summary: Clinical data over several decades on use of this drug and its metabolite (acyclovir [aciclovir]) in pregnant women have not identified a drug-related risk of major birth defects; insufficient data available on use of this drug regarding miscarriage or adverse maternal or fetal outcomes.

Comments:
-There are risks to the fetus associated with untreated herpes simplex during pregnancy.

Animal studies have failed to reveal evidence of embryofetal toxicity or teratogenicity for this drug or its metabolite; animal studies have revealed evidence of fetal harm at higher doses causing maternal toxicity. After this drug was administered orally to pregnant rats and rabbits during organogenesis, no adverse embryofetal effects were seen at acyclovir exposures (AUC) of up to about 4 (rats) and 7 (rabbits) times the exposure in humans at the maximum recommended human dose (MRHD); early embryo death, fetal growth retardation (weight and length), and variations in fetal skeletal development (primarily extra ribs, delayed ossification of sternebrae) were seen in rats and associated with maternal toxicity (at exposures about 6 times higher than human exposure at the MRHD). There are no controlled data in human pregnancy; outcomes from prospective studies and postmarketing experience indicate no malformative or fetal/neonatal toxicity.

The risk of neonatal herpes simplex virus (HSV) infection varies from 30% to 50% for genital HSV acquired in late pregnancy (third trimester), while the risk of neonatal infection is about 1% with HSV acquired in early pregnancy. A primary herpes occurrence during the first trimester has been associated with neonatal chorioretinitis, microcephaly, and (in rare cases) skin lesions; in very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth. Coinfection with HSV increases the risk of perinatal HIV transmission in women with a clinical diagnosis of genital herpes during pregnancy.

The Acyclovir and the Valacyclovir Pregnancy Registries were population-based international prospective studies that collected pregnancy data through April 1999. The Acyclovir Registry documented outcomes of 1246 exposures to acyclovir during pregnancy (756 with earliest exposure in the first trimester, 197 in the second trimester, 291 in the third trimester, and 2 unknown); the prevalence of major birth defects with first trimester and any trimester exposures to acyclovir was 3.2% and 2.6%, respectively. The Valacyclovir Pregnancy Registry documented outcomes of 111 exposures to this drug during pregnancy (28 with earliest exposure in the first trimester, 31 in the second trimester, and 52 in the third trimester); the prevalence of major birth defects with first trimester and any trimester exposures to valacyclovir was 4.5% and 3.9%, respectively. The estimated background risk of major birth defects is 2% to 4% in the US general population. Available studies have methodological limitations including insufficient sample size to support conclusions regarding overall malformative risk or comparisons of rates of specific birth defects.

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.

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This drug is a prodrug that is rapidly converted to acyclovir in the body. The dosage of acyclovir in milk after this drug is less than 1% to 2% of a typical infant dosage and would not be expected to cause any side effects in breastfed infants.

After a 500-mg oral dose in 5 lactating women, peak acyclovir levels in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum levels; the acyclovir AUC was 2.2 times (range: 1.4 to 2.6) higher in breast milk compared to maternal serum. After maternal dosing of 500 mg twice a day, a breastfed child would receive an oral acyclovir dosage of about 0.6 mg/kg/day; this drug (unchanged) was not detected in maternal serum, breast milk, or infant urine.

This drug was not detected in milk after 5 nursing mothers were given 500 mg orally every 12 hours for 5 days; this drug was not detected in the urine of their 5 infants. Median peak acyclovir levels in milk were 4.2 mg/L at 2 to 4 hours after the first dose and were similar after the last dose; according to author calculation, the median milk level at steady-state was 2.24 mg/L. The median half-life in milk was 2.1 hours (range: 1.3 to 12.2 hours). Based on median milk levels from this study, an exclusively breastfed infant would receive 0.34 mg/kg/day orally with this regimen, which is less than 1% of the dosage given to neonates. On day 5 of maternal therapy, median infant urine acyclovir level was 0.74 mg/L.

In a study of pregnant women with concurrent HIV and herpes simplex infections, mothers received zidovudine during pregnancy until 12 months postpartum and nevirapine at delivery; half of the women (n=74) also received this drug (500 mg orally twice a day) from 34 weeks gestation until 12 months postpartum. Milk samples (timing not provided) from 44 women collected at 2 weeks postpartum found detectable acyclovir in 35 samples, with a median level of 2.6 mg/L (range: 0.15 to 10.15 mg/L); 3 of the 9 women with undetectable milk acyclovir levels had missed at least 1 dose of this drug in the previous 2 days. At 6 weeks postpartum, all infants who received acyclovir in breast milk had normal serum creatinine (less than 0.83 mg/dL); their median serum creatinine, ALT, and growth were not different from unexposed infants, with the exception of 1 infant with an ALT level of 70.1 units/L. Infants whose mothers received this drug generally had side effects that were similar to the placebo group, except risk of eczema and oral thrush was lower in treated infants than in infants who received placebo.

LactMed: No special precautions are needed when used during breastfeeding.
-According to some authorities: Caution is recommended; this drug should be used only if clearly needed and the benefit to the mother outweighs the risk to the infant.

Excreted into human milk: Yes (as acyclovir [aciclovir], its primary metabolite)

Comments:
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug and any potential side effects in the breastfed child due to this drug or the mother's underlying condition.
-Based on its rapid conversion to acyclovir, this drug appears to be compatible with breastfeeding; acyclovir is considered compatible with breastfeeding by the American Academy of Pediatrics and other experts.
-No effects on the breastfed infant are expected.

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