Animal studies have failed to reveal evidence of teratogenicity or other adverse developmental effects; however, in rats, impaired fertility in females and decreased fetal weight occurred at doses providing systemic exposure about equivalent to and 50% greater than the usual doses recommended for humans, respectively. There are no controlled data in human pregnancy; available data indicate no malformative or fetal/neonatal toxicity.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6). This drug shows rapid and effective placental transfer, achieving near equivalent levels in maternal and cord blood (cord-to-maternal-blood ratio ranging from 0.6 to 1.02).

According to some experts, this drug is not recommended for initial antiretroviral therapy for antiretroviral-naive pregnant women or for nonpregnant adults; it has greater potential for side effects, complex lead-in dosing, and low barrier to resistance. This drug should be used with caution when starting antiretroviral therapy in women with CD4 cell count greater than 250 cells/mm3. Women who tolerate nevirapine-containing regimens and become pregnant while using them can continue therapy, regardless of CD4 cell count.

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

The APR has received prospective reports of over 2600 exposures to nevirapine-containing regimens (over 1100 exposed in the first trimester; over 1500 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 increased risk of overall birth defects and a 2-fold increase in 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 2.8% and 3.2%, respectively.

Severe and sometimes fatal hepatotoxicity has been reported in pregnant women receiving this drug long-term as part of a combination antiretroviral regimen. Women, especially those with CD4+ counts greater than 250 cells/mm3, have a greater risk of developing hepatotoxicity. It is not known whether pregnancy increases this risk. Close monitoring for clinical symptoms and of hepatic transaminases is recommended, especially during the first 18 weeks of therapy.

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.

Caution is recommended.

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

Risk summary: Malformative risk with use of this drug in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.
-In literature reports, exposure (Cmin) of the immediate-release formulation were up to 29% lower during pregnancy compared to postpartum; this reduction was not considered clinically significant.
-Severe hepatic events (including fatalities) reported in pregnant women using this drug chronically as part of combination therapy; regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not start this drug unless the benefit outweighs the risk.
-Females of reproductive potential should not use oral contraceptives as the only method for birth control; this drug may lower plasma levels of these agents.

See references

Breastfeeding is not recommended during use of this drug. If replacement feeding is not an option, the WHO recommends a triple-drug regimen for HIV-infected women who are nursing; this drug is included in alternative regimens.

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 serious 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.

Due to its long half-life, subtherapeutic drug levels can persist in breast milk and infant serum for relatively long periods, which may increase the risk of developing drug-resistant HIV infections when the mother uses this drug alone for prophylaxis.

Breast milk samples (n=4) were collected from 3 mothers using either 100 or 200 mg/day; milk levels averaged 76% (range: 54% to 104%) of maternal serum levels.

During labor, 21 women received a single 200 mg oral dose; milk samples were collected 48, 72, and 168 hours after dosing. Breast milk drug level was 454 mcg/L (range: 219 to 972 mcg/L) at 48 hours and declined to 103 mcg/L (range: 25 to 309 mcg/L) at 7 days postpartum; milk levels declined in parallel with maternal serum level with a half-life averaging 61 hours.

During the first 5 days in 3 women using 200 mg twice a day as part of a highly-active antiretroviral combination regimen, postpartum milk was collected just before and 2 hours after the dose of this drug. Breast milk drug levels from milk samples averaged 68% to 90% of the maternal serum level; further details regarding timing or actual breast milk levels were not provided.

Milk from 20 women using 200 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were analyzed at either 2 or 5 months postpartum; milk and serum samples were collected at about 4 hours (range: 1 to 8.5 hours) after the last maternal dose. The breast milk drug level averaged 6.8 mg/L; the infant serum drug level averaged 971 mcg/L (range: less than 16 to 2191 mcg/L).

Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with nevirapine, lamivudine, and [zidovudine or stavudine]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk nevirapine levels averaged 2.3 mg/L (n=34) for the first sample and 2.2 mg/L (n=36) for the second sample; these levels were 60% to 80% of the coinciding maternal serum levels.

Free and total nevirapine levels were measured in breast milk samples from 1 woman for 22 days after her last 200 mg dose, which was given as part of cART to prevent mother-to-child HIV transmission. This drug was detectable in whole breast milk for up to 17 days after the last dose at levels of 12.7 and 13.3 ng/mL in the right and left breast, respectively; free drug was detectable for up to 13 days after the last dose at levels of 17.8 and 13.2 ng/mL in the right and left breast, respectively. The total drug peak level and half-life for the right and left breast were 2.742 and 2.475 mcg/mL and 69.2 and 72 hours, respectively; the free drug peak level and half-life for the right and left breast were 1.378 and 1.66 mcg/mL and 65.2 and 50.8 hours, respectively.

At 6, 12, and 24 weeks postpartum, 21 breast milk and maternal serum samples were collected from mothers using this drug (dose not provided) as part of cART; analysis showed their infants had undetectable serum nevirapine levels (times of infant plasma sampling not provided). At about 15 hours after the last dose at 6 weeks postpartum (8 samples), 13 hours after the last dose at 12 weeks postpartum (7 samples), and 12 hours after the last dose at 24 weeks postpartum (6 samples), breast milk drug levels averaged 1.3, 3.4, and 1.2 mg/L, respectively; milk levels were about 12% (interquartile range [IQR]: 0 to 30%) of maternal plasma levels. At about 15 hours after the last maternal dose at 6 weeks of age (8 samples), 13 hours after the last maternal dose at 12 weeks of age (7 samples), and 12 hours after the last maternal dose at 24 weeks of age (6 samples), infant serum drug levels averaged 584, 607, and 233 mcg/L, respectively; infant serum levels were about 12% of maternal serum levels. In a related study by the same authors, the drug milk to plasma ratio was 0.82 in 39 patients.

Starting at 34 to 36 weeks postpartum and continuing until 6 months postpartum, 58 mothers used this drug (200 mg once a day for 14 days, then 200 mg twice a day), lamivudine, and zidovudine; breast milk and serum from the mothers (who were instructed to exclusively breastfeed for 5.5 months) and serum from their 58 infants were analyzed for these drugs. Breast milk and infant serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the previous dose. The breast milk nevirapine level across all visits averaged 4546 mcg/L; according to author estimation, a fully breastfed infant would receive 682 mcg/kg/day of this drug. At delivery and at 2, 6, 14, and 24 weeks postpartum, the infant dried blood spot nevirapine levels averaged 2963 mcg/L and 987, 1032, 734, and 303 mcg/L, respectively.

A single 200 mg dose was given to 62 women at about 5.2 hours before delivery. Breast milk was collected from each breast at delivery and 1, 2, and 6 weeks after the dose; 116 breast milk samples were collected and analyzed. Breast milk drug level averaged 1012 mcg/L (IQR: 657 to 1364 mcg/L) at delivery, 164 mcg/L (IQR: 75 to 213 mcg/L) at 1 week postpartum, and 17 mcg/L (IQR: 15 to 35 mcg/L) at 13 to 16 days postpartum; this drug was undetectable (less than 15 mcg/L) in breast milk at 6 weeks postpartum. Maternal plasma and breast milk drug levels declined with a half-life of 50.3 hours.

A single 200 mg oral dose was administered to 10 women at delivery; at 1 week postpartum, milk drug levels averaged 290 mg/L (range: 110 to 900 mg/L).

Milk samples were analyzed after mothers received a single 200 mg dose at the onset of labor. Of 51 mothers' milk samples, 47 had detectable drug 1 week after the dose (level averaged 112 mcg/L); at 2 weeks after the dose, the level averaged 15 mcg/L in 40 milk samples analyzed; at 4 weeks, this drug was undetectable (less than 10 mcg/L) in all 43 samples analyzed.

Of 58 mothers using 200 mg twice a day as part of cART, 57 provided 181 milk samples (total) at birth, 1, 3, and/or 6 months postpartum; breastfed infants of the 58 mothers had 58 blood samples (total) analyzed at 1, 3, and/or 6 months postpartum. Milk and infant blood samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. Breast milk drug level averaged 2901 mcg/L (range: 2097 to 4684 mcg/L). Infant plasma drug levels averaged 809 mcg/L (range: 535 to 1061 mcg/L), which was about 18% (range: 14% to 24%) of the maternal serum level.

Breast milk samples were collected at just before a dose at about 1 month postpartum from 15 women using nevirapine 200 mg twice a day (with zidovudine and lamivudine); infant blood was collected at about 1 month postpartum at 12 to 17 hours after last dose and about 1 hour (range: 6 minutes to 35 hours) after last breastfeeding from 9 of their partially or exclusively breastfed infants. Whole breast milk levels contained about 1.83 mg/L of this drug, which was about 27% of maternal blood levels; nevirapine was detectable in the serum of all 9 infants (level averaged 0.37 mg/L [range: 0.24 to 1.2 mg/L]).

From a study of 224 women who received a single 200 mg dose at delivery, 1212 breast milk samples were collected at 1 week and/or 4 weeks postpartum. At 1 week postpartum, drug was detectable in 98% of women (level averaged 0.22 mg/L); at 4 weeks, drug was not detectable in breast milk.

Breast milk samples were provided 0.5, 1, 2, 4, 8, and 12 hours after a dose by 5 HIV-infected nursing mothers using 200 mg every 12 hours. Peak and trough drug levels in breast milk averaged 5.2 mg/L (at 4 hours after dosing) and 4.3 mg/L (at 0.5 hours after dosing), respectively; 4 of their breastfed infants had serum drug levels of 529 and 556 mcg/L at 2 and 8 hours after maternal dosing, respectively.

Various pharmacokinetic parameters related to drug excretion into breast milk were calculated in 28 women using 200 mg twice a day who had genetic variations in CYP450 2B6; 3 polymorphisms in this enzyme resulted in differing amounts of drug excreted into breast milk, apparently related to differences in maternal plasma levels; these differences reflected variable infant plasma drug levels.

A study compared breastfed infants of women who received highly-active antiretroviral therapy with this drug (n=270) to a regimen that contained nelfinavir (n=206) as an alternative (both regimens contained zidovudine and lamivudine). Moderate rash was slightly more common in infants receiving this drug (than nelfinavir) via breast milk; no differences observed in the rates of severe rash, liver toxicity, or hyperbilirubinemia.

A study compared the frequency of rash, hepatotoxicity, and hyperbilirubinemia among 464 breastfed infants whose mothers were taking either this drug (n=258) or nelfinavir (n=206) with zidovudine and lamivudine for HIV infection during pregnancy and postpartum; infants were examined during postpartum weeks 1, 2, and 6. Moderate rash was reported in 7 infants exposed to this drug and 1 infant exposed to nelfinavir; rash developed at about 2 weeks postpartum. Hepatotoxicity developed in 4 infants exposed to nelfinavir and none exposed to this drug. High-risk hyperbilirubinemia occurred in 21 infants (all prior to 48 hours of age), but there was no difference in exposure between the 2 drugs.

See references