Use 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.
-Use of effective contraception during therapy has been recommended.

Animal studies of the components of this drug have failed to reveal evidence of teratogenicity, embryolethality, embryofetal toxicity, or an effect on reproductive function. For cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide, no adverse developmental effects observed when the components were administered separately during organogenesis at cobicistat exposures 1.6-times (rats) and 3.8-times (rabbits), at elvitegravir exposures up to 23-times (rats) and 0.2-times (rabbits), at emtricitabine exposures 60-times (mice) and 108-times (rabbits), and at tenofovir alafenamide exposures equal to (rats) and 53-times (rabbits) the human exposure at the recommended daily dose of these components in this combination drug. For cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (DF), no adverse developmental effects observed when the components were administered separately during organogenesis at cobicistat exposures 1.8-times (rats) and 4.3-times (rabbits), at elvitegravir exposures up to 23-times (rats) and 0.2-times (rabbits), and at emtricitabine exposures 60-times (mice) and 120-times (rabbits) the human exposures at the recommended daily dose of these components in this combination drug, and at tenofovir DF exposures 14-times (rats) and 19-times (rabbits) the human dose based on body surface area comparisons. Data in pregnant women (more than 1000 pregnancy outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with emtricitabine and tenofovir disoproxil. There are no controlled data in human pregnancy; however, available data showed no increase in overall risk of major birth defects for cobicistat, emtricitabine, and tenofovir DF compared with the background rate in the US reference population.

Exposures of cobicistat and elvitegravir were considerably lower during the second and third trimesters of pregnancy compared to postpartum. Reduced elvitegravir exposure may lead to virological failure and an increased risk of HIV-1 transmission to the child. This drug should not be started in pregnant women and patients who become pregnant during therapy with this drug should be switched to an alternative regimen. Viral load should be monitored closely during pregnancy.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with cobicistat and tenofovir alafenamide and as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with elvitegravir, emtricitabine, and tenofovir DF.

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 over 400 exposures to cobicistat-containing regimens (over 325 exposed in the first trimester; over 75 exposed in the second/third trimester) resulting in live births; there was no difference between cobicistat and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For cobicistat, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to cobicistat was 3.7% and 1.3%, respectively.

The APR has received prospective reports of over 300 exposures to elvitegravir-containing regimens (over 250 exposed in the first trimester; over 50 exposed in the second/third trimester) resulting in live births. For elvitegravir, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to elvitegravir was 3.6% and 1.5%, respectively.

The APR has received prospective reports of over 4700 exposures to emtricitabine-containing regimens (over 3325 exposed in the first trimester; over 1375 exposed in the second/third trimester) resulting in live births; there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For emtricitabine, 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 to emtricitabine was 2.6% and 2.3%, respectively.

The APR has received prospective reports of over 300 exposures to tenofovir alafenamide-containing regimens (over 225 exposed in the first trimester; over 75 exposed in the second/third trimester) resulting in live births; available data showed 12 birth defects in the first trimester compared with 1 birth defect in the second/third trimester. For tenofovir alafenamide, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to tenofovir alafenamide was 5.2% and 1.2%, respectively.

The APR has received prospective reports of over 5700 exposures to tenofovir DF-containing regimens (over 4000 exposed in the first trimester; over 1700 exposed in the second/third trimester) resulting in live births; there was no difference between tenofovir DF and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For tenofovir DF, 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 to tenofovir DF was 2.4% and 2.4%, 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

EMTRICITABINE:
Samples of breast milk obtained from 5 HIV-1-infected women show that emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants and achieve serum levels that may lead to emergence of viral resistance to emtricitabine. Breastfeeding infants whose mothers are treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in such infants are unknown.

During ongoing therapy, emtricitabine was measured after a 300-mg dose to 6 nursing mothers with HIV infection. Median peak breast milk level was 872 mcg/L (range: 696 to 1063 mcg/L) at 3 hours; 1 breastfed infant had detectable emtricitabine serum level of 17.5 mcg/L.

Emtricitabine (200 mg once a day) was part of a combination regimen for HIV in 16 Nigerian women exclusively breastfeeding their infants (on demand). Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, 8, and 12 hours after dosing; peak breast milk level from dried breast milk spots was 843 (interquartile range [IQR]: 702 to 1132 mcg/L) at 4 hours (IQR: 2 to 8 hours) after dosing. Infant blood samples were collected at 2 and 8 hours after maternal dosing; analysis of the dried blood spots showed only 3 samples with quantifiable (greater than 16.6 mcg/L) emtricitabine blood levels of 17.5, 18.8, and 19.4 mcg/L.

EMTRICITABINE-TENOFOVIR DF:
Preexposure prophylaxis, using emtricitabine 200 mg-tenofovir DF 300 mg daily, was administered by directly observed therapy for 10 days to 50 women without HIV infection who were breastfeeding their infants. On days 7 and 10 of therapy, peak and trough milk samples were collected 1 to 2 hours after dosing and 23 to 24 hours after the previous dose, respectively; a single infant blood sample was collected after the mother's 7th dose. Median peak and trough milk emtricitabine levels were 212.5 and 183 mcg/L, respectively; these levels correspond to a daily dose of 27.5 to 31.5 mcg/kg (estimated), which is about 0.5% of the proposed therapeutic dose for infants. Median peak and trough milk tenofovir levels were 3.2 and 3.3 mcg/L, respectively; these levels correspond to a daily dose of 0.47 to 0.49 mcg/kg (estimated), which is less than 0.01% of the proposed therapeutic dose for infants. Of 49 infant blood samples collected, 47 had detectable emtricitabine levels (median plasma level: 13.2 mcg/L) and 46 had undetectable (less than 0.31 mcg/L) tenofovir levels. Emtricitabine plasma levels were 16.6 mcg/L in infants younger than 13 weeks and 10.5 mcg/L in infants at least 13 weeks of age; the 3 detectable tenofovir levels were 0.9, 0.9, and 17.4 mcg/L. Diarrhea lasting 2 to 3 days was reported in 2 of the 50 breastfed infants; no other side effects were reported.

TENOFOVIR DF:
Bioavailability of tenofovir is very poor; it is available as tenofovir DF (more bioavailable), which is metabolized intracellularly to tenofovir diphosphate (active metabolite). Although unknown, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir is secreted in human milk. Average peak and trough tenofovir levels in breast milk were 14.1 and 6.8 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 0.03% of the proposed tenofovir dose for infants and attain trivial infant serum levels that would likely have no adverse outcomes.

In a multicenter study, a single 600 or 900 mg dose of tenofovir was administered to mothers during labor; samples of breast milk were collected at various times postpartum. In 75% of samples obtained from 25 mothers during the first 2 days postpartum, tenofovir was detected (greater than 2.5 mcg/L); levels ranged from 6.3 to 17.8 mcg/L. Only 1 of 21 milk samples had detectable tenofovir level (15.7 mcg/L) at 4 to 6 days postpartum.

Tenofovir (dose not provided; presumed 300 mg/day), lamivudine, and efavirenz were administered daily (between 6 and 8 PM) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples were collected in the morning from 33 women; tenofovir level was 5 mcg/L (IQR: 0 to 6.1 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; tenofovir level was 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma level of tenofovir at 6 and 12 months of age was 24 mcg/L (IQR: 0 to 51.6 mcg/L) and 0 mcg/L, respectively.

Tenofovir 300 mg/day was administered to 6 HIV-infected breastfeeding mothers; it was measured after dosing during ongoing therapy. Peak breast milk tenofovir level of 5.9 mcg/L (range: 5.5 to 8 mcg/L) was reached at about 3 hours (range: 1 to 7 hours) after dosing; none of the breastfed infants had detectable tenofovir serum levels.

Nigerian and Ugandan women (n=48) used tenofovir DF 300 mg once a day (either in the morning or evening) as part of combination HIV therapy. Expressed milk samples were collected before dosing and several times during the 12 hours after the morning dose (n=30) or at 12, 16, and 20 hours after the prior evening dose (n=18). Using dried breast milk spots, peak breast milk level averaged 5.98 mcg/L (IQR: 0 to 8.05 mcg/L) at about 4 hours (IQR: 1 to 6 hours) after dosing. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing; no infants had measurable (greater than 4.2 mcg/L) tenofovir blood level in dried blood spots.

Serum tenofovir levels were measured in 5 infants exclusively breastfed by 4 mothers using tenofovir 245 mg (presumably tenofovir DF 300 mg) daily; infant age averaged 1.8 months. In 4 infants, serum tenofovir was undetectable (less than 0.005 mg/L); in 1 infant, serum tenofovir was 0.0055 mg/L. At 4 months of age, no adverse outcomes (on standard developmental parameters) were observed in 2 of the infants exclusively breastfed for 3 months.

In a study of women and their infants using antiretroviral therapy for HIV infection, mothers who used a tenofovir-containing regimen were compared to those who did not. The risk of infant death decreased by 57% in infants breastfed and exposed to tenofovir compared to infants who were not breastfed; no alterations in growth and development were observed in breastfed infants during 2 years of follow-up.

A study of 136 breastfed infants of mothers who used tenofovir, efavirenz, and lamivudine during pregnancy and postpartum measured bone markers at 1, 6, and 12 months of age; markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants' bone markers in the study.

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred.

Cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide:
-Excreted into human milk: Yes (emtricitabine); Unknown (cobicistat, elvitegravir, tenofovir alafenamide)
-Excreted into animal milk: Yes (cobicistat, elvitegravir, tenofovir)

Cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (DF):
-Excreted into human milk: Yes (emtricitabine, tenofovir); Unknown (cobicistat, elvitegravir)
-Excreted into animal milk: Yes (cobicistat, elvitegravir)

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.

See references