This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus.
-According to some authorities: Use of the oral solution is contraindicated.
-According to some authorities: Use of the oral solution should be avoided.

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.
-This drug is recommended for pregnant patients with no documented lopinavir-associated resistance substitutions.
-Once-daily dosing is not recommended during pregnancy.
-The oral solution should not be used during pregnancy due to the ethanol content; it contains about 42% (v/v) ethanol and about 15% (w/v) propylene glycol.
-No dose adjustment needed during postpartum period.
-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 treatment-related malformations; embryonic and fetal developmental toxicities were observed in rats at maternally toxic doses (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and ossification delays, and decreased survival between birth and postnatal day 21). This drug has been evaluated in over 3000 pregnant women (including over 1000 during the first trimester). In a pharmacokinetic trial, the safety profile was similar for 12 HIV-infected pregnant women and non-pregnant adults. Available human data show no difference in the risk of overall major birth defects compared to the background rate in the US reference population; malformative risk is unlikely in humans.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with lopinavir and ritonavir.

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 3900 exposures to lopinavir-containing regimens (over 1400 exposed in the first trimester; over 2500 exposed in the second/third trimester) resulting in live births; there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For lopinavir, 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 lopinavir was 2.1% and 3%, respectively.

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 ritonavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For ritonavir, 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 ritonavir was 2.3% and 2.9%, respectively.

The Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission recommends lopinavir-ritonavir (plus a preferred dual-nucleoside reverse transcriptase inhibitor backbone) as an alternative protease inhibitor regimen for antiretroviral-naive pregnant patients. Pharmacokinetic studies of standard twice-daily dosing showed reduced lopinavir plasma levels during pregnancy of about 30% compared to levels seen in nonpregnant adults; increasing the dose by 50% resulted in exposure equal to that seen in nonpregnant adults receiving standard doses. Some experts recommend an increased dose (e.g., lopinavir 600 mg-ritonavir 150 mg twice a day) in the second and third trimesters, especially in protease inhibitor-experienced patients and patients who start treatment during pregnancy with a baseline viral load over 50 copies/mL. If standard dosing is used, virologic response and lopinavir drug levels should be monitored. The Panel does not recommend once-daily dosing or use of the oral solution during pregnancy.

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

Low levels of lopinavir appear in breast milk and can be found in the serum of some breastfed infants; measurable levels of ritonavir are excreted in milk and low levels can be found in the blood of some breastfed infants. Although lopinavir has been associated with impaired adrenal gland function when administered directly to infants, the effect is dose related; no infant side effects were clearly due to the small amounts of lopinavir in breast milk. No side effects in breastfed infants have been reported with ritonavir.

In 1 study, nursing mothers used lopinavir and ritonavir 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. Neither component was 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 lopinavir level in breast milk averaged 1834 mcg/L (range: 557 to 3950 mcg/L); the lopinavir plasma level in infants averaged 105 mcg/L (range: 12 to 518 mcg/L), which was about 8% (range: 0 to 16%) of the maternal serum level. 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.

A drug regimen that included lopinavir 400 mg twice a day, ritonavir, zidovudine, and lamivudine was used for 53 to 182 days in 15 women; 5 infants were partially or exclusively breastfed. Breast milk samples were collected immediately prior to a dose at about 1 month postpartum; the lopinavir level in whole breast milk averaged 0.06 mg/L, which was about 0.7% of maternal blood levels. At about 1 month postpartum, infant blood was collected at 11 to 16 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after nursing; 2 of 5 infants had measurable lopinavir plasma levels of less than 1 mg/L.

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 lopinavir and ritonavir were found in 117 and 112 of 121 breast milk samples, respectively; over the 6 hours, breast milk levels averaged 1.43 mg/L for lopinavir and 79 mcg/L for ritonavir. Lopinavir and ritonavir were undetectable (less than 10 mcg/L) in all 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 levels averaged 4263 mcg/L (range: 1143 to 5573 mcg/L) for lopinavir and 240 mcg/L (range: 98 to 402 mcg/L) for ritonavir in the 8 women where they were quantified.

Mother-infant pairs were studied among mothers taking lopinavir 400 mg with ritonavir 100 mg twice a day as part of a multi-drug HIV regimen. At 1, 3, and 6 months postpartum, breast milk was hand expressed by mothers 1 to 2 hours after the morning dose; infants were breastfed (extent not provided) and plasma levels were measured postpartum. Breast milk lopinavir levels averaged 530 mcg/L (n = 6), 650 mcg/L (n = 8), and 590 mcg/L (n = 8) at 1, 3, and 6 months, respectively; the weight-adjusted infant dose was calculated to be 0.23% at 6 months. Infant plasma lopinavir levels averaged less than the lower limit of quantification of 264 mcg/L at 1 (n = 3), 3 (n = 9), and 6 months (n = 8); only 2 samples had measurable lopinavir. Among 9 breastfed infants, no side effects were noted by investigators or reported by mothers at 1, 3, and 6 months of age.

Lopinavir and ritonavir were measured in 117 breastfed (90% exclusive) infants whose mothers were using lopinavir plus ritonavir for HIV infection during pregnancy and postpartum. At 8 weeks postpartum, 2% had detectable lopinavir in their plasma (mean level of 0.17 mg/L); none of the infants had detectable ritonavir plasma levels. At 12 weeks postpartum, none of the infants had detectable lopinavir or ritonavir plasma levels. At 12 weeks postpartum, 96% of infants had lopinavir and 91% had ritonavir detectable in hair samples; concentrations averaged 5.1 ng/mg of hair (range: 0.13 to 15.8 ng/mg) for lopinavir and 0.15 ng/mg of hair (range: 0.03 to 0.42 ng/mg) for ritonavir. According to author interpretation, infant exposure to lopinavir and ritonavir during breastfeeding is negligible.

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.

See references