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Lopinavir / ritonavir Pregnancy and Breastfeeding Warnings

Lopinavir / ritonavir is also known as: Kaletra

Lopinavir / ritonavir Pregnancy Warnings

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus. -AU, UK: Use of the oral solution is contraindicated. AU TGA pregnancy category: B3 US FDA pregnancy category: Not assigned. Comments: -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; it contains alcohol and propylene glycol. -No dose adjustment needed during postpartum period.

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). Placental transfer to the fetus has been reported as low. There are no controlled data in human pregnancy; however, this drug has been evaluated in over 3000 pregnant women. In a pharmacokinetic trial, the safety profile was similar for pregnant women and non-pregnant adults. No difference in the risk of overall major birth defects compared to the background rate in the general population. 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 3000 exposures to lopinavir-containing regimens (over 1000 exposed in the first trimester); there was no difference between lopinavir and overall birth defects compared with the background birth defect rate in the general population. The APR has received prospective reports of over 5000 exposures to ritonavir-containing regimens (over 2000 exposed in the first trimester); there was no difference between ritonavir and overall birth defects compared with the background rate. In the US reference population of the Metropolitan Atlanta Congenital Defects Program, the background birth defect rate is 2.7%. For both lopinavir and 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 birth defects in the cardiovascular and genitourinary systems. The Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission consider lopinavir-ritonavir a preferred protease inhibitor for use during pregnancy. Pharmacokinetic studies suggest increasing the dose to lopinavir 600 mg-ritonavir 150 mg twice a day in the second and third trimester, especially in protease inhibitor-experienced patients. 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.

Lopinavir / ritonavir Breastfeeding Warnings

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). 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, average breast milk levels were 1.43 mg/L for lopinavir and 79 mcg/L for ritonavir. Infants could breastfeed freely during the study period. Lopinavir and ritonavir were undetectable (less than 10 mcg/L) in all of the 115 infant plasma samples. 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; average concentrations were 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; if replacement feeding is not an option, a different drug may be preferred. Excreted into human milk: Yes (lopinavir, ritonavir) Comments: -The effects in the nursing infant are unknown. -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.

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