On January 28, 2014 FDA approved changes to the Kaletra (lopinavir/ritonavir) label to include dosing recommendations in pregnant women. The main additions and revisions include the following:
2 DOSAGE AND ADMINISTRATION
2.4 Dosage Recommendations in Pregnancy
Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily KALETRA dosing is not recommended in pregnancy.
- There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.
- No dosage adjustment of KALETRA is required for patients during the postpartum period.
- Avoid use of KALETRA oral solution in pregnant women.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Risk Summary
Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.
Clinical Considerations
Dose Adjustments During Pregnancy and the Postpartum Period
Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period.
Once daily KALETRA dosing is not recommended in pregnancy.
Avoid use of KALETRA oral solution during pregnancy due to the alcohol content. KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v).
Data
Human Data
KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial. No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.
Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). For both lopinavir and ritonavir, sufficient numbers of 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.
Animal Data
Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a peri- and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.
No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
12 CLINICAL PHARMACOLOGY
12.3 Pharmacokinetics
Pregnancy
In an open-label pharmacokinetic study, 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg (two 200/50 mg tablets) twice daily as part of an antiretroviral regimen. Plasma concentrations of lopinavir were measured over 12-hour periods during the second trimester (20-24 weeks gestation), the third trimester (30 weeks gestation) and at 8 weeks post-partum. The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum, but this decrease is not considered clinically relevant in patients with no documented KALETRA-associated resistance substitutions receiving 400 mg/100 mg twice daily.
The completed and revised label can be found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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