FDA approved revisions to the GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide), STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) and TYBOST (cobicistat), labels regarding use during pregnancy. Additional edits were made with respect to drug interactions. Highlights of the changes to the labels are summarized below.
GENVOYA AND STRIBILD
The GENVOYA labeling is highlighted below and the same information is included in the STRIBILD label.
SECTION 2: DOSAGE AND ADMINISTRATION
2.5 Not Recommended During Pregnancy
GENVOYA is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters.
GENVOYA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with GENVOYA.
SECTION 4: CONTRAINDICATIONS
8.1 Pregnancy
Risk Summary
GENVOYA is not recommended during pregnancy. A literature report evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters (see Data).
Data
Human Data
A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.
TYBOST
SECTION 2: DOSAGE AND ADMINISTRATION
2.4 Not Recommended During Pregnancy
TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters.
TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters.
TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.
SECTION 4: CONTRAINDICATIONS
• Lomitapide was added
SECTION 7: DRUG INTERACTIONS – Table Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
SECTION 8: USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy. In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy.
Data
Human Data
Cobicistat coadministered with darunavir as a fixed dose combination, in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to enrollment and who were willing to remain on darunavir/cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial.
Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum.
One out of 6 individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five individuals had sustained virologic response (HIV-1 RNA < 50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir/cobicistat is initiated during pregnancy.
There were no new clinically relevant safety findings compared with the known safety profile of darunavir/cobicistat in HIV-1-infected adults.
SECTION 12: CLINICAL PHARMACOLOGY was updated to include the pharmacokinetic results of total and unbound darunavir and total cobicistat after administration of darunavir/cobicistat during the 2nd and 3rd trimester of pregnancy and Postpartum.
GENVOYA AND STRIBILD
The GENVOYA labeling is highlighted below and the same information is included in the STRIBILD label.
SECTION 2: DOSAGE AND ADMINISTRATION
2.5 Not Recommended During Pregnancy
GENVOYA is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters.
GENVOYA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with GENVOYA.
SECTION 4: CONTRAINDICATIONS
- Lomitapide was added
- The following clinical comment was added to hormonal contraceptives: Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are co-administered with GENVOYA
- Lopitapide was added to the Lipid-modifying agent section: Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases
- Fentanyl and tramadol were added to the narcotic analgesics section:
- Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.
- A dose decrease may be needed for tramadol with concomitant use
8.1 Pregnancy
Risk Summary
GENVOYA is not recommended during pregnancy. A literature report evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters (see Data).
Data
Human Data
A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.
TYBOST
SECTION 2: DOSAGE AND ADMINISTRATION
2.4 Not Recommended During Pregnancy
TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters.
TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters.
TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.
SECTION 4: CONTRAINDICATIONS
• Lomitapide was added
SECTION 7: DRUG INTERACTIONS – Table Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
- The following clinical comment was added to hormonal contraceptives: Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with TYBOST and atazanavir or darunavir
- Lopitapide was added to the Lipid-modifying agent section: Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases
SECTION 8: USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy. In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy.
Data
Human Data
Cobicistat coadministered with darunavir as a fixed dose combination, in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to enrollment and who were willing to remain on darunavir/cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial.
Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum.
One out of 6 individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five individuals had sustained virologic response (HIV-1 RNA < 50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir/cobicistat is initiated during pregnancy.
There were no new clinically relevant safety findings compared with the known safety profile of darunavir/cobicistat in HIV-1-infected adults.
SECTION 12: CLINICAL PHARMACOLOGY was updated to include the pharmacokinetic results of total and unbound darunavir and total cobicistat after administration of darunavir/cobicistat during the 2nd and 3rd trimester of pregnancy and Postpartum.
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Elizabeth Thompson
Division of Antiviral Products
Food and Drug Administration
Michael Stanfield Jr.
Division of Antiviral Products
Food and Drug Administration
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