FDA Notifications
FDA approves new atazanavir labeling
On Feb. 4, 2011, the Food and Drug Administration (FDA) approved new labeling for atazanavir (Reyataz®) to include dosing recommendations for treatment of HIV-1 infection during pregnancy and postpartum period.
The major revisions to the package insert are summarized below. Other, minor changes to the package insert and patient package insert were made for consistency:
DOSAGE AND ADMINISTRATION (2.3 Pregnancy)
Dosing During Pregnancy and the Postpartum Period:
Atazanavir should not be administered without ritonavir
Atazanavir should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir
For pregnant patients, no dose adjustment is required for atazanavir with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an H2-receptor antagonist or tenofovir, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a atazanavir dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [See Use in Specific Populations (8.1) and Clinical Pharmacology (12.3).]
8.1 Pregnancy
Risk Summary: atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. Nevertheless, because the studies in humans cannot rule out the possibility of harm, atazanavir should be used during pregnancy only if clearly needed.
Cases of lactic acidosis syndrome sometimes fatal and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women. All infants, including neonates exposed to atazanavir in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
Clinical Consideration
Dosing During Pregnancy and the Postpartum Period:
Atazanavir should not be administered without ritonavir.
Atazanavir should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
For pregnant patients, no dose adjustment is required for atazanavir with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when Atazanavir is coadministered with either an H2-receptor antagonist or tenofovir, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend an atazanavir dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery. [See Dosage and Administration (2, 2.3) and Clinical Pharmacology (12.3).]
Human Data
Clinical Trials: In clinical trial AI424-182, Atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir/ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times the upper limit of normal). There were no cases of lactic acidosis observed in clinical trial AI424-182.
Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12–19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.
12.3 Clinical Pharmacology
Pregnancy
The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir capsules with ritonavir were included in Table 17 of the package insert.
Below is a summary of the data contained in the table. Of note, limited data were available during 2nd trimester (n=5); whereas during the 3rd trimester and postpartum period 20 and 34 subjects, respectively were available.
In the 2nd trimester the Cmax, AUC and Cmin values were 3078.85 ng/mL, 27657.1 ngh/mL and 538.70 ng/mL, respectively.
In the 3rd trimester the Cmax, AUC and Cmin values were 3281.46 ng/mL 34251.5 ngh/mL and 668.48 ng/mL), respectively.
During Postpartum the Cmax, AUC and Cmin values were 5721.21 ng/mL, 61990.4 ngh/mL and 1462.59 ng/mL, respectively.
Atazanvir peak concentrations and AUCs were found to be approximately 28–43% higher during the postpartum period (4–12 weeks) than those observed historically in HIV-infected, non-pregnant patients.
Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in HIV-infected, non-pregnant patients.
The complete revised label will be posted soon at Drugs@FDA.
DHHS panel releases new ART guidelines
On Jan. 10, 2011, the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents released updated Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
The updated guidelines can be viewed and downloaded from the Adult and Adolescent Guidelines section of the AIDSinfo web site at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Key changes, summarized in the preface to the guidelines, entitled What's New in the Guidelines?, are highlighted in yellow throughout the guidelines document. The changes affect the following sections:
Introduction
CD4 T-cell Count
Viral Load Testing
Drug-Resistance Testing
What to Start: Initial Combination Regimens for the Antiretroviral-Naïve Patient
Hepatitis B (HBV)/HIV Coinfection
Mycobacterium Tuberculosis Disease with HIV Coinfection
Adverse Effects of Antiretroviral Agents
The following sections and their relevant tables have also been updated:
Coreceptor Tropism Assays
Treatment Goals
Initiating Antiretroviral Therapy in Treatment-Naïve Patients
What Not to Use
Virologic and Immunologic Failure (previously titled "Management of Patients with Antiretroviral Treatment Failure")
Regimen Simplification
Exposure-Response Relationship and Therapeutic Drug Monitoring for Antiretroviral Agents
Acute HIV Infection
HIV and Illicit Drug Users (with new Table)
HIV-2 Infection
Drug Interactions (and Tables)
Drug Characteristics Tables (Appendices)
Fixed dose ART approved by FDA
On Jan. 5, 2011, the Food and Drug Administration (FDA) granted tentative approval for a fixed-dose combination of lamivudine and zidovudine tablets, 30 mg/60 mg, indicated for use in combination with other antiretrovirals for the treatment of HIV-1 infection.
The tablets, manufactured by Matrix Laboratories Limited of Hyberdad, India, are intended for pediatric use, and can be dispersed in liquid for patients unable to swallow tablets.
The FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the U.S., existing patents and/or proprietary issues currently prevent marketing of the product in the United States. Tentative approval, however, does qualify the product for consideration for purchase under the President's Emergency Plan for AIDS Relief, or PEPFAR program.
As with all generic applications, FDA conducts an on-site inspection of the manufacturing facilities and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.
These products were reviewed for PEPFAR under the FDA guidance titled Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV, developed to clarify what regulatory requirements apply to such applications, what issues might be of concern, and how these issues should be addressed. The guidance is intended to encourage sponsors to submit applications for combination and co-packaged products, and to facilitate submission of such applications to FDA.
A list of all FDA approved and tentative approved antiretrovirals for PEPFAR can be found on the FDA web site at www.fda.gov.
On Feb. 4, 2011, the Food and Drug Administration (FDA) approved new labeling for atazanavir (Reyataz®) to include dosing recommendations for treatment of HIV-1 infection during pregnancy and postpartum period.Subscribe Now for Access
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