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HIV and AIDS
Human Immunodeficiency Virus and
Acquired Immunodeficiency Syndrome

FDA HIV/AIDS List Serve Archive 2008

On March 27, 2008, FDA approved a new HIV diagnostic test, the VITROS Anti-HIV 1+2 Reagent Pack and VITROS Anti-HIV 1+2 Calibrator, manufactured by Ortho-Clinical Diagnostics. The VITROS Anti-HIV 1+2 Reagent Pack and VITROS Anti-HIV 1+2 Calibrator is an in vitro chemiluminescent immunoassay intended for the in vitro qualitative detection of antibodies to human immunodeficiency virus types 1 and 2 in human serum and plasma using the VITROS ECi/ECiQ Immunodiagnostic System.

The results of the VITROS Anti-HIV 1+2 assay, in conjunction with other serological evidence and clinical information may be used as an aid in the diagnosis of infection with HIV-1 and/or HIV-2 in persons with signs or symptoms of, or at risk for, HIV infection.

The assay is highly sensitive and specific for the detection of anti-HIV types 1 and 2 antibody. The VITROS ECi/ECiQ Immunodiagnostic System is fully automated, reducing the potential for operator errors, with redundant checks to ensure integrity of the system. This automation allows for increased efficiency and convenience.

FDA-approved assays for diagnosis and donor screening for HIV are listed at http://www.fda.gov/cber/products/testkits.htm.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA has been made aware of recent, preliminary findings from analyses of data collected from "The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study," a large observational study of 33,347 HIV-1 infected patients living in North America, Europe and Australia. Patients in this study are being followed to evaluate the short- and long-term adverse effects of treatment with anti-HIV drugs.

Analyses of data collected through February 1, 2007 examined the risk of myocardial infarction (heart attack) in patients taking selected HIV drugs from the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs).  The NRTIs included in the analyses were zidovudine, stavudine, abacavir, didanosine, and lamivudine. No analyses were conducted evaluating the risk of heart attack when patients take tenofovir or emtricitabine, two other drugs in the class. The analyses, specifically, describe the relative risk of heart attack among cumulative use, recent use (currently using or use within the past 6 months), and past use (last use greater than 6 months ago) of these drugs.

These analyses showed that recent use of abacavir or didanosine was associated with an increased risk of heart attack. Patients taking either of these drugs had a greater chance of developing a heart attack than patients taking other medications. The risk did not appear to increase over time, but remained stable and appeared to be reversible after abacavir or didanosine were stopped.

In late 2007, GlaxoSmithKline (GSK), the manufacturer of abacavir, received the preliminary findings from the D:A:D Study analyses and conducted a search of their own clinical study databases. The results of the GSK analysis are inconclusive, but did not show an increased risk.

Bristol Myers Squibb (BMS), the manufacturer of didanosine, conducted an analysis of their clinical databases, and similarly, found no increased risk for heart attack with didanosine use. The results of the BMS analysis are also inconclusive.

Key findings from the D:A:D Study are as follows:

• The excess risk of heart attack in patients taking at least some NRTIs appears to be greater in patients with other risk factors for heart disease. Risk factors include a history of heart disease, high cholesterol, high blood pressure, diabetes, smoking, and age.
• Certain analyses found the risk of heart attack increased by 49% in patients taking didanosine and increased by 90% in patients taking abacavir.
• The increased risk for heart attack remained stable over the course of treatment and the effect was not seen 6 months after stopping the drugs.

FDA currently believes analyses conducted with D:A:D Study data are incomplete; no analyses were conducted evaluating the risk of heart attack when patients take tenofovir or emtricitabine, two other drugs in the class of NRTIs. However, FDA continues to evaluate the overall risks and benefits of abacavir and didanosine. This evaluation may result in the need to revise labeling for the products. Until this evaluation is complete, healthcare providers should evaluate the potential risks and benefits of each HIV-1 antiretroviral drug their patients are taking, including abacavir and didanosine.

This early communication is in keeping with FDA's commitment to inform the public about ongoing safety reviews of drugs. FDA will work with the manufacturers of abacavir and didanosine to fully evaluate the risks and benefits associated with the use of these products as part of an HIV treatment regimen. As soon as this process is complete, FDA will communicate the conclusions and recommendations to the public.

The FDA urges healthcare professionals to promptly report serious and unexpected adverse reactions associated with abacavir and didanosine to the FDA MedWatch reporting program, as described below.

• online at www.fda.gov/medwatch/report.htm
• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
• faxing the form to 1-800-FDA-0178
• by phone at 1-800-332-1088

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Reyataz (atazanavir) Capsule label has been updated to include the dosing recommendations for pediatric patients 6 to 18 years of age.

REYATAZ should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus (a type of brain damage caused by  excessive levels of bilirubin).

Important changes made to the product label include the following: 

Section 2.2 Recommended Pediatric Dosage was added to the label.

The recommended dosage of REYATAZ for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage.  REYATAZ Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.

Therapy-Naive Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-naive patients at least 6 years of age is shown in Table 1.

For treatment-naive patients at least 13 years of age and at least 39 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.

Table 1: Dosage for Treatment-Naive Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

Therapy-Experienced Pediatric Patients
The recommended dosage of REYATAZ with ritonavir in treatment-experienced patients at least 6 years of age is shown in Table 2.

Table 2: Dosage for Treatment-Experienced Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

In section 6 Adverse Reactions subsection 6.2 Clinical Trial Experience in Pediatric Patients was added and includes the following information:

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) was comparable to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (³5%, regardless of causality) reported in pediatric patients were cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in 2% of patients. The most common Grade 3–4 laboratory abnormality was elevation of total bilirubin (³3.2 mg/dL) which occurred in 49% of pediatric patients. All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

In section 14 Clinical Studies, subsection 14.3 Pediatric Patients was added and includes the following:

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age.  In this study, 182 patients (83 antiretroviral-naive and 99 antiretroviral-experienced) received once daily REYATAZ, with or without ritonavir, in combination with two NRTIs.

Ninety-nine patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. In this cohort, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at week 24 were 68% (28/41) and 33% (19/58), respectively. The overall proportions of antiretroviral-naive and ‑experienced patients with HIV RNA <50 copies/mL at week 24 were 59% (24/41) and 24% (14/58), respectively. The median increase from baseline in absolute CD4 count at 20 weeks of therapy was 171 cells/mm3 in antiretroviral-naive patients and 116 cells/mm3 in antiretroviral-experienced patients.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 20, 2008, the Food and Drug Administration (FDA) granted tentative approval to two fixed-dose combination products containing generic versions of stavudine/lamivudine/nevirapine 30mg/150mg/200mg Tablets, and stavudine/lamivudine/nevirapine 40mg/150mg/200mg Tablets, under expedited procedures for the President's Emergency Plan for AIDS Relief (PEPFAR) program. Both fixed dose combinations are manufactured by Strides Arcolab Limited of Bangalore, India, and indicated for the treatment of HIV-1 infection.

Each ingredient of this generic tablet is currently approved to treat HIV-1 in combination with other antiretroviral agents. The safety and effectiveness of the combination of stavudine/lamivudine/nevirapine in lowering viral load and increasing CD4+ cells has been demonstrated in previously conducted controlled studies of the individual ingredients used together.

Combination products such as these can significantly reduce pill burden. potentially resulting in improved therapeutic compliance with complex dosing regimens, as well as facilitating the storage and distribution of these HIV medications.

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 PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications 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 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 approvals and tentative approvals under these provisions can be found at http://www.fda.gov/oia/pepfar.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Tibotec Therapeutics, in cooperation with the U.S. Food and Drug Administration, issued a Dear Healthcare Professional letter to relay important, updated prescribing information for PREZISTA  (darunavir) tablets, that includes a warning about Hepatotoxicity.

The letter provides, in addition to other information, the following, which has been added to the WARNINGS section of the Prezista label:

"Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV1 disease taking multiple concomitant medications, having comorbidities including hepatitis B or C coinfection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

In addition, the Adverse Reaction section of the PREZISTA label and the Patient Package Insert have been updated to include this new information.

The letter, and the new label are available on line in pdf format..

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Updates have been made to Prezista (darunavir) tablets labeling to reflect significant new risk information. Changes have been made to the CLINICAL PHARMACOLOGY section to include data from 6 pharmacokinetic, drug interaction Phase 1 trials, and to the WARNINGS, PRECAUTIONS AND ADVERSE REACTIONS sections of the package insert to include hepatotoxicity information. Other updates include those made to PRECAUTIONS, updates to DOSAGE AND ADMINISTRATION, and changes to Table 11 to include information regarding a potential drug-drug interaction with rosuvastatin.

In the WARNINGS section, the following has been added:

"Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

The PRECAUTIONS section has been changed to read as follows:

"Patients with co-existing conditions
Hepatic Impairment: No dose adjustment of PREZISTA/rtv is necessary for patients with either mild or moderate hepatic impairment. There are no pharmacokinetic or safety data available for subjects with severe hepatic impairment, therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

Table 11, Established and Other Potentially Significant Drug Interactions, has been modified, under HMG-CoA Reductase Inhibitors, to include rosuvastatin, indicating increased concentration of rosuvastatin, with the following clinical comment: "Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/rtv."

The following sentence has been added to the CLINICAL PHARMACOLOGY section, under Absorption and Bioavailabilty: "In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters."

The following has been added under: Special Populations
"Hepatic Impairment: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/rtv 600/100 mg b.i.d. to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

In addition, there are updates to Table 4: Drug Interactions Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs, and Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir.

The last paragraph of the ADVERSE REACTIONS section now reads: "Patients co-infected with hepatitis B and/or hepatitis C virus: In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes (see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection."

In addition, the following has been added:

"Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:

Hepatobiliary System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia

Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
[this duplicate information was deleted from the Skin and Appendages section under the treatment-emergent adverse events occurring in less than 2% of de novo subjects]"

Changes were also made to DOSAGE AND ADMINISTRATION, to include the following: "Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment)."

The new label is available at Drugs@fda.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 29, 2008, FDA granted tentative approval for a generic formulation of efavirenz tablets, 600 mg, manufactured by Hetero Drugs Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR)

"Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Effective patent dates for efavirenz can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

This tentative approval is a generic version of Sustiva (efavirenz) tablets, a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), 600 mg. Sustiva is a products of Bristol Myers Squibb.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 29, 2008, FDA granted tentative approval for a generic formulation of stavudine capsules, 15 mg, 20 mg, 30 mg, and 40 mg, manufactured by Hetero Drugs Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR)

"Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

This tentative approval is a generic version of Zerit (stavudine) capsules, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), 15 mg, 20 mg, 30 mg, and 40 mg, Zerit which is a product of Bristol Myers Squibb.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

The  Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been revised. The new version includes updated information on:

• When to initiate therapy, including
  - Change in treatment recommendations for when to initiate therapy in HIV-infected children <12 months of age
  - Reduction from 4 to 3 age bands for recommendations on when to initiate therapy (<12 months, 1 to <5 years, and 5 years and older) 
  - Changes in immunologic thresholds for when to start in children 1 year or older
• Timing of diagnostic testing in HIV-exposed infants 
• The pediatric drug appendix and hyperlink on drug preparations, new dosage formulations, and pediatric studies 
• Recently approved antiretrovirals: maraviroc (including a new coreceptor tropism assay section), raltegravir, and etravirine 
• Revised antiretroviral toxicity hyperlink with new tables detailing toxicity management

Changes are highlighted in yellow throughout the text and tables. 

The updated guidelines are available for download from the Pediatric Guidelines section of the AIDSinfo Web site. You can also request to receive them by mail or email from the AIDSinfo Order Publications section.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 25, 2008, FDA approved a new 600 mg tablet strength for Prezista (darunavir), manufactured by Tibotec, Inc., Yardley, PA. The new 600 mg tablet facilitates dosing by reducing pill burden.

The recommended oral dose of Prezista tablets is 600 mg (two 300 mg tablets or one 600 mg tablet) twice daily taken with ritonavir 100 mg twice daily and with food.

The 600 mg formulation will be available in bottles of 60 tablets.

The 300 mg tablet will continue to be available.

Darunavir is a protease inhibitor, which inhibits the formation of mature virus in HIV infected cells.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 14, 2008, FDA granted approval for a generic formulation of Zidovudine Tablets, 300 mg, manufactured by Matrix Laboratories, Inc. of Hyderabad, India. The application was reviewed under the expedited review provisions of the President’s Emergency Plan for AIDS Relief (PEPFAR).  However, because patent protections for the reference product, Retrovir Tablets,300 mg, made by GlaxoSmithKline have expired, this generic product can be marketed in the United States, as well as being available for purchase under the PEPFAR program.

A list of all FDA approved generic antiretroviral drugs for the treatment of HIV is available on the web at http://www.fda.gov/oashi/aids/viralsgeneric.html

Zidovudine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for the treatment of HIV in combination with other antiviral medications.

As with all FDA-approved generics, this product must meet all of FDA's manufacturing quality, and clinical safety and effectiveness standards.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 4, 2008, FDA granted tentative approval for a generic formulation of atazanavir sulfate capsules, 100 mg, 150 mg, and 200 mg, manufactured by Emcure Pharmaceuticals of Pune, India. The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR).

Indicated for the treatment of HIV infection in combination with other antiviral medications, atazanavir is a member of the protease inhibitor class of antiretroviral drugs.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

While tentatively approved generic products meet FDA-required standards, they cannot yet be fully approved for sale in the U.S. because of existing patent protections. However, tentative approval does make the product eligible for purchase under the PEPFAR program for treatment use in nations where PEPFAR is active.

This product is a generic formulation of Reyataz Capsules, 100 mg, 150 mg, and 200 mg, made by Bristol Myers Squibb Co. which remains subject to existing patents as listed in the agency's publication titled "Approved Drug Products with Therapeutic Equivalence Evaluations," also known as the "orange book ." 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA has approved a new formulation of Epivir (lamivudine) designed to facilitate dosing in appropriate pediatric patients who can reliably swallow tablets. Epivir is now available as 150 mg scored tablets. The scored tablets allow for dosing recommendations in pediatric patients. The DOSING AND ADMINISTRATION section of the Epivir label was revised as follows:

Pediatric Patients

The recommended oral dose of EPIVIR Oral Solution in HIV-1-infected pediatric patients 3 months to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.

EPIVIR is also available as a scored tablet for HIV-1-infected pediatric patients who weigh ≥14 kg for whom a solid dosage form is appropriate. Before prescribing EPIVIR Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow EPIVIR Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of EPIVIR Tablets for HIV-1-infected pediatric patients is presented in Table 1.

Epivir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) manufactured by GlaxoSmithKline.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

On January 29, 2008, FDA granted tentative approval for a generic version of lamivudine tablets, 150 mg and 300 mg, manufactured by Hetero Drugs Limited,  Hyderabad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it is not yet eligible to be marketed in the U.S. because of existing patents and/or exclusivity rights. However, this tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

This is a generic version of Epivir, manufactured by GlaxoSmithKline, which is subject to existing patent protection.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

On January 29, 2008, t he following changes were made to several sections of the December 1, 2007 version of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents:

What to Start: Initial Combination Regimens for the Antiretroviral-Naïve Patient?

The Panel revised its recommendations for several "preferred" and "alternative" antiretroviral components for treatment-naïve patients:

• "Abacavir + lamivudine" has been changed from "alternative" to "preferred" 2-NRTI component in patients who have tested negative for HLA-B*5701 (AII).
• Zidovudine + lamivudine" has been changed from "preferred" to "alternative" 2-NRTI component (BII).
• "Ritonavir-boosted saquinavir" has been changed from a PI-option that was considered as "Acceptable as initial antiretroviral components but inferior to preferred or alternative components" to an "alternative" PI component (BII).
• The following options are no longer recommended as components for initial therapy in treatment-naïve patients:
  • Nelfinavir as PI component
  • Stavudine + lamivudine as 2-NRTI components
  • Abacavir + zidovudine + lamivudine as a triple-NRTI combination regimen

A new topic entitled "Other Treatment Options Under Investigation: Insufficient Data to Recommend" has been added, which includes a review of recent clinical trial data in treatment-naïve patients for ritonavir-boosted darunavir­based regimens, maraviroc-based regimens, and raltegravir-based regimens.

Treatment Interruption

This section has been updated with recent data on short-term and long-term treatment interruption. The Panel reaffirms our recommendation that aside from unplanned or planned short-term interruption due to illnesses precluding oral therapy or toxicities, long-term treatment interruption is not recommended unless in the context of a clinical trial (DI).

Acute HIV Infection

• A new table on "Identifying, diagnosing, and managing acute HIV- 1 infection" has replaced the table on "Associated signs and symptoms of acute retroviral syndrome and percentage of expected frequency".
• The Panel also recommends that since clinically significant resistance to PIs is less common than resistance to NNRTIs in antiretroviral-naïve persons who harbor drug resistant virus, if therapy is initiated before drug resistance test results are available, consideration should be given to using a PI-based regimen (BIII).

Mycobacterium Tuberculosis Disease or Latent Tuberculosis Infection with HIV Coinfection
This section has been updated with the following information:

• Discussions and recommendations on the timing of initiation of antiretroviral therapy in patients with active tuberculosis (TB), with emphasis on the risks and benefits of concomitant therapy related to overlapping toxicities, drug interactions, CD4 cell counts, and potential for immune reconstitution inflammatory syndrome.
• Recommendation for repeat testing to detect latent TB infection in persons who had CD4 count <200 cells/mm3 and have tested negative prior to antiretroviral therapy and have improved CD4 count to >200 cells/mm3 (BII).

Table Updates:

• Various tables have been updated to include information regarding etravirine, updates on various antiretroviral drugs, as well as new atazanavir dosing recommendations when used in combination with proton pump inhibitors or H2 receptor antagonists.
• The following tables have been removed from the document:
  • Antiretroviral components that are acceptable as initial antiretroviral components but are inferior to preferred or alternative components"; and
  • Treatment outcome of selected clinical trials of combination antiretroviral regimens in treatment-naïve patients with 48-week follow-up data".

The complete January 29, 2008 version of the adult treatment guidelines is available on the aidsinfo web site at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  Changes will display highlighted in yellow.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Food and Drug Administration (FDA), on January 18, 2007, granted accelerated approval for etravirine 100 mg tablets, a non-nucleoside reverse transcriptase inhibitor (NNRTI), an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV virus replication.  It is the first NNRTI to demonstrate antiviral activity in patients with NNRTI-resistant virus. Etravirine will be sold under the trade name Intelence.

Etravirine is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV -1) infection in antiretroviral treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

Accelerated approval is a regulatory mechanism that allows earlier approval of drugs used to treat serious or life-threatening conditions, based on surrogate endpoints that demonstrate meaningful therapeutic advantage over existing treatment.  Accelerated approval is based on evidence of a drug's effect on a surrogate endpoint that reasonably suggests clinical benefit.  Accelerated approval requires any necessary studies to establish and define the degree of clinical benefit to patients be completed before traditional approval can be granted.

FDA granted this accelerated approval based on 24 week viral load and CD4 data from 1,203 adults in two randomized, double-blind, placebo-controlled trials (DUET-1 and -2 studies) conducted in clinically advanced, antiretroviral treatment-experienced adults with evidence of resistance to NNRTI(s) and protease inhibitors (PIs). The studies compared 599 patients receiving etravirine 200 mg twice daily plus optimized background regimen with 604 patients receiving optimized background regimen plus placebo.  All patients received darunavir/rtv (DRV/rtv) as part of their optimized background regimen.

The 24 week pooled analysis of the DUET studies showed significantly more patients in the etravirine arm as compared to the placebo arm achieved undetectable viral load (less than 50 copies/mL); 59.8 percent vs. 40.2 percent (p<0.0001), and significantly greater mean increase in CD4+ cell count from baseline of 81 vs. 64 cells/mm3 (p<0.0022).

The most common adverse events reported were rash (16.9 percent) and nausea (13.9 percent).

In general, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. Patients developing a rash while taking etravirine should contact their doctor.

Rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported. Treatment with etravirine should be discontinued if severe rash develops.

Elevations in total cholesterol and low density lipoprotein (LDL) and initiation of lipid lowering therapy were more common in etravirine-treated subjects compared with those in the placebo arm.

Etravirine should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) as pharmacokinetics of etravirine have not been studied in these patients.

To avoid drug interactions, patients starting etravirine treatment should tell their doctors about all the medications they take. Information about drug interactions is contained in the etravirine package insert.

The long-term effects of etravirine are not known, and its safety and effectiveness in children ages 16 years and younger has not been studied.

Etravirine also has not been studied in pregnant women. Women who are taking HIV medications when they get pregnant are advised to consult their physician or other health care professional about use of etravirine during pregnancy and about registering with the Antiviral Pregnancy Registry.

Etravirine is distributed by Tibotec Therapeutics, Bridgewater, N.J., a division of Ortho Biotech Products, L.P.

Richard Klein
HIV/AIDS Program Director
Food and Drug Administration

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The Reyataz (atazanavir) package insert was revised to include information regarding the administration of atazanavir and/or atazanavir/ritonavir with food, proton pump inhibitors, H2 receptor antagonists, acetaminophen, and fluconazole. Additionally, dosing information in patients with renal impairment was included.

Please refer to http://www.fda.gov/cder/foi/label/2007/021567s014lbl.pdf for complete labeling. Below are highlight of the major recent changes.

The Dosage and Administration section and Precautions: Drug Interaction Table 11 were updated to include drug interaction information regarding the use of Reyataz and proton pump inhibitors and H2-Receptor antagonists.

The dose recommendations for therapy-naïve patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

• H2-receptor antagonist: The H2-receptor antagonist dose should not exceed a 40 mg dose equivalent of famotidine twice daily. Reyataz 300 mg and ritonavir 100 mg should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
• proton-pump inhibitors: The proton-pump inhibitor dose should not exceed a 20 mg dose equivalent of omeprazole and must be taken approximately 12 hours prior to the Reyataz 300 mg and ritonavir 100 mg dose.

The dose recommendations for therapy-experienced patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

• Whenever an H2-receptor antagonist is given to a patient receiving Reyataz with ritonavir, the H2-receptor antagonist dose should not exceed a dose equivalent to famotidine 20 mg twice daily, and the Reyataz and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
  • Reyataz 300 mg (one 300-mg capsule or two 150-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist.
  • Reyataz 400 mg (two 200-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
• Proton-pump inhibitors should not be used in treatment-experienced patients receiving Reyataz.

In addition, the Dosage and Administration section was updated to provide dosing information in patients with renal impairment as follows:

• For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for Reyataz. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive Reyataz 300 mg with ritonavir 100 mg. Reyataz should not be administered to HIV-treatment experienced patients with end stage renal disease managed with hemodialysis.

No dose adjustments are needed when Reyataz is co-administered with acetaminophen or fluconazole.

The Clinical Pharmacology section was updated to include the following information:

• results of a food effect study with Reyataz 300 mg with ritonavir 100 mg with a light meal and high fat meal (see Clinical Pharmacology: Food Effect).
• results of a study in adult subjects with severe renal impairment, including those on hemodialysis is presented (see Clinical Pharmacology: Special Populations: Impaired Renal Function).
• results of drug-drug interaction studies with acetaminophen famotidine, fluconazole, and omperazole (See Clinical Pharmacology: Table 4: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of C administered Drugs and Table 5: : Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Reyataz.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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