FDA Notifications

New nucleic acid test screens for 2 HIV types

On Dec. 30, 2008, the Food and Drug Administration (FDA) approved the first nucleic acid test (NAT) that screens for the presence of two divergent types of HIV in donated blood plasma and human tissue. Nucleic acid is the term commonly used to refer to the chemical compounds that make up the genetic material in the virus. The new FDA-approved test detects nucleic acid from HIV-2 and from HIV-1 Group O. HIV-2 infections and HIV-1 Group O infections are predominantly found on the African continent. Some cases of infection with these two types of viruses have also been detected in the United States.

The new test, called cobas TaqScreen MPX Test, will allow blood donor testing laboratories to use nucleic acid technology to screen for additional HIV strains, further assuring that donated blood and tissue are free from infection and providing better protection for patients. However, FDA is not requiring screening with the new test at this time.

In addition to HIV-2 and HIV-1 Group O, the MPX test simultaneously detects nucleic acid from the most common form of HIV, HIV-1 Group M, as well as the Hepatitis C Virus and the Hepatitis B Virus.

The MPX test is designed for use with plasma specimens from human donors of whole blood and blood components, but not for testing donated source plasma, which is collected specifically for further processing and manufacturing.

The test is also intended for screening tissue specimens obtained from living donors whose heart is still beating. It is not intended for use on specimens from donors whose heart is no longer beating.

The cobas TaqScreen MPX Test runs on the fully-automated cobas s 201 System. It is manufactured by Roche Molecular Systems Inc., Pleasanton, CA.

FDA approved 3 generic formulations of stavudine

On Dec. 29, 2008, the FDA granted approval for three generic formulations of stavudine. Stavudine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI), which is intended to be used in combination with other anti-retroviral agents for the treatment of HIV-1 infection.

The approved generic formulations are stavudine capsules (15 mg, 20 mg, 30 mg and 40 mg), and Stavudine for Oral Solution (1 mg/mL), both manufactured by Aurobindo Pharma; and stavudine capsules (15 mg, 20 mg, 30 mg and 40 mg) manufactured by Hetero Drugs Limited, both of Hyberdad, India.

The FDA has determined that Aurobindo's stavudine for oral solution and stavudine capsules are bioequivalent and, therefore, therapeutically equivalent to Zerit oral solution 1 mg/mL and 15 mg, 20 mg, 30 mg, and 40 mg capsules, respectively, made by Bristol-Myers Squibb.

Similarly, Hetero's stavudine capsules were determined to be bioequivalent, and thus therapeutically equivalent to Zerit Capsules, 15 mg, 20 mg, 30 mg, and 40 mg.

The patent and pediatric exclusivity protections associated with the originator product have expired, so these generic formulations are approved for marketing in the United States.

Generic emtricitabine is approved by the FDA

On Dec. 23, 2008, the FDA granted tentative approval for a generic version of emtricitabine capsules 200 mg, manufactured by Matrix Laboratories, Ltd., of Hyderabad, India, reviewed under the expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR). Emtricitabine is a Nucleoside Reverse Transcriptase Inhibitor (NRTI).

"Tentative approval" means that FDA has concluded that a drug product has met the 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.

This tentative approval is for a generic formulation of Emtriva Capsules, 200 mg made by Gilead Sciences, Inc., which is subject to patent protection and pediatric exclusivity. 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.

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

Abacavir approved for pediatric patients

On Dec. 19, 2008, the FDA approved abacavir (Ziagen) 300 mg scored tablets with corresponding dosing information for pediatric patients weighing 14 kg or more using the scored tablet.

The Dosage and Administration and the Clinical Pharmacology sections were revised as follows:

The recommended oral dose of abacavir oral solution in HIV-1-infected pediatric patients greater than 3 months of age is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.

Abacavir is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than 14 kg for whom a solid dosage form is appropriate. Before prescribing abacavir tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow abacavir tablets, the oral solution formulation should be prescribed.

Pediatric Patients: The pharmacokinetics of abacavir have been studied after either single or repeat doses of abacavir in 68 pediatric patients. Following multiple-dose administration of abacavir 8 mg/kg twice daily, steady-state AUC (0-12 hr) and Cmax were 9.8 ± 4.56 mcg•hr/mL and 3.71 ± 1.36 mcg/mL (mean ± SD), respectively. In addition, to support dosing of Ziagen scored tablet (300 mg) for pediatric patients 14 to greater than 30 kg, analysis of actual and simulated pharmacokinetic data indicated comparable exposures are expected following administration of 300 mg scored tablet and the 8 mg/kg dosing regimen using oral solution.

Ziagen is a member of the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class, is a product of GlaxoSmithKline.

Tentative approval for fixed-dose combo abacavir/lamivudine

On Dec. 19, 2008, the FDA granted tentative approval for fixed-dose combination scored tablets, made by Aurobindo Pharma Limited of Hyberdad, India, containing abacavir sulfate and lamivudine, 60mg/30mg, indicated in combination with other antiretrovirals for the treatment of HIV-1 infection. The tablets are dispersible in water, intended for pediatric patients 3 months - 16 years of age.

Abacavir sulfate and lamivudine are members of the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class of anti-viral drugs. Fixed-dose combination products such as this one can help facilitate shipment, storage, and multi-drug treatment for HIV infected individuals.

FDA's tentative approval of this product means that although existing patents and/or exclusivity prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under the President's Emergency Program for AIDS Relief, or PEPFAR.

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 is available on the FDA website.

FDA OKs new pediatric dosing for darunavir

On Dec. 18, 2008, the FDA approved new pediatric dosing recommendations for a new 75 mg darunavir (Prezista) tablet formulation for patients from 6 to less than 18 years of age.

Section 1 Indications and Usage, Section 2 Dosage and Administration, and Section 3 Dosage Forms and Strengths were modified to reflect the changes.

Dosing recommendations are provided based on the pharmacokinetic, activity and safety data from study TMC114-C212 in children 6- <18 years of age. A description of study TMC114-C212 including the pharmacokinetic, safety and activity results, and rationale for dose selection for children were included in Section 6 Adverse Reactions, Section 8 Use in Specific Populations, Section 12 Clinical Pharmacology and Section 14 Clinical Studies as shown below.

Darunavir, co-administered with ritonavir (darunavir/rtv), and with other antiretroviral agents, is indicated for the treatment of HIV infection in pediatric patients 6 years of age and older.

This indication is based on 24-week analyses of plasma HIV RNA levels and CD4+ cell counts from an open-label Phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to less than 18 years of age. Do not use once daily dosing in pediatric patients.

Healthcare professionals should pay special attention to accurate dose selection of darunavir, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should select the appropriate dose of darunavir/rtv for each individual child based on body weight (kg) and should not exceed the recommended dose for treatment-experienced adults.

Before prescribing darunavir, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of darunavir tablets may not be appropriate.

The recommended dose of darunavir/rtv for pediatric patients (6 to less than 18 years of age and weighing at least 44 lbs (20 kg)) is based on body weight and should not exceed the recommended treatment-experienced adult dose (darunavir/rtv 600/100 mg b.i.d.). Darunavir tablets should be taken with ritonavir twice daily and with food.

The safety and efficacy of darunavir/rtv in pediatric patients 3 to < 6 years of age have not been established.

Darunavir/rtv should not be used in pediatric patients below 3 years of age.

Darunavir 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.

Darunavir/rtv has been studied in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 44 lbs (20 kg) in combination with other antiretroviral agents.

Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. ADRs to darunavir/rtv (all grades, ? 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).

Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%, Grade 4: 0%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%, Grade 4: 0%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).

Darunavir/rtv should not be used in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.

The pharmacokinetics, safety, tolerability, and efficacy of darunavir/rtv in pediatric patients 3 to less than 6 years of age have not been established.

Darunavir/rtv once daily should not be used in pediatric patients.

The safety, pharmacokinetic profile, and virologic and immunologic responses of darunavir/rtv were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.

The pharmacokinetics of darunavir in combination with ritonavir in 74 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 44 lbs (20 kg) showed that the administered weight-based dosages resulted in darunavir exposure comparable to that in treatment-experienced adults receiving darunavir/rtv 600/100 mg twice daily.