FDA Notifications

Generic didanosine approved by FDA

On Sept. 24, 2008, FDA approved a generic formulation of Didanosine (ddI) Delayed Release Capsules, 125 mg, 200 mg, 250 mg, and 400 mg, manufactured by Aurobindo Pharma Limited, Hyberdad, India. Didanosine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI), which helps keep HIV, the virus that causes AIDS, from reproducing, and is intended to be used with other anti-retroviral agents for the treatment of HIV-1 infection.

The application was reviewed under the expedited review provisions of the President's Emergency Plan for AIDS Relief (PEPFAR). Approval of the generic formulation means that there are no existing patents and/or exclusivities preventing marketing of this product in the United States, and qualifies it for purchase under the PEPFAR program outside the U.S.

This is a generic version of Videx EC, made by Bristol Myers Squibb Co.

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

A list of approved and tentatively approved antiretrovirals associated with PEPFAR can be found at http://www.fda.gov/oia/pepfar.htm.

A list of approved generic drugs used in the treatment of HIV infection will be found at http://www.fda.gov/oashi/aids/viralsgeneric.html.

FDA approved pediatric efficacy supplement for Retrovir syrup

On Sept. 19, 2008, FDA approved a pediatric efficacy supplement for zidovudine (Retrovir) syrup, capsules and tablets allowing for a twice daily dosing regimen in children six weeks to 18 years of age. It also provides for dosing by weight in addition to dosing by body surface area.

Previously, zidovudine dosing recommendations for the treatment of HIV in children included three times daily dosing with dose calculated using body surface area. The new label has recommendations for twice daily or three times daily dosing by weight or by body surface area. The new recommendations should allow for more convenient dosing (twice daily) of zidovudine in children. The main changes include revisions to the Dosage and Administration section to include twice daily dosing in children as follows.

Pediatric Patients (6 weeks to <18 years of age): Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of zidovudine for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing zidovudine capsules or tablets, children should be assessed for the ability to swallow capsules or tablets. If a child is unable to reliably swallow a zidovudine capsule or tablet, the zidovudine syrup should be prescribed.

Retrovir Syrup should be used to provide accurate dosage when whole tablets or capsules are not appropriate.

Alternatively, dosing for zidovudine can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.

Additionally, the label was converted to Physician Labeling Rule (PLR) format to make product labeling more informative and accessible. The pregnancy related sections were modified with the conversion to PLR format to make the data more accessible to clinicians but content was not revised.

The complete revised label will be available soon at Drugs@FDA, http://www.fda.gov/cder/drugsatfda/datafiles/. Retrovir is a product of GlaxoSmithKline.

Abacavir tablet approved for pediatric patients

On Sept. 12, 2008, FDA granted tentative approval for abacavir sulfate 60 mg scored tablet for use in pediatric patients. Abacavir sulfate 60 mg scored tablets are manufactured by Aurobindo Pharma Limited, Hyberdad, India. Abacavir sulfate is an antiviral agent in the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class.

"Tentative approval" means that FDA has concluded that a drug product meets 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 outside the United States under the President's Emergency Plan for AIDS Relief (PEPFAR).

The application was reviewed under expedited review provisions developed for 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, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application prior to granting approval or tentative approval to these applications.

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

FDA approves pediatric efficacy supplement for didanosine capsules

On Sept. 29, 2008, the FDA approved a pediatric efficacy supplement for didanosine (Videx) EC Delayed-Release Capsules, expanding the indication to include children weighing at least 20 kg.

The main changes include revisions to the Dosage and Administration section as follows: The recommended total daily dose to be administered once daily to pediatric patients weighing at least 20 kg who can swallow capsules is based on body weight (kg), consistent with the recommended adult dosing guidelines. Please consult the complete prescribing information for Videx Pediatric Powder for Oral Solution for dosage and administration of pediatric patients weighing less than 20 kg or who can not swallow capsules.

Section 8.4 Pediatric Use was updated to state the following: Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14). Additional pharmacokinetic studies in pediatric patients support use of the Videx EC in pediatric patients who weigh at least 20 kg.

Section 12.3 was added to describe the population pharmacokinetic analysis for children: A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from 9 clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme.

The results and conclusion from the hepatic impairment study were included in Section 12.3.

Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched controls.

The following new language for disposal of unused medicines was incorporated in Section 17.

Dispose of unused medicines through community take-back disposal programs when available or place didanosine EC in an unrecognizable closed container in the household trash.

Additionally, the label was converted to Physician Labeling Rule (PLR) format to make product labeling more informative and accessible.

The revised label will be available soon at Drugs@FDA, http://www.fda.gov/cder/drugsatfda/datafiles/. Videx EC is a product of Bristol-Myers Squibb.

Alternative dosing regimen for atazanavir is approved

On Sept. 30, 2008, the FDA approved an alternative dosing regimen for atazanavir (Reyataz) for HIV-1 infected treatment-naïve patients who can take ritonavir. The recommended dosage is Reyataz 300 mg with ritonavir 100 mg once daily for treatment-naïve patients. The following revisions with respect to the new dosing regimen in treatment-naïve patients were added to the package insert. Other minor revisions were made throughout the label.

Section 2.1 – Recommended Adult Dosage; Dose Recommendations for Therapy-Naive Patients: For treatment-naive patients, the recommended dosage is atazanavir 300 mg with ritonavir 100 mg once daily (all as a single dose with food);

• Or for treatment-naive patients who are unable to tolerate ritonavir, the recommended dosage is atazanavir 400 mg (without ritonavir) once daily taken with food.

The warnings and precautions rash subsection 5.3 was revised to update information from the atazanavir/ritonavir study in treatment-naïve patients as follows.

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with atazanavir. The median time to onset of rash was 7 weeks after initiation of atazanavir and the median duration of rash was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of equal to or greater than 2%) are presented for the individual clinical studies [see Adverse Reactions (6.1)]. Dosing with atazanavir was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was less than 1%. Atazanavir should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported in patients receiving atazanavir. [See Contraindications (4).]

Section 6.0 adverse reactions was updated to include results from the treatment-naïve study as follows:

6.1 Clinical Trial Experience in Adults; Treatment-Emergent Adverse Reactions in Treatment-Naive Patients: The safety profile of atazanavir in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received atazanavir 300 mg with ritonavir 100 mg and 1089 patients received atazanavir 400 mg or higher (without ritonavir).

The most common adverse reactions are nausea, jaundice/scleral icterus, and rash.

6.3 Patients Co-infected With Hepatitis B and/or Hepatitis C Virus: Liver function tests should be monitored in patients with a history of hepatitis B or C.

In study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels greater than 5 times ULN developed in 8% (5/60) of the atazanavir/ritonavir-treated patients and 6% (3/50) of the lopinavir/ritonavir-treated patients. AST levels greater than 5 times ULN developed in 8% (5/60) of the atazanavir/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

Section 12.3 Microbiology was updated to include resistance information form the treatment-naïve study as follows: Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted atazanavir vs. Unboosted atazanavir: Study AI424-089 compared atazanavir 300 mg once daily with ritonavir 100 mg vs. atazanavir 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients.

Additionally the clinical trials section was updated to include the efficacy results from the treatment-naïve study as follows:

14.1 Adult Patients Without Prior Antiretroviral Therapy; Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment naive subjects. Study AI424-138 is a 96-week open-label, randomized, multi-center study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19–72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL).

The complete revised label will be available soon at Drugs@FDA, http://www.fda.gov/cder/drugsatfda/datafiles/. Enter "Reyataz" in the search window, and follow links for "Label Information."