Pediatric HIV infection guidelines are revised
The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been revised. The new version includes updated information on:
• Recommended antiretroviral regimens for initial therapy;
• Nelfinavir, which now meets FDA limits for ethyl methane sulfonate (EMS) .
The changes in this revision 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.
Generic abacavir and lamivudine combo approved
On Sept. 3, 2008, the U.S. Food and Drug Administration (FDA) granted tentative approval for the first generic combination formulation of abacavir sulfate and lamivudine tablets, 600 mg/300 mg, manufactured by Aurobindo Pharma Limited, Hyberdad, India. Abacavir sulfate and lamivudine are antiviral agents in the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class. Combining two therapeutic agents in a single pill facilitates dosing, storage and distribution, and may contribute to improved patient adherence to drug regimens.
"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.
This tentative approval is a generic version of Epzicom Tablets, 600 mg/300 mg, a product of SmithKline Beecham Corporation. Epzicom 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, 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.
Norvir label changes approved
The FDA approved, on Aug. 29, 2008, changes to the product label for ritonavir (Norvir) Soft Gelatin Capsules, and Norvir Oral Solution reflecting new, post marketing information regarding QT/QTc interval and PR interval prolongation information from Study M06-80.
The patient package insert has been updated, as well, with language related to electrocardiogram changes and cardiac arrhythmias.
The following information was added to the product label:
• Under Clinical Pharmacology — QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.
PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir. See PRECAUTIONS –PR Interval Prolongation.
• Under Precautions – PR Interval Prolongation: Ritonavir prolongs the PR interval in some patients. Postmarketing cases of second or third degree atrioventricular block have been reported in patients.
Ritonavir should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. See CLINICAL PHARMACOLOGY — Effects on Electrocardiogram.
• Under Information for Patients — Cardiovascular System: First –degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS — PR Interval Prolongation).
• Under Adverse Reactions —Cardiovascular System: First –degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS – PR Interval Prolongation).
In addition, the following information has been added to the Patient Product Insert, under the section What are the Possible Side Effects of Norvir?
Changes in the electrocardiogram (EKG). Consult your physician if you experience dizziness, lightheadedness, fainting spells or abnormal heart beat, Patients with heart defects or conduction defects should avoid ritonavir.
Updates made to Reyataz package insert
The atazanavir (Reyataz) package insert has been updated to include important drug-drug interaction information regarding the administration of Reyataz with or without ritonavir and nevirapine, efavirenz, hormonal contraceptives, orally and parenterally administered midazolam, H2-receptor antagonists, and drugs that are substrates of cytochrome P450 2C8. Below is a summary of the changes.
• Nevirapine: Do not coadminister atazanavir with nevirapine because nevirapine substantially decreases Reyatz exposures, and potential risk exists for nevirapine associated toxicity due to increased nevirapine exposures.
• Efavirenz: Efavirenz decreases Reyataz exposure: For treatment-naïve patients the recommended dose is Reyataz 400 mg with ritonavir 100 mg and efavirenz 600 mg once daily. Efavirenz should be taken on an empty stomach preferably at bedtime
For treatment-experienced patients: Do not coadminister Reyataz with efavirenz because efavirenz decreases Reyataz exposure.
• Hormonal Contraceptives: Use with caution if co-administration of Reyataz or Reyataz/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ/ritonavir, it is recommended the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If Reyataz is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
Potential safety risk includes substantial increases in progesterone exposure. The long-term effect of increases in concentration of the progestational agent are unknown and could include risk of insulin resistance, dyslipidemia and acne.
Coadministration of Reyataz or Reyataz/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectible contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of non-hormonal contraception are recommended.
• Midazolam: Coadministration of oral midazolam with Reyataz is contraindicated. Concomitant use of parenteral midazolam with Reyataz may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
• H2-receptor antagonists: The packaged insert already contains the following dosing information for treatment naïve patients: Reyataz 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. H2-receptor antagonist dose comparable to famotidine 40 mg twice daily can be used with Reyataz 300 mg with ritonavir 100 mg in treatment-naïve patients.
The label was updated to add the following:
• For treatment-naïve patients unable to tolerate ritonavir, Reyataz 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
• Substrates of CYP2C8: Atazanavir is a weak inhibitor of CY2C8. Caution should be used when Reyataz without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g. paclitaxel, repaglinide). When Reyataz with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.
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