FDA approved changes to the EPIVIR (lamivudine) label

DOSAGE AND ADMINISTRATION was updated to increase the recommended total daily dosage for EPIVIR oral solution from 8 mg/kg/day to 10 mg/kg/day in HIV-1 infected pediatric patients aged 3 months and older. The specific wording in the package insert is as follows:

Oral Solution

The recommended dosage of EPIVIR oral solution in HIV 1-infected pediatric patients aged 3 months and older is 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution

The WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and the CLINICAL PHARMACOLOGY, Pharmacokinetics sections were revised to include drug interaction information with sorbitol-containing solutions based on data from a pharmacokinetic trial conducted in healthy subjects. The following text was added to the package insert.

WARNINGS AND PRECAUTIONS: Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution

Pediatric subjects who received EPIVIR oral solution (at weight band-based doses approximating 8 mg per kg per day) concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets

 

EPIVIR scored tablet is the preferred formulation for HIV 1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of HIV-1 viral load when treating with EPIVIR oral solution. 

DRUG INTERACTIONS: Sorbitol

Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine

CLINICAL PHARMACOLOGY: Pediatric Patients: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of EPIVIR in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution (dosed at approximately 8 mg per kg per day) achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV 1-infected adults. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both EPIVIR tablets and oral solution are lower in children than adults. The relative bioavailability of EPIVIR oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. Lower lamivudine exposures in pediatric patients receiving EPIVIR oral solution is likely due to the interaction between lamivudine and concomitant solutions containing sorbitol (such as ZIAGEN). Modeling of pharmacokinetic data suggests increasing the dosage of EPIVIR oral solution to 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily) is needed to achieve sufficient concentrations of lamivudine . There are no clinical data in HIV-1 infected pediatric patients coadministered with sorbitol-containing medicines at this dose.

PATIENT COUNSELING INFORMATION was updated to advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received EPIVIR oral solution.

The updated label will soon be available at drugs@fda or DailyMed

Steve Morin

Office of Health and Constituent Affairs
Food and Drug Administration

KImberly Struble
Division of Antiviral Products
Food and Drug Administration

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