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FDA Approves Once Daily Kaletra For Therapy Naive Patients
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This report combines information from both the FDA statement & the Abbott Press Release because both contain information worth reporting. The antiviral effect of once daily (QD) & twice daily (BID) were similar in the study (Study #418) comparing the two dose regimens as you can see in the Table below (71% qd vs 65% bid, {LLQ); the once daily regimen was associated with higher rates of diarrhea; and the once daily regimen is approved by the FDA for therapy naive patients & not for therapy experienced patients because as the FDA says trough concentrations are 60% lower for the qd regimen & because there are no studies of the once daily regimen in treatment-experienced patients. Jules Levin
:ABBOTT RECEIVES FDA APPROVAL FOR A ONCE-DAILY KALETRA BASED (LOPINAVIR/RITONAVIR) TREATMENT REGIMEN
ABBOTT PARK, Ill., May 2, 2005 - Abbott announced today that it received U.S. Food and Drug Administration (FDA) approval to market a once-daily dosing regimen for Kaletra (lopinavir/ritonavir), a protease inhibitor used in combination with other anti-HIV medications, for the initial treatment of HIV. The new dosing regimen for Kaletra offers physicians and patients increased flexibility in managing their individual HIV treatment without sacrificing the proven efficacy of the twice-daily dosing option, in patients new to HIV therapy. This new dosing option is available in both liquid and soft gel capsule formulations.
Approval for the new regimen is based on data from a clinical study conducted in 190 patients new to HIV therapy which evaluated the effectiveness of the once-daily and twice-daily Kaletra doses, both administered in combination with once-daily tenofovir and emtricitabine, over a period of 48 weeks. Results demonstrated comparable virologic responses (HIV RNA less than 50 copies per milliliter) between the once- and twice-daily dosing groups. Kaletra once-daily was generally well tolerated (SEE STUDY DATA BELOW). In both the once-daily and twice-daily arms, the most frequent drug-related adverse events of moderate or greater intensity reported were diarrhea and nausea, although diarrhea was observed more frequently in the once-daily arm.
Particular caution should be used when taking Viagra, Cialis or Levitra since the interaction with Kaletra may result in an increase in their related side effects. Patients should discuss all medicines, including those without a prescription and herbal preparations that they are taking or plan to take with their physician or pharmacist.
Once-daily Kaletra should not be administered in combination with Sustiva, Viramune, Agenerase, Viracept, Tefretol, Phenobarbitol and Dilantin.
FDA STATEMENT
FDA today approved the use of KALETRA 800/200mg once-daily administration for the treatment of HIV-infection in therapy-naive adult patients, based on review and analysis of two clinical trials comparing safety and efficacy of lopinavir (LPV)/ritonavir (RTV) 800/200 mg once daily (qd) and LPV/RTV 400/100 mg twice daily (bid), for a duration of at least 48 weeks in antiretroviral-naive HIV-1 infected subjects.
At this time, once daily Kaletra is not approved for treatment experienced patients because trough concentrations of lopinavir are approximately 60% than that observed in the twice-daily regimen and because there are no clinical studies comparing the two dosing schedules in treatment-experienced individuals.
The following is a summary of the labeling changes-
CLINICAL PHARMACOLOGY:
Pharmacokinetic data for Kaletra given as 800/200 mg once daily in HIV-1 infected antiretroviral naive adult subjects were added.
Specifically, the following text was included.
The pharmacokinetics of once daily KALETRA have been evaluated in HIV-infected subjects naive to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir 300 mg as part of a once daily regimen.
Multiple dosing of 800/200 mg KALETRA QD for 4 weeks with food (n=24) produced a mean + SD lopinavir peak plasma concentration (Cmax) of 11.8 + 3.7 E g/mL, occurring approximately 6 hours after administration.
The mean steady-state trough concentration prior to the morning dose was 3.2 + 2.1 E g/mL and minimum concentration within a dosing interval was 1.7 + 1.6 E g/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 + 361.4 E g *h/mL
A statement that KALETRA once daily has not been evaluated in pediatric patients was included.
INDICATIONS AND USAGE:
The following information was added:
Once-daily administration of KALETRA is not recommended in therapy-experienced patients.
When initiating treatment with KALETRA in therapy-naive patients, it should be noted that the incidence of diarrhea was greater for KALETRA once daily compared to KALETRA twice daily in Study 418 (57% vs 35% - events of all grades and probably or possibly related to drug: 16% vs 5% - events of at least moderate severity and probably or possibly related to drug).
Description of Clinical Studies
Results from study M02-418 were included as follows.
Study 418: KALETRA QD + tenofovir DF + emtricitabine compared to KALTERA BID + tenofovir DF + emtricitabine
Study 418 is an ongoing, randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg QD plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg BID plus tenofovir DF and emtricitabine in 190 antiretroviral treatment naive patients.
Patients had a mean age of 39 years (range: 19 to 75), 54% were Caucasian and 78% were male. Mean baseline CD4 cell count was 260 cells/mm3 (range 3 to 1006 cells/mm3) and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (range: 2.6 to 6.4 log10 copies/mL).
Treatment response and outcomes of randomized treatment are presented in Table 6:
PRECAUTIONS
In this section,
Table 10: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted
Interaction was revised to include information that-
KALETRA should not be administered once daily in combination with efavirenz, nevirapine, amprenavir, nelfinavir, carbamazepine, phenobarbital, or phenytoin. In addition, statements that KALETRA once daily has not been studied in combination with indinavir or saquinavir was included.
ADVERSE REACTIONS:
The adverse reaction profile and laboratory abnormalities observed in the Kaletra once daily study were included in this section.
DOSAGE AND ADMINISTRATION
This section was modified to include dosing instructions for therapy-naive and therapy-experienced patients as follows:
Adults:
Therapy-Naive Patients
- KALETRA 400/100 mg (3 capsules or 5.0 mL) twice daily taken with food
- KALETRA 800/200 mg (6 capsules or 10 mL) once daily taken with food
Therapy-Experienced Patients
- KALETRA 400/100 mg (3 capsules or 5.0 mL) twice daily taken with food
Once-daily administration of KALETRA is not recommended in therapy-experienced patients
In addition, the following statements were added:
KALETRA should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
KALETRA once daily has not been evaluated in pediatric patients.
KALTERA is manufactured by Abbott Laboratories, North Chicago, IL.
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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