New Kaletra (lopinavir/ritonavir) Tablets and Oral Solution once daily dosing regimen in certain adult patients

On April 27, 2010, FDA approved a new dosing regimen for Kaletra (lopinavir/ritonavir) tablets and oral solution. Kaletra can be administered once daily (800/200 mg) in patients with less than three lopinavir resistance associated substitutions. Once daily administration of KALETRA is not recommended for adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Of note, once daily administration of Kaletra is not recommended in pediatric patients.

The major revisions to the package insert are summarized below. The complete revised label will be posted soon at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory.

6.1 Adults - Clinical Trials Experience
In study 802, the incidence of diarrhea of any severity during 48 weeks of therapy was 50% in patients receiving KALETRA tablets once daily compared to 39% in patients receiving KALETRA tablets twice daily. Moderate or severe drug-related diarrhea occurred in 14% of patients receiving KALETRA tablets once daily as compared to 11% in patients receiving KALETRA tablets twice daily. At the time of discontinuation, 19 (6.3%) patients receiving KALETRA tablets once daily had ongoing diarrhea, as compared to 11 (3.7%) patients receiving KALETRA tablets twice daily. Discontinuations due to any adverse reaction occurred in 4.3% of patients receiving KALETRA tablets once daily compared to 7.0% in patients receiving KALETRA tablets twice daily.

A table for the treatment-emergent adverse reactions of moderate or severe intensity and grade 3-4 laboratory abnormalities can be found in the revised prescribing information.

12 CLINICAL PHARMACOLOGY

12.3 Pharmacokinetics

The pharmacokinetics of once daily KALETRA has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (Cmax, AUC[0-24h], Ctrough) with once daily KALETRA administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment naïve subjects.

14 CLINICAL STUDIES

14.2 Patients With Prior Antiretroviral Therapy

Study 802: KALETRA Tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Coadministered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral Experienced, HIV-1 Infected Subjects

M06-802 was a randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of KALETRA tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Of the enrolled subjects, 55% on both treatment arms had not been previously treated with a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti HIV treatment regimen. Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once daily (n = 300) or KALETRA 400/100 mg twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian, and 66% were male. Mean baseline CD4+ cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 1.7 to 6.6 log10 copies/mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 18.

Through 48 weeks of treatment the mean change from baseline for CD4 + cell count was 136 cells/mm³ for the QD group and 122 cells/mm³ for the BID group.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration