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FDA Approves Once-daily Lopinavir/ritonavir (Kaletra) for Certain Treatment-experienced HIV Patients

SUMMARY: The U.S. Food and Drug Administration (FDA) announced this week that it has approved Kaletra, the boosted protease inhibitor coformulation of lopinavir/ritonavir, for once-daily use by previously treated HIV positive adults without extensive lopinavir resistance. Kaletra was initially granted early access approval for twice-daily use by treatment-experienced patients in September 2000; once-daily dosing was later approved for treatment-naive individuals. The new dose regimen -- indicated for treatment-experienced adults with less than 3 lopinavir resistance-associated viral mutations -- is supported by Study 802, a randomized Phase 3 clinical trial showing comparable efficacy, safety, and tolerability between one-daily and twice-daily dosing over 48 weeks.

By Liz Highleyman

Below is text of the FDA announcement describing the approval and detailing changes to the Kaletra label information.

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.

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 naive 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.

Table 18.
Outcomes of Randomized Treatment Through Week 48 (Study 802)
Outcome
Kaletra
Once Daily + NRTIs (n = 300)
Kaletra
Twice Daily +
NRTIs (n = 299)
Virologic Success (HIV-1 RNA < 50 copies/mL)
57%
54%
Virologic failure (1)
22%
24%
No virologic data in Week 48 window
5%
7%
Discontinued study due to adverse event or death (2)
13%
12%
Discontinued study for other reasons (3), Missing data during window but on study
3%
3%
1. Includes patients who discontinued prior to Week 48 for lack or loss of efficacy and patients with HIV-1 RNA = 50 copies/mL at Week 48.

2. Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48.

3. Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons.

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.

This gives treatment-experienced patients who have HIV that responds to Kaletra another dosing option as determined by their physician.

4/30/10

Sources

R Klein and K Struble (U.S. Food and Drug Administration). New Kaletra (lopinavir/ritonavir) Tablets and Oral Solution once daily dosing regimen in certain adult patients. HIV/AIDS Update. April 27, 2010.

Abbott. Abbott Receives FDA Approval for Once-Daily Dosing of Kaletra (lopinavir /ritonavir) for Treatment-Experienced Patients. Press release. April 28, 2010.


 

 

 

 

 

 

 

 

 

 

 

 

 

 


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