FDA Approves Lopinavir/Ritonavir 800/200mg Once Daily for Treatment of HIV in Therapy-naïve Adults

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Kaletra Capsule

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Kaletra

Kaletra Product Information
(22-page PDF File)

FDA last week approved the use of lopinavir/ritonavir (Kaletra) 800/200mg once daily administration (in combination with 2 NRTIs) for the treatment of HIV-infection in therapy-naïve adult patients.

The approval is based on the 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-naïve 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% lower than that observed in the twice daily regimen and because there are no clinical studies comparing the two dosing schedules in treatment-experienced individuals.

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- naïve adult subjects were added. Specifically, the following text was included:

The pharmacokinetics of once daily KALETRA have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine (Emtriva) 200 mg and tenofovir (Viread) 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 µg/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 3.2 + 2.1 µg/mL and minimum concentration within a dosing interval was 1.7 + 1.6 µg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 + 361.4 µg ·h/mL

Indications and Usage

The following information was added:

A statement that KALETRA once daily has not been evaluated in pediatric patients was included (See "Precautions" below).

Once-daily administration of KALETRA is not recommended in therapy-experienced patients.

When initiating treatment with KALETRA in therapy-naïve 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, multi-center 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 naïve 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).

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-naïve and therapy-experienced patients as follows:

Adults: Therapy-Naïve 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.

Precautions

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 (Sustiva), nevirapine (Viramune), amprenavir (Agenerase) or nelfinavir (Viracept).

KALETRA once daily has not been studied in combination with indinavir or saquinavir was included.

KALETRA once daily has not been evaluated in pediatric patients.

New Tablet Formulation of Kaletra

Adapting technology previously used only in plastics manufacturing, Abbott has developed a new tablet formulation of Kaletra, which will reduce the pill burden for people living with HIV and eliminate the need to refrigerate the medication.

"Protease inhibitors are notoriously difficult to formulate," said Eugene Sun, vice president, Global Pharmaceutical Clinical Development. "We took the Meltrex technology we got from Knoll, and used it here to solve one of our toughest problems. This enabled us to take a co-formulated protease inhibitor - essentially a solidified solution - and create a tablet.

"Additionally, the new formulation will eliminate the need to refrigerate the medication, which in the past has been a significant barrier to distribution," Sun said. "This new formulation will greatly enhance our ability to get this medicine into the hands of the patients who need it most."

05/02/05

Sources
US Food and Drug Administration. FDA Approves Lopinavir/Ritonavir 800/200mg Once Daily for Treatment of HIV in Therapy-naïve Adults. May 29, 2005.
Abbott Laboratories. New Technology Strengthens Abbott's Fight Against HIV. Press Release. April 29, 2005.

Additional Articles on Kaletra

FDA Approves Lopinavir/Ritonavir 800/200mg Once Daily for Treatment of HIV in Therapy-naïve Adults - 5/04/05

Use of Lopinavir/Ritonavir in HIV-infected Patients Failing First-line Protease Inhibitor-based HAART - 4/20/05

Atazanavir Plus Ritonavir or Saquinavir Compared to Lopinavir/Ritonavir in Patients Experiencing Multiple Virological Failures - 4/11/05

Lopinavir/ritonavir Combination and Total/HDL Cholesterol Ratio - 4/04/05

Lipid Disorders in Treatment-naive HIV Patients Using Lopinavir/Ritonavir-based HAART - 3/25/05

Steady State Pharmacokinetics of Amprenavir, Lopinavir and Efavirenz Combinations - 3/16/05

Kaletra Independently Reduces HIV Replication in Cerebrospinal Fluid
G. Van den Brande and Others. Abstract 403. - 3/11/05

Virological response and Resistance to Lopinavir/Ritonavir in Subtype C Patients
Z. Grossman and Others. Abstract 719. - 3/11/05

6-Month Follow-up of Once-daily Lopinavir/ritonavir in HIV-infected Children
G. Verweel and Others. Abstract 769. - 3/11/05

Kaletra Independently Reduces HIV Replication in Cerebrospinal Fluid and in the Brain - 3/04/05

Steady State Pharmacokinetics of Amprenavir, Lopinavir and Efavirenz Combinations - 2/28/05

Efavirenz with Two Nucleoside Analogs Is Superior for Regimen Simplification - 2/28/05

A Comparison of Dyslipidemias Associated with Either Lopinavir/Ritonavir- or Indinavir/Ritonavir-based Antiretroviral Therapy - 2/11/05

Combivir Plus PI Kaletra HIV Prophylaxis May Increase Tolerability - 2/04/05

Development and Validation of a Population Pharmacokinetic Model for Ritonavir - 2/04/05

Combining Fosamprenavir with Lopinavir/Ritonavir Substantially Reduces Amprenavir and Lopinavir Exposure: ACTG Protocol A5143 Results - 1/31/05

First Enzyme Immunoassay for the Quantification of Plasma and Intracellular Lopinavir in HIV Patients - 1/12/05

Lopinavir/Ritonavir Plus Nevirapine as a Nucleoside-sparing Approach in Treatment-experienced HIV Patients - 1/12/05

Lack of Effect of Gastric Acid Reducing Agents on Lopinavir/ritonavir Plasma Concentrations in HIV-Infected Patients.
Richard J Bertz, PhD and others. Abstract 201.

Antiretroviral Therapy in Special Populations: Response to Lopinavir/ritonavir, Tenofovir DF, and Emtricitabine in Antiretroviral-Naïve Patients by Gender, Race/Ethnicity, and Hepatitis Co-infection Status.
P Easterbrook and others. Abstract P15.

Immunologic, Virologic and Metabolic Data from the CLARE (CORE Center Lopinavir/r (LPV/r) Antiretroviral Effectiveness) Cohort.
A OM and others. Abstract 330.

Lopinavir/ritonavir (LPV/r)-Based Therapy in Antiretroviral (ARV)-Naïve, HIV-Infected Patients: 6-Year Follow-up of Study 720
R Gulick and others. Abstract P28.

Efficacy and Tolerance of Lopinavir/ritonavir in Clinical Practice: An Observational Prospective Cohort of 1278 Patients.
A. Lafeuillade and others. Abstract 140.