April 29, 2005 FDA today approved the use of KALETRA 800/200mg once-daily administration
for the treatment of HIV-infection in therapy-naïve 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-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%
than that observed in the twice daily regimen and because there are no
clinical studies comparing the two dosing schedules in treatment-experienced
individuals.

KALETRA PI (April 29, 2005

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 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 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 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

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-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, 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 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).

Treatment response and outcomes of randomized treatment are
presented in Table 6:

Responder Total virologic
Rebound Never suppressed Death Discontinued due to:
failure
through week 48 Adverse event Other 

Kaletra QD + 
TDF+FTC (N=115) 71% 10% 6%
3% 0% 12% 9%

Kaletra BID +
TDF+FTC (N=75) 65% 9% 5%
4% 1% 7% 19%

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-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

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