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Kaletra labeling changes approved

FDA approved, on April 20, 2009, changes to the product label for Kaletra (lopinavir/ritonavir) Tablets and Oral Solution, to include results from Study 730 comparing treatment with KALETRA 800/200 mg once-daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice-daily plus tenofovir DF and emtricitabine in antiretroviral treatment-naïve patients.

Results from this study were included in section 6 ADVERSE REACTIONS and section 14 CLINICAL STUDIES as follows.

The following statement:

"When initiating treatment with KALETRA in therapy-naïve patients, it should be noted the incidence of diarrhea was greater with KALETRA capsules once-daily compared to KALETRA capsules twice-daily in Study 418 (57% vs. 35% - reactions of all grades; 16% vs. 5% - reactions of at least moderate severity) [See ADVERSE REACTIONS ( 6.1) and DOSAGE AND ADMINISTRATION (2.1)]."

was removed from the label, Section 2 DOSAGE AND ADMINISTRATION, 2.1 Adult Patients, Therapy-Naïve Patients.

Information regarding incidence of diarrhea in Study 730 is included in section 6 Adverse Reactions. Information from study 418 comparing once daily and twice daily dosing of Kaletra capsules was removed from the label because the capsule formulation is no longer marketed and Study 730 provides the more relevant longer term data for once daily and twice daily dosing with Kaletra tablets.

6 ADVERSE REACTIONS

6.1 Adults - Clinical Trials Experience
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. In study 730, the incidence of diarrhea of any severity during 48 weeks of therapy was 60% in patients receiving KALETRA tablets once daily compared to 57% in patients receiving KALETRA tablets twice daily. More patients receiving KALETRA tablets once-daily (14, 4.2%) had ongoing diarrhea at the time of discontinuation as compared to patients receiving KALETRA tablets twice-daily (6, 1.8%). In study 730, discontinuations due to any adverse reaction were 4.8% in patients receiving KALETRA tablets once-daily as compared to 3% in patients receiving KALETRA tablets twice-daily.

Table 6. Grade 3-4 Laboratory Abnormalities Reported in≥ 2% of Adult Antiretroviral-Naïve Patients
  Study 730
(48 Weeks)
 
Variable Limit1 KALETRA Once Daily
+ TDF +FTC  (N=333)
KALETRA Twice Daily
+ TDF +FTC  (N=331)
Chemistry High      
Glucose
> 250 mg/dL
0%
<1%
 
Uric Acid
> 12 mg/dL
<1%
1%
 
SGOT/
AST2
> 180 U/L
1%
2%
 
SGPT/
ALT2
>215 U/L
1%
1%
 
GGT
>300 U/L
N/A
N/A
 
Total
Cholesterol
>300 mg/dL
4%
3%
Triglycerides
>750 mg/dL
3%
6%
 
Amylase
>2 x ULN
N/A
N/A
 
Lipase
>2x ULN
3%
5%
 
Chemistry
Low
     
Calculated Creatinine Clearance
<50 mL/min
2%
2%
 
Hematology
Low
     
Neutrophils
<0.75 x 109/L
2%
1%
 
1   ULN = upper limit of the normal range; N/A = not Applicable.

2   Criterion for Study 730 was >5x ULN (AST/ALT).

14 CLINICAL STUDIES

14.1 Patients Without Prior Antiretroviral Therapy

Study 730:  KALETRA Tablets once-daily + tenofovir DF + emtricitabine compared to KALETRA Tablets twice-daily + tenofovir DF + emtricitabine.

Study 730 was a randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once-daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once-daily (n = 333) or KALETRA 400/100 mg twice-daily (n = 331).  Further stratification within each group was 1:1 (tablet vs. capsule).  Patients administered the capsule were switched to the tablet formulation at Week 8 and maintained on their randomized dosing schedule.  Patients were administered emtricitabine 200 mg once-daily and tenofovir DF 300 mg once-daily. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL (range: 1.7 to 7.0 log10 copies/mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 17.

Table 17. Outcomes of Randomized Treatment Through Week 48 (Study 730)
Outcome KALETRA Once Daily +TDF + FTC
(n = 333)
KALETRA Twice Daily + TDF+FTC (n= 331)
Responder1
78%
77%
Virologic failure2
10%
8%
   Rebounded
  Never suppressed through Week 48
5%
5%
5%
3%
Death
1%
<1%
Discontinued due to adverse events
4%
3%
Discontinued for other reasons3
8%
11%
1  Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.

2   Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.

3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Through 48 weeks of therapy, 78% in the KALETRA once-daily arm and 77% in the KALETRA twice-daily arm achieved and maintained HIV-1 RNA < 50 copies/mL (95% confidence interval for the difference, -5.9% to 6.8%). Mean CD4+cell count increases at Week 48 were 186 cells/mm3 for the KALETRA once-daily arm and 198 cells/mm3 for the KALETRA twice-daily arm.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration