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The Kaletra (lopinavir and ritonavir), Soft Gel Capsules and Oral Solution, labeling has been revised to include long-term (week 144-204) efficacy and safety results from two phase II trials. Specifically, the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included in the label. In addition, results of a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment and Week 104 mice and rat data were submitted to update the respective sections of the package insert.

The following changes appear in the revised labeling.

CLINCIAL PHARMACOLOGY:

Information from a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment was added. Specifically, the following text was included.

Multiple doses of KALETRA 400/100 mg bid to HIV and HCV co-infected subjects with mild to moderate hepatic impairment (n=12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-infected subjects with normal hepatic function (n=12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs 99.31%, respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment.

Results from drug-drug interaction studies with fosamprenavir (Lexiva) and tenofovir (Viread) were included.

INDICATIONS AND USAGE and Description of Clinical Studies:

These sections were updated to include long-term efficacy results from two uncontrolled dose-ranging studies. Specifically the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included as follows: 

Through 204 weeks of treatment in study 720, the proportion of patients with HIV RNA <400 (<50) copies/mL was 71% (70%) [n=100], and the corresponding mean increase in CD4 cell count was 440 cells/mm³.  Twenty-eight patients (28%) discontinued the study, including 9 (9%) discontinuations due to adverse events and 1 (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV RNA <400 (<50) copies/mL was 54% (50%) [n=70], and the corresponding mean increase in CD4 cell count was 212 cells/mm³.  Twenty-seven patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths.

WARNINGS:

 

The erectile dysfunction drugs tadalafil (Cialis), and vardenafil (Levitra) were included with sildenafil (Viagra) under Pharmacokinetics: Drug-Drug Interactions, as follows:

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse events including hypotension, syncope, visual changes and prolonged erection (see PRECAUTIONS: Drug Interactions and the complete prescribing information for sildenafil tadalafil, and vardenafil.)




PRECAUTIONS:

The following statement regarding immune reconstitution syndrome was added.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis) which may necessitate further evaluation and treatment.

        Drug Interactions

·        Table 9: Established and Other Potentially Significant Drug Interactions was updated to include information with tenofovir, fosamprenavir, voriconazole, tadalafil, vardenafil and hormonal contraceptives as follows.

o       KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for tenofovir-associated adverse events

o       An increased rate of adverse events has been observed with coadministration with KALETRA and fosamprenavir. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

o       Coadministration of voriconazole (VFEND) with KALETRA has not been studied. However, administration of voriconazole with ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time. Until data are available, voriconazole should not be administered to patients receiving KALETRA

o       Use tadalafil (Cialis) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events

o       Use vardenafil (Levitra) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events

o       Because contraceptive steroid concentrations may be altered when KALETRA is coadministered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

Carcinogenesis, Mutagenesis and Impairment of Fertility

·        Results from the long-term carcinogenicity studies with KALETRA were included as follows.

o       Long-term carcinogenicity studies of KALETRA in animal systems have not been completed. Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of

hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. However, neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration

ADVERSE REACTIONS:

·        Table 10 (Adverse Events) and 11 (laboratory abnormalities) were updated to include the Week 204 data from study M97-720 and the Week 144 data from study M97-7

·       Stevens Johnson Syndrome and erythema multiforme were added under Skin and Appendages to the postmarketing experience Section.

The complete revised label will be available soon on the "Drugs@FDA <mailto:Drugs@FDA>"  <http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm>website at <http://www.accessdata.fda.gov/scripts/cder/drugsatfda/>

Richard Klein                                                  

Office of Special Health Issues                         

Food and Drug Administration                          

Kimberly Struble

Division of Antiviral Drug Products

Food and Drug Administration

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