March 11 ,2008 - Updates have been made to Prezista (darunavir) tablets labeling to reflect significant new risk information. Changes have been made to the CLINICAL PHARMACOLOGY section to include data from 6 pharmacokinetic, drug interaction Phase 1 trials, and to the WARNINGS, PRECAUTIONS AND ADVERSE REACTIONS sections of the package insert to include hepatotoxicity information. Other updates include those made to PRECAUTIONS, updates to DOSAGE AND ADMINISTRATION, and changes to Table 11 to include information regarding a potential drug-drug interaction with rosuvastatin.

In the WARNINGS section, the following has been added:

"Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

The PRECAUTIONS section has been changed to read as follows:

"Patients with co-existing conditions
Hepatic Impairment: No dose adjustment of PREZISTA/rtv is necessary for patients with either mild or moderate hepatic impairment. There are no pharmacokinetic or safety data available for subjects with severe hepatic impairment, therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

Table 11, Established and Other Potentially Significant Drug Interactions, has been modified, under HMG-CoA Reductase Inhibitors, to include rosuvastatin, indicating increased concentration of rosuvastatin, with the following clinical comment: "Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/rtv."

The following sentence has been added to the CLINICAL PHARMACOLOGY section, under Absorption and Bioavailabilty: "In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters."

The following has been added under: Special Populations
"Hepatic Impairment: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/rtv 600/100 mg b.i.d. to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

In addition, there are updates to Table 4: Drug Interactions Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs, and Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir.

The last paragraph of the ADVERSE REACTIONS section now reads: "Patients co-infected with hepatitis B and/or hepatitis C virus: In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes (see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection."

In addition, the following has been added:

"Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:

Hepatobiliary System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia

Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
[this duplicate information was deleted from the Skin and Appendages section under the treatment-emergent adverse events occurring in less than 2% of de novo subjects]"

Changes were also made to DOSAGE AND ADMINISTRATION, to include the following: "Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment)."

The new label will be posted soon at DailyMed to replace the 08/2007 version.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration