Darunavir - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir.

Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis or in patients who have pre-treatment elevations of transaminases.

Post-marketing cases of liver injury, including some fatalities, have been reported.

Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported.

Discontinue treatment if severe reaction develops.

Use with caution in patients with a known sulfonamide allergy.

Patients may develop new onset diabetes mellitus or hyperglycemia.

Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome. ( 5.7 , 5.8 ) Patients with hemophilia may develop increased bleeding events.

Darunavir/ritonavir is not recommended in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age.

5.1 Importance of Co-administration with Ritonavir Darunavir must be co-administered with ritonavir and food to achieve the desired antiviral effect.

Failure to administer darunavir with ritonavir and food may result in a loss of efficacy of darunavir.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

5.2 Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir.

During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir.

Patients with pre-existing 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 darunavir/ritonavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir 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 darunavir/ritonavir treatment.

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 darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.

5.3 Severe Skin Reactions During the clinical development program (n=3,063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects.

Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program.

During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis have been reported.