Tipranavir - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Co-administration with Ritonavir: APTIVUS must be co-administered with ritonavir and food to achieve the desired antiviral effect.

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

Hepatic Impairment: Discontinue for signs and symptoms of clinical hepatitis or asymptomatic increases in ALT/AST >10 times ULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitant increases in total bilirubin.

Monitor liver function tests prior to therapy and frequently thereafter.

Intracranial Hemorrhage/Platelet Aggregation and Coagulation: Use with caution in patients at risk for increased bleeding or who are receiving medications that increase the risk of bleeding. ( 5.3 , 5.5 ) The concomitant use of APTIVUS/ritonavir and certain other drugs may result in known or potentially significant drug interactions.

Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.4 , 7.2 ) Rash: Discontinue and initiate appropriate treatment if severe skin reaction occurs or is suspected.

Use with caution in patients with a known sulfonamide allergy.

Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia , immune reconstitution syndrome , redistribution/accumulation of body fat , and elevated lipids.

Monitor cholesterol and triglycerides prior to therapy and periodically thereafter.

Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.

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

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

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

5.2 Hepatic Impairment and Toxicity Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS co-administered with 200 mg of ritonavir.

These have generally occurred in subjects with advanced HIV-1 disease taking multiple concomitant medications.

A causal relationship to APTIVUS/ritonavir could not be established.

Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly.

Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation.

All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity.

Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment.

If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued.

If asymptomatic elevations in AST or ALT between 5 – 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued.

Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation.

In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced subjects, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48.

In a study of treatment-naïve subjects, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir 500 mg/200 mg through week 48.