Hepatic Impairment

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 patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/r 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/r 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/r, 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/r 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/r 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 transaminases 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 patients, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/r through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminases elevations while receiving APTIVUS/r 500 mg/200 mg through week 48
• Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/r to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased

Intracranial Hemorrhage

Incidence of intracranial hemorrhage

• 0.2% of patients reported intracranial hemorrhage (ICH)
• APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal ICH
• Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events
• No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH
• Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS