tipranavir and Intracranial-Hemorrhages

Tipranavir (TPV), a protease inhibitor, has box warnings for intracranial hemorrhage (ICH) and hepatotoxicity (including hepatic failure and death). A box warning is a labeling statement about serious adverse events leading to significant injury and/or death. A box warning is the most serious warning placed in the labeling of a prescription medication. As a result of the respective morbidity and mortality associated with ICH and hepatic failure, the Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) was searched for reports of these adverse events in HIV-infected patients receiving a tipranavir/ritonavir (TPV/r)-based regimen. This search comprised part of the FDA's safety analysis for traditional approval. From July 2006 to March 2007, 10 cases of ICH were identified in AERS. From June 2005 to March 2007, 12 cases of liver-associated deaths were identified. One patient experienced liver failure and fatal ICH. Most patients with these events had additional risk factors. Among patients with liver-associated deaths, 3 had HIV-RNA less than 400 copies per milliliter at the time of hepatic failure. Among 10 patients who discontinued TPV/r when hepatic failure developed, median number of days post-TPV/r to death was 23 (range, 2-69 days). Review of AERS did not identify new safety concerns regarding ICH. Among most patients with liver-associated deaths, death appears to occur soon after hepatic failure develops. If considering TPV/r, careful assessment of risk/benefit is suggested for patients at risk for ICH and hepatic failure.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Intracranial Hemorrhages; Liver Failure; Male; Middle Aged; Pyridines; Pyrones; Ritonavir; Sulfonamides; United States; United States Food and Drug Administration

The US Food and Drug Administration has issued a warning that tipranavir may be associated with increased risk of intracranial hemorrhage. We studied 2 large cohorts to estimate the background rate of intracranial hemorrhage and compared it with rates reported among persons who had been exposed to tipranavir.

Topics: Adult; Age Factors; Anti-HIV Agents; California; Cohort Studies; Databases, Factual; Female; HIV Infections; Humans; Intracranial Hemorrhages; Male; Medicaid; Middle Aged; Pyridines; Pyrones; Risk Factors; Sulfonamides; United States; Veterans

A 55-year-old HIV-infected patient on antiretroviral treatment with Ritonavir-boosted Tipranavir as part of HAART developed intracranial haemorrhage during the acute phase of cryptococcal meningitis. CT scan and MRI confirmed the intracranial haemorrhage. Positive cryptococcal antigen and cultures of both blood and CSF confirmed the diagnosis of meningitis caused by Cryptococcus neoformans. There was no evidence of any bleeding disorder, use of aspirin or antiplatelet agents. The patient was treated with Liposomal Amphotericin B for cryptococcal meningitis. No special treatment was needed for the intracranial haemorrhage, but Tipranavir was discontinued and replaced by Kaletra and Saquinavir. Intracranial haemorrhage could be related to Tipranavir and cryptococcal meningitis was a predisposing factor. Headache stopped 3 days after starting antifungal treatment. To the best of our knowledge, this is the first reported case of intracranial haemorrhage related to Tipranavir treatment after the end of the "RESIST" studies and the only one related to meningitis.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Causality; Cryptococcus neoformans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Meningitis, Cryptococcal; Middle Aged; Pyridines; Pyrones; Sulfonamides; Tomography, X-Ray Computed

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Intracranial Hemorrhages; Pyridines; Pyrones; Ritonavir; Sulfonamides

Topics: Drug Labeling; HIV Protease Inhibitors; Humans; Intracranial Hemorrhages; Pyridines; Pyrones; Ritonavir; Sulfonamides; United States; United States Food and Drug Administration