Dear Doctor letter issued in the U.S. relating to 14 reports of intracranial haemorrhage (ICH) events with tipranavir/r
3 August 2006. Related: Treatment alerts.
On 30 June 30, 2006 Boehringer Ingelheim and FDA informed Healthcare Professionals in the US about important new findings related to tipranavir (Aptivus) capsules, co-administered with ritonavir, 500mg/200mg. Boehringer Ingelheim identified 14 reports of intracranial haemorrhage (ICH) events, including 8 fatalities, in 6,840 HIV-1 infected individuals receiving tipranavir capsules in combination antiretroviral therapy in clinical trials.
Many of the patients experiencing ICH in the tipranavir clinical development program had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension or alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. An increased risk of ICH was previously observed in patients with advanced HIV-1 disease/AIDS.
Further investigations are ongoing to assess the role of tipranavir in ICH.
No pattern of abnormal coagulation parameters were observed in patients receiving tipranavir in general, or preceding the development of ICH. Routine measurement of coagulation parameters is not currently indicated in the management of patients on tipranavir. However, in in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving tipranavir/ritonavir.
According to the Dear Healthcare Provider letter, tipranavir/ritonavir should be used with caution in patients who may be at risk for increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants.
Information on ICH risk and platelet aggregation inhibition findings will be included in the following sections of the Package Insert:
The new Black Box Warning reads:
APTIVUS CO-ADMINISTERED WITH 200 MG RITONAVIR HAS BEEN ASSOCIATED WITH REPORTS OF BOTH FATAL AND NON-FATAL INTRACRANIAL Haemorrhage. (SEE WARNINGS) APTIVUS CO-ADMINISTERED WITH 200 MG RITONAVIR HAS BEEN ASSOCIATED WITH REPORTS OF CLINICAL HEPATITIS AND HEPATIC DECOMPENSATION INCLUDING SOME FATALITIES. EXTRA VIGILANCE IS WARRANTED IN PATIENTS WITH CHRONIC HEPATITIS B OR HEPATITIS C CO-INFECTION, AS THESE PATIENTS HAVE AN INCREASED RISK OF HEPATOTOXICITY. (SEE WARNINGS)
INDICATIONS AND USAGE (new usage bullet)
- Use caution when prescribing
WARNINGS
Intracranial Haemorrhage
Tipranavir, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial haemorrhage (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 tipranavir.
Platelet Aggregation Inhibition
In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving tipranavir/ritonavir.
Tipranavir/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants.
PRECAUTIONS, Information for Patients
Patients should be informed that tipranavir co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial haemorrhage.
Patients should report any unusual or unexplained bleeding to their physician.
ADVERSE REACTIONS (added term to Nervous System Disorders)
Intracranial haemorrhage
ANIMAL PHARMACOLOGY AND TOXICOLOGY
In preclinical studies, tipranavir treatment induced changes in coagulation parameters (increased prothrombin and activated partial thromboplastin times) in rodents. At higher doses and in extreme cases, these changes led to bleeding in multiple organs and death. The mechanism for this effect is unknown. This effect was not seen in preclinical studies with dogs.
Source: FDA list serve
PDF copy of the Dear Healthcare Provider letter: http://www.fda.gov/medwatch/safety/2006/Aptivus-tipranavir_DHCP.pdf
The revised product labeling is available in PDF format at: http://www.fda.gov/medwatch/safety/2006/Aptivus_PI.pdf
Comment
Intracranial haemorrhage (ICH) events are rare events and the rate reported in patients using tipranavir/r was similar to those previously reported in advanced patients with HIV.
The EMEA have not yet decided whether a similar Dear Doctor will be issued in Europe, and the timeline for this process means that any similar communication is unlikely within the next month.