Today (June 30, 2006),
Boehringer Ingelheim and FDA informed Healthcare
Professionals about important new findings related to
Aptivus (tipranavir) capsules, co-administered with
ritonavir, 500mg/200mg. Boehringer Ingelheim identified
14 reports of intracranial hemorrhage (ICH) events,
including 8 fatalities, in 6,840 HIV-1 infected
individuals receiving Aptivus capsules in combination
antiretroviral therapy in clinical trials.
Many of the patients experiencing ICH in the Aptivus
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 Aptivus
in ICH.
No pattern of abnormal coagulation parameters were
observed in patients receiving Aptivus in general, or
preceding the development of ICH. Routine measurement of
coagulation parameters is not currently indicated in the
management of patients on Aptivus. However,
in
in vitro experiments, tipranavir was observed to
inhibit human platelet aggregation at levels consistent
with exposures observed in patients receiving
Aptivus/ritonavir.
According to the
Dear Healthcare Provider
letter, APTIVUS/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:
* Boxed Warnings
* Indications and Usage
* Warnings
* Precautions - Information for Patients
* Adverse Reactions
* Animal Pharmacology / Toxicology (new section)
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 HEMORRHAGE. (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)"
A pdf copy of the Dear
Healthcare Provider letter
is available in pdf format on the FDA web site at
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
Richard Klein
Office of
Special Health Issues
Food and
Drug Administration
Jeffrey Murray
Division of Antiviral Products
Food and Drug Administration
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