June 22, 2005, On June 22, 2005 The US Food and Drug Administration (FDA)
granted accelerated approval of APTIVUS (tipranavir), a protease inhibitor.
APTIVUS, co-administered with 200 mg of ritonavir, is indicated for use as part of
combination antiretroviral treatment of HIV-1 infected adult patients with
evidence of viral replication, who are highly treatment-experienced or have
HIV-1 strains resistant to multiple protease inhibitors.
FDA reviewed and approved APTIVUS within a six month time frame.
Clinical Study Results
The approval of APTIVUS/ritonavir is based on analyses of plasma HIV-1 RNA
levels in two controlled phase III studies of APTIVUS/ritonavir of 24 weeks
duration. Both studies were conducted in clinically advanced, 3-class
antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence
of HIV1 replication despite ongoing antiretroviral therapy. The results of
the two phase III studies showed a statistically significant greater
percentage of HIV-positive patients taking APTIVUS/ritonavir achieved
treatment response versus the comparator group (40% vs. 18%). Treatment
response was defined as a confirmed 1 log10 or greater decrease in HIV RNA
from baseline.
Dosage and Administration
The approved dose of APTIVUS is 500 mg taken with 200 mg of ritonavir, twice
daily with food. APTIVUS must be co-administered with 200 mg of ritonavir to
exert its therapeutic effect. Failure to correctly co-administer APTIVUS
with ritonavir will result in reduced plasma levels of tipranavir that will
be insufficient to achieve the desired antiviral effect. Taking the drug
with food improves absorption.
Usage Information:
The following points should be considered when initiating therapy with
APTIVUS/ritonavir:
* The use of other active agents with APTIVUS/ritonavir is associated
with a greater likelihood of treatment response.
* Genotypic or phenotypic resistance testing and/or treatment history
should guide the use of APTIVUS/ritonavir. The number of baseline primary
protease inhibitor mutations affects the virologic response to
APTIVUS/ritonavir.
* Because APTIVUS can cause serious liver toxicity, liver function
tests should be performed at initiation of therapy with APTIVUS/ritonavir
and monitored frequently throughout the duration of treatment
* Use caution when prescribing APTIVUS/ritonavir to patients with
elevated transaminases, Hepatitis B or C co-infection, or other underlying
hepatic (liver) impairment
* APTIVUS used with low-dose ritonavir has many drug interactions.
Therefore, patients should report to their health care provider the use of
any other prescription, non-prescription medication or herbal products,
particularly St. John's Wort. Certain medicines such as antiarrhythmics
(medicines that treat irregular heart beats), antihistamines, ergot
derivatives (found in some medicines to treat migraine headaches), medicines
that speed up the digestive tract, herbal products, some medicines that
lower cholesterol levels, and medicines to treat mental problems should
never be given with APTIVUS plus ritonavir because serious side effects
could occur.
Patients receiving estrogen-based birth control pills or patches should be
instructed that additional or alternative forms of birth control should be
used when taking APTIVUS.
The extensive drug-drug interaction potential of APTIVUS/ritonavir when
co-administered with multiple classes of drugs must be considered prior to
and during APTIVUS/ritonavir use.
* The risk-benefit of APTIVUS/ritonavir has not been established in
treatment-naïve adult patients or pediatric patients.
* There are no study results demonstrating the effect of
APTIVUS/ritonavir on clinical progression of HIV-1.
Safety Information:
The most commonly (> 3%) reported adverse reactions were diarrhea, nausea,
fatigue, headache and vomiting. The most commonly reported laboratory
abnormalities were elevated liver enzymes, cholesterol and triglycerides.
Hepatotoxicity
The APTIVUS label includes a Black Box warning regarding hepatoxicity.
Specifically, APTIVUS co-administered with low dose 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.
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.
In addition, APTIVUS is contraindicated in patients with moderate and severe
(Child-Pugh Class B and C, respectively) hepatic insufficiency.
Sulfa Allergy
APTIVUS should be used with caution in patients with a known sulfonamide
allergy. Tipranavir contains a sulfonamide component. The potential for
cross-sensitivity between drugs in the sulfonamide class and tipranavir is
unknown.
Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and
possible photosensitivity have been reported in subjects receiving
APTIVUS/ritonavir. In Phase 2 and 3 trials rash was observed in 14% of
females and in 8-10% of males receiving APTIVUS/ritonavir. Additionally, in
one drug interaction trial in healthy female volunteers given a single dose
of ethinyl estradiol (a hormonal contraceptive) followed by
APTIVUS/ritonavir, 33% of subjects developed a rash. Rash accompanied by
joint pain or stiffness, throat tightness, or generalized pruritus (itching)
has been reported in both men and women receiving APTIVUS/ritonavir.
Ongoing Clinical Trials
Boehringer Ingelheim agreed to continue to evaluate the safety and efficacy
of APTIVUS in the following patient populations:
* Pediatric patients
* Treatment-naïve adults
* HIV-positive women
* Hepatitis co-infected patients
Additional drug-drug interaction studies are planned.
Currently there are seven other protease inhibitors approved by FDA for the
treatment of HIV infection. These medications work at the final stages of
viral replication and attempt to prevent HIV from making new copies of
itself by interfering with the HIV protease enzyme. As a result, the new
copies of HIV are not able to infect new cells
The manufacturer of APTIVUS is Boehringer Ingelheim Pharmaceuticals.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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