Tipranavir: An Overview
.
Brand Name: Aptivus
Drug Class: Protease Inhibitor
HIV
and Hepatitis.com maintains a section on the website devoted to
comprehensive overviews of all
FDA-approved anti-HIV drugs. Following is an updated
version of the protease
inhibitor tipranavir (Aptivus)
overview that includes information on indications for usage, dosing, drug and
food interactions, potential adverse events and side effects,
and pharmacology.
Links to other HIV and Hepatitis.com articles on tipranavir
are also posted in this section.
The
US Food and Drug Administration (FDA) approved tipranavir
on June 22, 2005 for use in combination with other anti-HIV drugs
in the treatment of HIV infection in adults. Studies of tipranavir
use in children and infants
aged 2-18 years are currently underway.
As
with other antiretrovirals, tipranavir cannot
cure or prevent
HIV infection or AIDS and may not reduce the risk
of transmitting
HIV to others.
Indications
for Usage
The
FDA has approved tipranavir in combination with the protease inhibitor
ritonavir (Norvir) for use in adult HIV patients who have
active HIV replication, have used other anti-HIV medications or
who show evidence of HIV strains that are resistant
to multiple protease inhibitors. tipranavir/ritonavir
in combination should be used in combination with other active
anti-HIV agents to produce a greater likelihood of a robust treatment
response.
When
considering use of tipranavir, genotypic
and phenotypic
resistance testing should be performed to help
determine which additional agents may yield the best outcome in
combination with tipranavir.
Due
to FDA concerns about the safety of the tipranavir/ritonavir combination, the agency recommends to clinicians
that tipranavir should be prescribed
only to HIV patients for whom other effective drug regimens are
not available. In addition, tipranavir
is contraindicated in individuals with known hypersensitivity
to any of the ingredients in this product. It is also contraindicated
in individuals with moderate and severe hepatic insufficiency.
Dosing
Information
Tipranavir is available in 250 mg soft gel capsules and is taken
with ritonavir. The recommended dosing
regimen is 500 mg tipranavir taken with
200 mg ritonavir twice daily.
Drug
and Food Interactions
Absorption
of tipranavir increases when taken with a high-fat meal. Antacids
reduce absorption of tipranavir, requiring
timing adjustments of antacid use.
Tipranavir/ritonavir at the recommended
dosage is an inhibitor of CYP 3A and may thus increase plasma
concentrations of agents that are primarily metabolized by this
enzyme. Coadministration of tipranavir/ritonavir
with drugs that are highly dependent on CYP 3A for clearance are
contraindicated. These drugs include amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine,
methylergonamine, cisapride,
St. John's
wort, lovastatin, simvastatin, pimozide, midazolam, and triazolam.
When
used with other antiretrovirals in vitro, tipranavir
was shown to be additive to antagonistic with other PIs, generally
additive with non
nucleoside reverse transcriptase inhibitors (NNRTIs)
and nucleoside
reverse transcriptase inhibitors (NRTIs), and synergistic with the fusion
inhibitor enfuvirtide (Fuzeon).
Patients
should tell their doctor about any other medications they are
taking, including prescription, nonprescription (over-the-counter),
or herbal medications.
It is particularly important for doctor s to know if a patient
is allergic to sulfa drugs, because people with sulfa allergies
may be at a higher risk of having an allergic reaction to tipranavir.
Potential
Adverse Events and Side Effects
Like
all anti-HIV drugs, tipranavir may cause some unwanted side effects. The most
common side effects are diarrhea,
nausea, fatigue, headache, and vomiting.
Adverse effects
leading to discontinuation of treatment were reported in 7.8 percent
of individuals receiving tipranavir.
Other adverse effects include rash,
elevated lipid levels, fat
redistribution, and immune
reconstitution syndrome. Women using estrogens
may have an increased risk of non serious rash. Individuals with
hemophilia
may have increased risk of bleeding.
Tipranavir in combination with ritonavir
has been associated clinical hepatitis
(liver inflammation) and hepatic
decompensation, including some fatalities. Extra vigilance
is warranted in individuals with advanced HIV disease or those
with chronic
hepatitis B or hepatitis
C co-infection [with HIV] as these individuals
have an increased risk of hepatotoxicity.
Symptoms of hepatitis include fatigue, malaise, anorexia, nausea,
jaundice, bilirubinemia, acholic
stools, liver tenderness, or hepatomegaly.
Pharmacology
The
most common amino acid substitutions that occurred in more than
20 percent of virologic
failure isolates were L33/I/F, V82t, and I84V.
Tipranavir resistance was detected at
virologic rebound after an average of
38 weeks of tipranavir/ritonavir treatment
with a median 14-fold decrease in tipranavir
susceptibility. Cross-resistance to PIs has been observed. Tipranavir-resistant
viruses that emerged in vitro had decrease susceptibility to the
PIs amprenavir (Agenerase), atazanavir (Reyataz), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), and ritonavir (Norvir) but remained sensitive to saquinavir (Invirase).
Genotypic or phenotypic analysis of baseline virus may help determine
tipranavir susceptibility before initiating treatment.
Tipranavir is in FDA
Pregnancy Category C. No adequate or well-controlled
studies of tipranavir have been done in pregnant women. In laboratory
animal studies, no teratogenecitiy was
detected in pregnant rats and rabbits at exposure levels approximately
1.1-fold those of human exposure. Fetal toxicity was observed
in rats at exposure levels approximately 0.2-fold those of human
exposure. Tipranavir should be used
during pregnancy only when clearly needed.
An
Antiretroviral Pregnancy Registry has been established to monitor
the outcomes of pregnant women exposed to antiretroviral agents,
including amprenavir. Physicians may
register patients by calling 800-258-4263.
Alternative
methods of non-hormonal contraception should be used when estrogen-based
oral contraceptives are coadministered
with tipranavir/ritonavir. Women using estrogens as hormone replacement
therapy should be clinically monitored for signs of estrogen deficiency.
Storage
Store
tipranavir capsules at 20
C to 800 C (360 to 460 F) prior
to opening the bottle. After opening, store at 250
C (770 F); excursions permitted to 15 to 300
C (59 to 860 F). Use within 60 days after opening.
Contact
Information
Boehringer Ingelheim Pharmaceuticals
Inc
900 Ridgebury
Rd / PO
Box 368
Ridgefield, CT,
06877-0368
800- 542-6257
Links
to other Tipranavir Articles on HIV and Hepatitis.com
10/12/05
Sources
National Institutes
of Health
US Food and Drug Administration
Boehringer Ingelheim
Suggested
Reading
A
Lazzarin and others. Tipranavir/ritonavir (TPV/r) demonstrates superior
treatment response to lopinavir/r (LPV/r),
amprenavir/r (APV/r) or saquinavir/r
(SQV/r) in PI-experienced patients from the TPV RESIST-1 and RESIST-2
trials. Abstract WePe6.3C07. Program and Abstracts
of the 3rd IAS Conference on HIV Pathogenesis and Treatment.
July 24-27, 2005. Rio
de Janeiro, Brazil.
P
Cahn and others.
24-week data from RESIST-2: Phase 3 study of the efficacy and
safety of either tipranavir/ritonavir
(TPV/r) or an optimized ritonavir (RTV)-boosted
standard-of-care (SOC) comparator PI (CPI) in a large randomized
multicenter trial in treatment-experienced
HIV+ patients. Abstract : PL 14.3.
7th International Congress on Drug Therapy in HIV Infection; November
14 - 18, 2004. Glasgow,
U.K.
S McCallister and others. A 14-Day Dose-Response Study of the
Efficacy, Safety, and Pharmacokinetics of the Nonpeptidic
Protease Inhibitor Tipranavir in Treatment-Naive
HIV-1-Infected Patients. J Acquir
Immune Defic Syndr.
35(4):376-382. April 20, 2004
P Yeni. Tipranavir:
a protease inhibitor from a new class with distinct antiviral
activity. J Acquir Immune Defic
Syndr. 34 Suppl
1:S91-S94. September 2003.
B
A Larder and others. Tipranavir
inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.
AIDS 14(13): 1943-1948. September 8, 2000.
