On June 22, 2005, the US Food and Drug Administration (FDA) granted accelerated approval of tipranavir(Aptivus), a protease inhibitor manufactured by Boehringer Ingelheim. Tipranavir, co-administered with 200mg 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.
US FDA advice is reproduced below.
Clinical study results
The approval of tipranavir / ritonavir is based on analyses of plasma HIV-1 RNA levels in two controlled phase III studies of tipranavir / 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 tipranavir / ritonavir achieving 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 tipranavir is 500mg taken with 200mg of ritonavir, twice daily with food. Tipranavir must be co-administered with 200mg of ritonavir to exert its therapeutic effect. Failure to correctly co-administer tipranavir 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 tipranavir / ritonavir:
- The use of other active agents with tipranavir / ritonavir is associated with a greater likelihood of treatment response.
- Genotypic or phenotypic resistance testing and/or treatment history should guide the use of tipranavir / ritonavir. The number of baseline primary protease inhibitor mutations affects the virologic response to tipranavir / ritonavir.
- Because tipranavir can cause serious liver toxicity, liver function tests should be performed at initiation of therapy with tipranavir / ritonavir and monitored frequently throughout the duration of treatment
- Use caution when prescribing tipranavir / ritonavir to patients with elevated transaminases, Hepatitis B or C co-infection, or other underlying hepatic (liver) impairment
- Tipranavir used with low-dose ritonavir has many drug interactions. Therefore, patients should report to their health care provider the use of any other prescription or 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 tipranavir 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 tipranavir.
The extensive drug-drug interaction potential of tipranavir / ritonavir when co-administered with multiple classes of drugs must be considered prior to and during tipranavir / ritonavir use.
- The risk-benefit of tipranavir / ritonavir has not been established in treatment-naïve adult patients or pediatric patients.
- There are no study results demonstrating the effect of tipranavir / ritonavir on clinical progression of HIV-1.
Safety information
The most commonly (> 3%) reported adverse reactions were diarrhoea, nausea, fatigue, headache and vomiting. The most commonly reported laboratory abnormalities were elevated liver enzymes, cholesterol and triglycerides.
Hepatotoxicity
The tipranavir label includes a Black Box warning regarding hepatoxicity. Specifically, tipranavir 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 tipranavir / ritonavir, and frequently throughout the duration of treatment.
In addition, tipranavir is contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency.
Sulfa allergy
Tipranavir 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 tipranavir / ritonavir. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving tipranavir / ritonavir. Additionally, in one drug interaction trial in healthy female volunteers given a single dose of ethinyl estradiol (a hormonal contraceptive) followed by tipranavir / ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalised pruritus (itching) has been reported in both men and women receiving tipranavir / ritonavir.
Ongoing clinical trials
Boehringer Ingelheim agreed to continue to evaluate the safety and efficacy of tipranavir in the following patient populations:
- Pediatric patients
- Treatment-naïve adults
- HIV-positive women
- Hepatitis co-infected patients
Additional drug-drug interaction studies are planned.