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Tipranavir (Aptivus): Uses & Side Effects from this HIV/AIDS Drug

What is tipranavir (Aptivus), and what is it used for?

Aptivus (tipranavir), co-administered with 200 mg of ritonavir, is indicated for 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.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled 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 HIV-1 replication despite ongoing antiretroviral therapy. 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 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.
  • 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 impairment.
  • 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.
  • 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.

What is the dosage for tipranavir (Aptivus)?

The recommended dose of Aptivus (tipranavir) Capsules is 500 mg (two 250 mg capsules), coadministered with 200 mg of ritonavir, twice daily. Aptivus Capsules, co-administered with 200 mg of ritonavir should be taken with food. Bioavailability is increased with a high fat meal.

What are the side effects of tipranavir (Aptivus?)

Aptivus may cause serious side effects, including:

  • Liver problems, including liver failure and death. Your doctor should do blood tests to monitor your liver function during treatment with Aptivus. Patients with liver diseases such as Hepatitis B and Hepatitis C may have worsening of their liver disease with Aptivus and should have more frequent monitoring blood tests.
  • Rash. Mild to moderate rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving Aptivus. Some patients who developed rash also had joint pain or stiffness, throat tightness, or generalized itching.
  • Increased bleeding in patients with hemophilia. This can happen in patients taking Aptivus or other protease inhibitor medicines.
  • Diabetes and high blood sugar (hyperglycemia). This can happen in patients taking Aptivus or other protease inhibitor medicines. Some patients have diabetes before starting treatment with Aptivus which gets worse. Some patients get diabetes during treatment with Aptivus. Some patients will need changes in their diabetes medicine. Some patients will need new diabetes medicine.
  • Increased blood fat (lipid) levels. Your doctor should do blood tests to monitor your blood fat (triglycerides and cholesterol) during treatment with Aptivus. Some patients taking Aptivus have large increases in triglycerides and cholesterol. The long-term chance of having a heart attack or stroke due to increases in blood fats caused by Aptivus is not known at this time.
  • Changes in body fat. These changes have happened in patients taking Aptivus. and other antiHIV medicines. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen.

The cause and long-term health effects of these conditions are not known. The most common side effects include diarrhea, nausea, vomiting, stomach pain, tiredness and headache.

Women taking birth control pills may get a skin rash. It may be hard to tell the difference between side effects caused by Aptivus, by the other medicines you are also taking, or by the complications of HIV infection. For this reason it is very important that you tell your doctor about any changes in your health.

You should report any new or continuing symptoms to your doctor right away. Your doctor may be able to help you manage these side effects. The list of side effects is not complete. Ask your doctor or pharmacist for more information.

What drugs interact with tipranavir (Aptivus?)

Aptivus co-administered with 200 mg of ritonavir can alter plasma exposure of other drugs and other drugs may alter plasma exposure of tipranavir.

Potential for tipranavir/ritonavir to Affect Other Drugs 1. Aptivus co-administered with 200 mg of ritonavir at the recommended dose, is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of Aptivus/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events should be contraindicated.

Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring. Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir/ritonavir on CYP 2D6 is inhibition, because ritonavir is a CYP 2D6 inhibitor. The in vivo net effect of tipranavir administered with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19 is not known.

Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases and whether tipranavir induces CYP 1A2, CYP 2C9 and CYP 2C19. 3. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well.

Data suggest that the net effect of tipranavir co-administered with 200 mg of ritonavir is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor. 4. It is difficult to predict the net effect of Aptivus administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.

Potential for Other Drugs to Affect tipranavir

  1. Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of Aptivus/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Coadministration of Aptivus/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations.
  2. Co-administration of Aptivus/ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of Aptivus/ritonavir 500/200 mg twice daily. Drug interaction studies were performed with Aptivus, co-administered with 200 mg of ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions.

Is tipranavir (Aptivus) safe to use while pregnant or breastfeeding?

Teratogenic Effects, Pregnancy

Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats.

No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/Kg/day and 150 mg/Kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/Kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 µM·h or approximately 0.8-fold human exposure at the recommended dose.

In rats and rabbits, fetal toxicity was not noted at 40 mg/Kg/day and 150 mg/Kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 µM/340 µM·h and 8.4 µM/120 µM·h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/Kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/Kg/day (~0.8-fold human exposure).

No post-weaning functions were affected at any dose level. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. Aptivus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to Aptivus, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse effects of tipranavir, mothers should be instructed not to breastfeed if they are receiving Aptivus.

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What else should I know about tipranavir (Aptivus)?

Aptivus (tipranavir) is the brand name for tipranavir (TPV), a non-peptidic protease inhibitor (PI) of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.

Aptivus soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin.

How does tipranavir (Aptivus) work?

Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.


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