Aptivus

Protease Inhibitor

Common Name: tipranavir (TPV)

Brand Name: Aptivus

Class: HIV protease inhibitor (PI)

Standard dose: Two 250 mg capsules with two 100 mg capsules of Norvir, both twice daily. Must be taken with Norvir. Oral solution available; both formulas available for children and adults. Must be taken with food. Take missed dose as soon as possible but do not double up on your next dose.

AWP: $1,172.26 / month for Aptivus only

Manufacturer contact: Boehringer-Ingelheim,
www.aptivus.com, 1 (800) 542-6257

AIDSInfo:
1 (800) HIV-0440 (448-0440), www.aidsinfo.nih.gov

Potential side effects and toxicity: Mostly gastrointestinal-related; mild diarrhea, nausea, vomiting, abdominal pain, and fatigue. In clinical trials, symptoms have been managed by having a light snack with the drug. Rash, including sensitivity to the sun, has occurred with Aptivus. Rash was more common in children. Also, women taking birth control pills may be at higher risk for rash. If a severe rash occurs, Aptivus should be discontinued. See Viramune. Stop using Aptivus if rash appears with joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin, and call your health care provider right away. Other side effects may include headache, fever, fatigue, dry mouth, and dizziness. Caution should be used in people with mild liver impairment, since Aptivus concentrations may be increased. Should not be taken by people with moderate to severe hepatitis. Be sure to know your hepatitis status if you are about to or are taking this drug! During clinical studies, bleeding in the brain occurred in people taking Aptivus/Norvir who had medical conditions or were receiving other medications that may have increased the risk of this. Use with caution by people who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet drugs, anticoagulants, or supplemental high doses of vitamin E. Aptivus has a "sulfa" component to it, so it should be used cautiously in patients with "sulfa" allergies. Immune Reconstitution Inflammatory Syndrome (IRIS) may occur as the immune system regains strength; report symptoms of illness, such as shingles and TB, to health care provider.

As seen with other protease inhibitors (except unboosted Reyataz), there can be increased levels of cholesterol and triglycerides which may be associated with an increased risk of heart disease. Other possible side effects seen with protease inhibitors are lipodystrophy (body fat changes, including thinning of the face, arms and legs, with or without fat accumulation in the stomach, breasts and sometimes the upper back), onset of new cases or worsening of diabetes (see your doctor promptly), and increased bleeding in hemophiliacs. See Norvir for more details on potential side effects.

Potential drug interactions: Aptivus/Norvir interacts with many other drugs, so it is important to tell your health care professional of the medications you are taking. See the package insert. Aptivus lowers Intelence levels, and the two should not be combined. Do not take with Tambocor, Rythmol, quinidine, oral Versed (midazolam), Halcion, rifampin, pimozide, ergot alkaloids (such as Cafergot, Wigraine, Methergine, and D.H.E. 45), or the herb St. John's wort. Do not use simvastatin or lovastatin for the treatment of high lipids. It also increases the concentrations of Lipitor and Crestor, and the lowest possible dose should be used in combination with Aptivus. Other lipid-lowering alternatives are Lescol and pravastatin, but they should be used with caution due to potential for liver toxicity. Increased levels of the inhaled and nasal sprays with fluticasone (found in Advair, Flonase, Flovent), can occur with Aptivus/Norvir and therefore should be used with caution. Aptivus can lower blood levels of Ziagen, Videx, and Retrovir (zidovudine, AZT). The clinical significance of this interaction is not known. No significant changes were seen when combining Aptivus with Sustiva or Viramune. Should not be taken with other protease inhibitors because it greatly lowers their blood levels. Cialis, Levitra, and Viagra levels are increased; doses should not exceed 10 mg Cialis or 2.5 mg Levitra per 72 hours, or 25 mg Viagra per 48 hours.

Methadone doses may need to be increased. Trazodone concentrations may increase; a lower dose of trazodone is recommended. Calcium channel blockers should be monitored for side effects. Monitoring may be required when taking Coumadin or immunosuppressants. Carbamazepine, Dilantin (phenytoin), or phenobarbital may decrease Aptivus levels, so alternate seizure medications should be used and monitoring of Aptivus drug levels is recommended. Caution should be used with valproic acid, which may be less effective due to decreased concentrations when used with Aptivus. Caution must be exercised when using itraconazole or fluconazole. Rifabutin requires a reduced dose. Norvir and Aptivus capsules contain alcohol (but should not be enough to trigger relapse), so be cautious with Antabuse or Flagyl. Oral solution contains vitamin E; do not take with additional vitamin E beyond that found in a standard multivitamin.

Tips: Due to its resistance profile and its drug interactions, Aptivus is less popular than the other newer PI, Prezista. Take with food to minimize stomach problems. Do not take at the same time as antacids. Aptivus is expected to do less well for people with combinations of certain protease-related mutations. See package insert for a list of mutations. Although Aptivus has to be taken with 200 mg twice daily of Norvir, it actually lowers the blood levels of Norvir, so you may not see as much of the GI side effects as you might expect. The capsules should be refrigerated prior to opening. Aptivus must be used within 60 days after the bottle is opened, and then can be stored at temperatures between 59 to 85°F. Please see package insert for more complete potential side effects and interactions.

Doctor

Aptivus (two capsules of tipranavir plus two capsules of ritonavir) was approved in 2005 for combination antiretroviral treatment only in those individuals with HIV infection who have evidence of viral replication, are highly treatment-experienced, and/or have HIV strains resistant to multiple protease inhibitors. This antiretroviral was approved for use in the pediatric population in 2008. While Aptivus gives us an active drug choice in those who have failed multiple PIs, the data suggesting a drug effect on clotting cells and brain hemorrhage with its use made it difficult to see the sunlight on Aptivus from underneath this shadow. Personally, I have not seen either of these problems with use of the drug. Problematic for us has been liver function and lipid abnormalities (not helped by the ritonavir dosing). With newer drugs in the PI and other antiretroviral classes now available, we have not used much of this drug. However, when an active PI is needed for salvage therapy, tipranavir may be a viable choice, though genetic testing should be done to confirm that. -- Frank M. Graziano, M.D., Ph.D.

Activist

Aptivus is considered a "salvage" drug -- not for first-timers or those just starting antiretroviral therapy. Aptivus seems to have efficacy when taken with Fuzeon, but should never be taken with another PI (other than Norvir), as it decreases other PI levels. Aptivus has to be taken twice a day and may also increase lipid levels and cause more liver toxicity than other PIs on the market. Required refrigeration may also be problematic, particularly in developing countries. -- Morris Jackson

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