Tipranavir Dosage

Usual Adult Dose for HIV Infection

Tipranavir 500 mg plus ritonavir 200 mg orally twice a day

Usual Pediatric Dose for HIV Infection

2 to 18 years: Tipranavir 14 mg/kg plus ritonavir 6 mg/kg or tipranavir 375 mg/m2 plus ritonavir 150 mg/m2 orally twice a day

Pediatric dosage should not exceed the usual adult dosage.

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

Mild hepatic impairment (Child-Pugh Class A): Caution is recommended because tipranavir plasma concentrations may increase.

Moderate or severe hepatic impairment (Child-Pugh Class B or C): Contraindicated

Dose Adjustments

2 to 18 years: The dose may be reduced to tipranavir 12 mg/kg plus ritonavir 5 mg/kg or tipranavir 290 mg/m2 plus ritonavir 115 mg/m2 in patients who cannot tolerate the usual dose or develop toxicity provided their virus is not resistant to multiple protease inhibitors

Precautions

Hepatitis, hepatic decompensation, and fatalities have been associated with tipranavir/ritonavir therapy; however, a causal relationship could not be determined. Patients should be monitored for signs of hepatitis (fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic feces, liver tenderness, or hepatomegaly) and be advised to discontinue tipranavir/ritonavir and seek medical attention if these symptoms occur.

All patients should have close laboratory and clinical monitoring, especially patients with chronic hepatitis B or hepatitis C coinfection as they are at a greater risk of developing hepatotoxicity. Liver function tests are recommended before beginning therapy and frequently during treatment.

Tipranavir/ritonavir treatment should be discontinued if asymptomatic increases in aspartate transaminase (AST) or alanine transaminase (ALT) greater than 10 times upper limit of normal (ULN) or asymptomatic increases in AST or ALT between 5 to 10 times ULN and elevations in total bilirubin greater than 2.5 times ULN occur. Patients with chronic hepatitis B or hepatitis C coinfection or increased transaminases are at a 2-fold greater risk of developing Grade 3 or 4 transaminase elevations or liver decompensation. Grade 3 and 4 hepatic transaminase elevations occurred in 10.3% of treatment-experienced patients in 2 large studies and in 20.3% of treatment-naive patients in 1 study, both through 48 weeks.

Tipranavir/ritonavir coadministration is contraindicated with drugs that are highly dependent on CYP450 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs include alfuzosin, amiodarone, bepridil, flecainide, propafenone, quinidine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, oral midazolam, triazolam, lovastatin, simvastatin, and sildenafil for treatment of pulmonary arterial hypertension. Other contraindicated drugs (which may lead to loss of efficacy) include St. John's Wort and rifampin. Tipranavir/ritonavir may potentially interact with many other drugs that are CYP450 and P-gp substrates, CYP450 inhibitors, or CYP450 3A inducers. Dose adjustments and additional monitoring may be required.

Tipranavir must be coadministered with ritonavir in order to achieve a therapeutic plasma concentration and effect.

Tipranavir coadministered with 200 mg of ritonavir has been associated with fatal and nonfatal intracranial hemorrhage (ICH). Concomitant administration of other medications may contribute to this event. No pattern of abnormal coagulation has been observed in patients preceding the development of ICH. Routine measurement of coagulation parameters is not currently indicated in the management of patients on tipranavir.

Platelet aggregation inhibition has been observed in in vitro experiments at human therapeutic levels. Tipranavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions, who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking high doses of supplemental vitamin E.

Rash (including urticarial rash, maculopapular rash, and possible photosensitivity) has been reported in 8% of males and 10% of females receiving tipranavir/ritonavir. Rash in conjunction with joint pain or stiffness, throat tightness, and generalized pruritus and cases of severe rash with myalgia, fever, erythema, desquamation, and mucosal erosions have been reported. If severe skin rash develops, tipranavir/ritonavir should be discontinued and appropriate therapy should be started.

Tipranavir contains a sulfonamide moiety and should be used with caution in patients with a known sulfonamide allergy.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and in some cases, diabetic ketoacidosis have been reported in HIV-infected patients receiving protease inhibitors. However, no causal relationship has been established. Patients may require initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. Hyperglycemia persisted in some cases after discontinuation of protease inhibitor therapy.

Spontaneous bleeding episodes have been reported in hemophiliac patients while receiving protease inhibitors. No causal relationship has been established, however, hemophiliacs should be monitored closely for bleeding during protease inhibitor therapy.

Tipranavir/ritonavir therapy has been associated with large increases in total cholesterol, triglycerides, and liver enzymes. Levels should be monitored before starting therapy and periodically during treatment, and managed appropriately.

Immune reconstitution syndrome has occurred during combination antiretroviral therapy. Patients responding to therapy may develop an inflammatory response to indolent or residual opportunistic infections and require evaluation and treatment.

Women who are taking estrogen-based contraceptives should be advised to use additional or alternate methods of contraception during treatment. There may be an increased risk of rash in women also taking hormonal contraceptives.

Use in combination with other antiretroviral agents will increase the likelihood of treatment response.

Tipranavir/ritonavir is not recommended for use in treatment-naive patients.

The potential for HIV cross-resistance among protease inhibitors exists but has not been fully explored. It is unknown what effect tipranavir therapy will have on the activity of subsequently administered protease inhibitors. Selection of antiretroviral agents for a patient's medication regimen should be guided by treatment history, and genotypic or phenotypic testing, and with specialist consultation.

Because children's dosages are calculated based on body weight or body surface area, special vigilance is recommended during calculation of dose, transcription of medication order, dispensing information, and dosing instructions to reduce the risk of medication errors.

Safety and efficacy have not been established in pediatric patients less than 2 years of age.

Dialysis

No adjustment recommended.

Other Comments

Tipranavir coadministered with ritonavir capsules or solution may be taken with or without meals. Tipranavir coadministered with ritonavir tablets must only be taken with meals.

Tipranavir capsules should be swallowed whole and not chewed. If a patient is unable to reliably swallow a tipranavir capsule, then the oral solution should be used. The oral solution should be administered using a calibrated dosing syringe.

Unopened bottles of tipranavir capsules should be refrigerated. After opening, the capsules may be stored at room temperature (25 degrees C, 77 degrees F) and must be used within 60 days. Unopened bottles of tipranavir oral solution should be stored at room temperature and should not be refrigerated or frozen. After opening, the oral solution must be used within 60 days.

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