Tipranavir

Pronunciation: tye-PRAN-a-vir
Class: Protease inhibitor

Trade Names

Aptivus
- Capsules 250 mg
- Oral solution 100 mg/mL

Pharmacology

Tipranavir is a nonpeptide protease inhibitor that prevents formation of mature virions by inhibiting virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells.

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Pharmacokinetics

Absorption

In combination with ritonavir, T max is approximately 3 h; C max is approximately 95 mcM (women) and 78 mcM (men). No significant changes in C max and AUC were observed under fed conditions when given in combination with ritonavir.

Distribution

Greater than 99.9% protein bound (albumin and alpha-1 acid glycoprotein). Vd is 7.7 L (women) and 10.2 L (men).

Metabolism

Metabolized primarily by CYP3A4. Metabolism in presence of ritonavir is minimal.

Elimination

The half-life is approximately 6 h. Approximately 82% is excreted in feces (mostly as unchanged tipranavir) and 4% in urine. Cl is 1.15 L/h (women) and 1.27 L/h (men).

Special Populations

Renal Function Impairment

Because renal Cl is negligible, renal impairment is not expected to decrease total body Cl.

Hepatic Function Impairment

Tipranavir and ritonavir plasma concentrations are increased in patients with mild hepatic impairment (Child-Pugh class A). Tipranavir is contraindicated in patients with moderate to severe hepatic impairment.

Elderly

No change in median trough tipranavir concentrations as age increased for either gender through 65 yr of age.

Gender

Women generally have higher tipranavir concentrations. No dosage adjustment is necessary.

Race

White men generally had more variability in tipranavir concentrations than black men, but the median concentration and the range making up the majority of the data are comparable between races.

Indications and Usage

In combination with ritonavir for the treatment of HIV-1–infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than 1 protease inhibitor.

Contraindications

Moderate and severe (Child-Pugh class B and C, respectively) hepatic impairment; use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious or life-threatening events (eg, antiarrhythmic agents [amiodarone, bepridil, flecainide, propafenone, quinidine], cisapride, ergot derivative [eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine], oral midazolam, pimozide, triazolam, St. John's wort, rifampin, lovastatin, simvastatin); hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO 500 mg (two 250 mg capsules or 5 mL oral solution), coadministered with ritonavir 200 mg, twice daily.

Children 2 to 18 yr of age

14 mg/kg with ritonavir 6 mg/kg (or 375 mg/m 2 with ritonavir 150 mg/m 2 ) twice daily (max, tipranavir 500 mg with ritonavir 200 mg twice daily). If toxicity or intolerance develop, decrease the dose to tipranavir 12 mg/kg with ritonavir 5 mg/kg (or tipranavir 290 mg/m 2 with ritonavir 115 mg/m 2 ) twice daily, provided their virus is not resistant to multiple protease inhibitors.

General Advice

  • Must be coadministered with ritonavir 200 mg to achieve effective plasma levels on twice-daily regimen.
  • May be taken with or without food.
  • Swallow capsules whole. Do not open, crush, or chew.

Storage/Stability

Store capsules in refrigerator (36° to 46°F) prior to opening bottle. After opening bottle, store capsules at controlled room temperature (59° to 86°F) and use within 60 days. Store oral solution at 59° to 86°F; do not refrigerate or freeze. Use the oral solution within 60 days after first opening the bottle.

Drug Interactions

Aluminum- and magnesium-containing antacids

Tipranavir/ritonavir plasma concentrations may be reduced, decreasing the pharmacologic effects. Consider separating the administration times by as much as possible.

Antiarrhythmic agents (eg, amiodarone, bepridil, flecainide, propafenone, quinidine), cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), lovastatin, oral midazolam, pimozide, rifampin, simvastatin, St. John's wort, triazolam

Coadministration with tipranavir in combination with ritonavir is contraindicated.

Anticholinergic agents (eg, darifenacin, fesoterodine, solifenacin, tolterodine)

Plasma concentrations of the anticholinergic agent may be elevated, increasing the pharmacologic effects and risk of adverse reactions. When coadministered with tipranavir, the daily dose of darifenacin should not exceed 7.5 mg, the daily dose of solifenacin should not exceed 5 mg, the daily dose of tolterodine should not exceed 2 mg, and the daily dose of fesoterodine should not exceed 4 mg.

Anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin)

Tipranavir plasma concentrations may be reduced, decreasing the efficacy. Use with caution.

Aripiprazole

Aripiprazole plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the patient and adjust the aripiprazole dose as needed.

Atorvastatin, rosuvastatin

Concurrent use increases the risk of myopathy, including rhabdomyolysis. Start with the lowest possible dose of atorvastatin or rosuvastatin and monitor carefully. Consider using fluvastatin or pravastatin as alternative therapy.

Azole antifungal agents (eg, fluconazole, itraconazole, ketoconazole, voriconazole)

Fluconazole may increase tipranavir concentrations. Dosage adjustment is not needed. High doses (more than 200 mg) of fluconazole, itraconazole, and ketoconazole are not recommended. Studies have not been done with itraconazole, ketoconazole, or voriconazole.

Calcium channel blockers (eg, diltiazem, felodipine, nicardipine, nisoldipine, verapamil), hypoglycemic agents (ie, glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide), immunosuppressive agents (eg, cyclosporine, sirolimus, tacrolimus)

Interactions with these agents have not been studied; however, caution is warranted and monitoring is recommended.

Clarithromycin

Concurrent use may increase tipranavir and clarithromycin levels. Dosage adjustment is not needed in patients with healthy renal function. For patients with CrCl 30 to 60 mL/min, decrease clarithromycin dose 50%. For patients with CrCl less than 30 mL/min, decrease the clarithromycin dose 75%.

Colchicine

Colchicine plasma concentrations may be increased. Life-threatening and fatal colchicine toxicity may occur. Avoid coadministration in patients with hepatic or renal impairment. In patients with healthy renal and hepatic function, coadministration of tipranavir and colchicine should be undertaken using a max dosage of colchicine 0.3 mg twice daily with careful monitoring for colchicine-related adverse effects.

Delavirdine

Delavirdine may increase plasma concentrations and pharmacologic effects of tipranavir. Tipranavir may decrease plasma concentrations and pharmacologic effects of delavirdine. Dosage reduction of tipranavir may be needed during coadministration of delavirdine. Dosage increases may be required for delavirdine when coadministered with tipranavir.

Desipramine

Although not studied, increased desipramine levels are expected. Dosage reduction and concentration monitoring of desipramine are recommended.

Digoxin

Tipranavir may increase plasma concentrations and pharmacologic effects of digoxin. Closely monitor for clinical and laboratory signs of digoxin toxicity when tipranavir is added to a stable digoxin regimen. Digoxin dose reductions may be necessary.

Disulfiram, metronidazole

Because tipranavir capsules contain alcohol, a disulfiram-like reaction may occur.

Dronedarone

Dronedarone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Avoid coadministration.

Efavirenz

Efavirenz coadministered with tipranavir/ritonavir (500 mg/100 mg twice daily) may cause tipranavir concentrations to decrease. Higher doses of tipranavir/ritonavir did not cause changes in tipranavir pharmacokinetics.

Eplerenone

Eplerenone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Close clinical monitoring is indicated when eplerenone is coadministered with tipranavir. Adjust the eplerenone dose as needed.

Erlotinib

Erlotinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. In patients receiving erlotinib, monitor for erlotinib adverse reactions when tipranavir is started. Adjust the erlotinib dose as needed.

Estrogens, estrogen-containing hormonal contraceptives

Concurrent use may decrease ethinyl estradiol 50%. Use alternative methods of nonhormonal contraception. Monitor patients taking estrogen-based hormone replacement therapy for signs of estrogen deficiency. Patients also may have an increased risk of rash.

Eszopiclone

Eszopiclone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Close monitoring is indicated when eszopiclone is coadministered with tipranavir. Consider reducing the eszopiclone dose when coadministered with tipranavir.

Fluticasone

Concomitant use of fluticasone and tipranavir/ritonavir may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. This combination is not recommended unless the potential benefit outweighs the risk of systemic corticosteroid adverse reactions.

Garlic

Garlic may reduce tipranavir plasma concentrations, decreasing the pharmacologic effects. Avoid garlic ingestion.

Loperamide

Coadministration may decrease the concentrations of both tipranavir and loperamide. Monitor tipranavir concentrations and the response of the patient. If an interaction is suspected, adjust therapy as indicated.

Maraviroc

Maraviroc plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the response of the patient and adjust the maraviroc dose as needed.

Midazolam (IV)

Increased risk of prolonged or increased sedation or respiratory depression. Monitor closely and adjust dose of midazolam as needed.

Nevirapine

Tipranavir plasma concentrations may be reduced, decreasing the efficacy. Monitor tipranavir concentrations and the clinical response of the patient when nevirapine is started or stopped. Adjust the tipranavir dose as needed.

NRTIs (eg, abacavir, didanosine, zidovudine)

Didanosine and zidovudine may decrease tipranavir concentrations. Plasma levels of NRTIs may be decreased. The clinical relevance is currently unknown. Separate didanosine dosing from tipranavir/ritonavir by at least 2 h.

Omeprazole

Omeprazole dosage may need to be increased when coadministered with tipranavir and ritonavir.

Opioid analgesics (eg, meperidine, methadone)

Interactions with these agents have not been studied; however, methadone and meperidine concentrations may be reduced, decreasing the pharmacologic effect. The concentrations of the meperidine metabolite, normeperidine, may be elevated, increasing the risk of seizures. Dosage increase and long-term use of meperidine is not recommended.

Phosphodiesterase type 5 inhibitors (ie, sildenafil, tadalafil, vardenafil)

Although not studied, coadminister with caution. The phosphodiesterase type 5 inhibitor dose should not exceed the following: sildenafil 25 mg within 48 h, tadalafil 10 mg every 72 h, vardenafil 2.5 mg every 72 h.

Protease inhibitors (ie, amprenavir, lopinavir, saquinavir)

Protease inhibitor concentrations may be decreased. Coadministration is not recommended.

Protein-tyrosine kinase inhibitors (eg, dasatinib, sunitinib, sorafenib)

Protein-tyrosine kinase inhibitor plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the response of the patient and adjust the protein-tyrosine kinase inhibitor dose as needed.

Quetiapine

Quetiapine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the response of the patient and adjust the quetiapine dose as needed.

Ranolazine

Ranolazine plasma concentrations may be elevated, increasing the risk of dose-related prolongation of the QTc interval, torsades de pointes–type arrhythmias, and sudden death. Coadministration of ranolazine and other potent or moderate CYP3A4 inhibitors such as tipranavir/ritonavir is contraindicated.

Rifabutin

Coadministration of tipranavir with rifabutin may increase concentrations of rifabutin and its metabolite. Reduce rifabutin dose 75% (eg, 150 mg every other day) and increase monitoring.

SSRIs (ie, fluoxetine, paroxetine, sertraline)

Although not studied, SSRI dose may need to be adjusted upon initiation of tipranavir/ritonavir.

Tenofovir

Coadministration may decrease the concentrations of both tipranavir and tenofovir. Monitor tenofovir and tipranavir concentrations and the response of the patient. If an interaction is suspected, adjust therapy as indicated.

Trazodone

Concomitant use of trazodone and tipranavir/ritonavir may increase plasma concentrations of trazodone. If trazodone is used with a CYP3A4 inhibitor such as tipranavir/ritonavir, use the combination with caution and consider a lower dose of trazodone.

Valproic acid

Valproic acid plasma concentrations may be reduced, decreasing the efficacy. Use with caution.

Vasopressin receptor antagonists (eg, conivaptan, tolvaptan)

Vasopressin receptor antagonist plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Warfarin

Although not studied, monitor the INR frequently upon initiation of tipranavir/ritonavir.

Adverse Reactions

The following adverse reactions were reported in patients receiving tipranavir/ritonavir.

Cardiovascular

Intracranial hemorrhage (less than 2%).

CNS

Fatigue (6%); headache (5%); insomnia, peripheral neuropathy (2%); dizziness, malaise, sleep disorder, somnolence (less than 2%).

Dermatologic

Rash (3%); acquired lipodystrophy, exanthema, lipoatrophy, lipohypertrophy, pruritus (less than 2%).

GI

Diarrhea (15%); nausea (9%); vomiting (6%); abdominal pain (4%); abdominal pain upper (2%); abdominal distension, anorexia, decreased appetite, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis (less than 2%).

Genitourinary

Renal insufficiency (less than 2%).

Hematologic-Lymphatic

Anemia (3%); neutropenia (2%); thrombocytopenia (less than 2%).

Hepatic

Cytolytic hepatitis, hepatic failure, hepatic steatosis, hepatitis, hyperbilirubinemia, toxic hepatitis (less than 2%).

Lab Tests

Increased triglycerides (36%); increased cholesterol (16%); increased ALT (15%); increased AST (10%); increased amylase (6%); decreased WBC (5%); GGT increased (2%); abnormal liver function tests, increased hepatic enzymes, increased lipase (less than 2%).

Metabolic-Nutritional

Hypertriglyceridemia (4%); hyperlipidemia, weight decreased (3%); dehydration (2%); diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity (less than 2%).

Musculoskeletal

Myalgia (2%); muscle cramps (less than 2%).

Respiratory

Cough (6%); dyspnea (2%).

Miscellaneous

Pyrexia (8%); hypersensitivity, influenza-like illness (less than 2%).

Precautions

Warnings

Tipranavir coadministered with 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 C coinfection because of increased risk of hepatotoxicity. Tipranavir administration with ritonavir has been associated with fatal and nonfatal intracranial hemorrhage.


Monitor

Assess liver function prior to initiating therapy and frequently thereafter for duration of treatment. Monitor patient for signs or symptoms of hepatitis (eg, acholic stools, anorexia, bilirubinuria, fatigue, hepatomegaly, jaundice, liver tenderness, malaise, nausea). Perform cholesterol and triglyceride testing prior to starting therapy and at periodic intervals during therapy.


Pregnancy

Category C .

Lactation

Undetermined. HIV-infected mothers should not breast-feed infants to avoid risking potential transmission of HIV to infant.

Children

Risk-benefit has not been established in children younger than 2 yr of age.

Elderly

Exercise caution in the administration and monitoring of tipranavir, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hepatic Function

Use with caution in patients with mild hepatic impairment (Child-Pugh class A). Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Special Risk Patients

Use with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions, or who are receiving medication known to increase the risk of bleeding (eg, antiplatelet drugs, anticoagulants, supplemental high doses of vitamin E).

Coadministration with ritonavir

Tipranavir must be coadministered with ritonavir to exert its therapeutic effects.

Diabetes mellitus/hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes, and hyperglycemia have been reported in patients receiving protease inhibitor therapy.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance, have been reported.

Hemophilia

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, and increased need for factor VIII have been reported in patients with hemophilia A and B treated with protease inhibitors.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

Lipid elevations

Large increases in total cholesterol and triglycerides have been reported.

Rash

Mild to moderate rashes, including urticarial, maculopapular, possible photosensitivity, and rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus, have been reported.

Sulfa allergy

Tipranavir contains a sulfonamide moiety. Use with caution in patients with known sulfonamide allergy.

Vitamin E

Patients should not take supplemental vitamin E more than a standard multivitamin because tipranavir oral solution contains vitamin E higher than the Reference Daily Intake.

Overdosage

Symptoms

None known.

Patient Information

  • Advise patient or caregiver to read the patient information leaflet before starting therapy and with each refill.
  • Instruct patient that a dose of ritonavir must be taken at the same time as each dose of the tipranavir in order to ensure max benefit. Caution patient that taking tipranavir by itself can result in therapeutic failure.
  • Instruct patient to take tipranavir exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Advise patient to take tipranavir with or without food. Caution patient to swallow capsules whole and not to crush, chew, or open.
  • Advise patient that if a dose is missed, to take the dose as soon as possible and then return to normal schedule. However, if a dose is skipped, caution patient not to double the dose to catch up, but to continue with normal schedule.
  • Instruct patient to discontinue therapy and immediately seek medical evaluation if signs or symptoms of clinical hepatitis develop (eg, appetite loss, dark urine, frequent or persistent nausea, general body discomfort or flu-like symptoms, pale stools, persistent fatigue, tenderness or swelling in right side of stomach area below ribs, yellowing of skin or eyes).
  • Inform patients that tipranavir coadministered with ritonavir has been associated with reports of both fatal and nonfatal intracranial hemorrhage. Instruct patients to report any unusual or unexplained bleeding to health care provider.
  • Advise patient that tipranavir may cause changes in body fat distribution (eg, increased amount of fat in upper back and neck, breasts, and around the back, chest, and stomach area; or loss of fat from arms, legs, and face) and that the cause and long-term health effects of these changes are not know at this time. Advise patient to report changes in body fat distribution to health care provider.
  • Inform patient that tipranavir does not completely eliminate HIV-1 virus and, therefore, does not reduce risk of transmitting HIV-1 to others. Appropriate precautions (eg, practice safe sex using a latex or polyurethane condom to lower chance of sexual contact with semen, vaginal secretions, or blood; not using or sharing dirty needles) must still be followed.
  • Advise patient that tipranavir is not a cure for HIV-1 infection, and illnesses associated with HIV-1 infection, including opportunistic infections, may continue to be acquired. Patient should remain under health care provider's care.
  • Instruct patient not to take any prescription or OTC medications, herbal preparations, or dietary supplements, particularly St. John's wort, unless advised by health care provider. Caution patient not to start any new medication or dietary supplement without talking to health care provider first.
  • Instruct patients with diabetes to monitor blood glucose more frequently when drug is started and to inform health care provider of significant changes in readings.
  • Advise women using estrogen-based hormonal contraceptives to use additional or alternative contraceptive measures during therapy with tipranavir/ritonavir. Also, patients may have a greater chance of developing a rash while using estrogen-based hormonal contraceptives.
  • Caution HIV-infected mother that breast-feeding could cause HIV-1 infection in the baby.
  • Advise patients taking tipranavir oral solution not to take supplemental vitamin E more than a standard multivitamin because tipranavir oral solution, when taken at the max recommended dose, contains more than the Reference Daily Intake of vitamin E.
  • Inform patients that rash, including flat or raised rashes or sensitivity to the sun, have been reported and that some patients who developed rash may also experience joint pain/stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin.
  • Tell patients to report any history of sulfa allergy to health care provider.

Copyright © 2009 Wolters Kluwer Health.

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