Tipranavir (Monograph)

Brand name: Aptivus
Drug class: HIV Protease Inhibitors
VA class: AM800
Chemical name: 2-Pyridinesulfonamide, –(3-[[1R]-1-[[6R]-5,6-dihydro-4-hydroxy-2-oxo-6-[2-phenylethyl]-6-propyl-2H-pyran-3-yl]propyl]phenyl)-5-(trifluoromethyl)-
Molecular formula: C₃₁H₃₃F₃N₂O₅S
CAS number: 174484-41-4

Medically reviewed by Drugs.com on Feb 26, 2024. Written by ASHP.

Warning

Clinical hepatitis and hepatic decompensation, including some fatalities, reported.¹ (See Hepatic Effects under Cautions.)
Extra vigilance warranted in HIV-infected patients with chronic HBV or HCV coinfection since these individuals are at increased risk of hepatotoxicity.¹ (See Hepatic Impairment under Cautions.)
Intracranial hemorrhage, including some fatalities, reported.¹ (See Intracranial Hemorrhage under Cautions.)

Introduction

Antiretroviral; HIV protease inhibitor (PI).¹ ⁴

Uses for Tipranavir

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥2 years of age.¹ Must be used in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretrovirals.¹

Used in patients who are antiretroviral-experienced and infected with HIV-1 resistant to multiple HIV PIs.¹

Not labeled by FDA for initial treatment in antiretroviral-naive patients,¹ and use in such patients is not recommended.²⁰⁰

Not recommended for initial treatment in antiretroviral-naive adults and adolescents because of inferior virologic efficacy and higher rate of adverse events compared with other ritonavir-boosted PIs and because higher ritonavir dosage required for boosting plasma tipranavir concentrations compared with other PIs.²⁰⁰

Not recommended for initial treatment in antiretroviral-naive pediatric patients because higher ritonavir dosage required for boosting plasma tipranavir concentrations compared with other ritonavir-boosted PIs and rare, but serious, adverse events reported (i.e., intracranial hemorrhage).²⁰¹

Consider the following factors when initiating ritonavir-boosted tipranavir: Use with other active antiretrovirals is associated with greater likelihood of treatment response; genotypic or phenotypic viral resistance testing and/or treatment history should guide therapy; number of baseline primary PI mutations affects virologic response to the drug; caution advised in patients at increased risk of hepatotoxicity or bleeding or in patients receiving certain drugs concomitantly.¹ (See Cautions and see Interactions.)

Tipranavir Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).¹ ²⁰⁰ Do not use without low-dose ritonavir.¹ ²⁰⁰

Take tipranavir and low-dose ritonavir at same time.¹

If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.¹

If tipranavir is taken with ritonavir tablets, take the drugs with a meal.¹

Capsules

Swallow tipranavir capsules whole;¹ do not chew.¹

Assess children for ability to swallow capsules;¹ consider oral solution in those unable to reliably swallow capsules.¹

Oral Solution

Use oral solution in those who have difficulty swallowing capsules.¹

Oral solution is a clear yellow viscous liquid;¹ supplied with an oral dispensing syringe.¹

Dosage

Pediatric Patients

Treatment of HIV Infection

Oral

Dosage is based on body weight or body surface area.¹ To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.¹

Children 2–18 years of age: 14 mg/kg (375 mg/m²) twice daily with ritonavir 6 mg/kg (150 mg/m²) twice daily.¹ If this dosage is not tolerated due to adverse effects, consider reducing dosage to 12 mg/kg (290 mg/m²) twice daily with ritonavir 5 mg/kg (115 mg/m²) twice daily provided the virus is not resistant to multiple HIV PIs.¹

Adults

Treatment of HIV Infection

Oral

500 mg twice daily with low-dose ritonavir (200 mg twice daily).¹

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Do not exceed adult dosage.¹

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not necessary.¹

Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.¹

Renal Impairment

Renal clearance of tipranavir negligible;¹ decreased total body clearance not expected in renal impairment.¹ Some experts state dosage adjustment not necessary.²⁰⁰

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Tipranavir

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C).¹
Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, certain antiarrhythmics, cisapride, ergot alkaloids, lurasidone, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], oral midazolam, triazolam, lovastatin, simvastatin).¹ (See Specific Drugs under Interactions.)
Concomitant use with potent CYP3A inducers (e.g., rifampin, St. John’s wort [Hypericum perforatum]) since such use may result in decreased plasma concentrations of tipranavir and possible loss of virologic response.¹ (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Mild to moderate rash, including maculopapular rash and possible photosensitivity reactions reported.¹ Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus also reported.¹ Discontinue if severe rash occurs.¹

Rash reported in healthy, HIV-negative women who received a single dose of ethinyl estradiol followed by ritonavir-boosted tipranavir.¹ ⁶ (See Estrogens/Progestins under Interactions.)

Sulfonamide Sensitivity

Tipranavir contains a sulfonamide moiety;¹ use with caution in patients with known sulfonamide allergy.¹ Potential for cross-sensitivity between drugs with sulfonamide moieties and tipranavir unknown.¹

Hepatic Effects

Hepatitis and hepatic decompensation (including some fatalities) reported;¹ causal relationship not established.¹ Hepatotoxicity generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs.¹

Increased concentrations of serum hepatic transaminases (grade 3 and 4) reported.¹

Evaluate hepatic function prior to and frequently during treatment.¹ HIV-infected patients with coexisting HBV or HCV infection or elevated serum transaminases prior to therapy may be at increased risk for hepatotoxicity, including further transaminase increases or hepatic decompensation.¹

Discontinue if signs or symptoms of hepatitis develop, if asymptomatic increases in serum AST or ALT of >10 times the ULN occur, or if asymptomatic increases in AST or ALT of 5–10 times the ULN and increases in total bilirubin of >2.5 times the ULN develop.¹

Clinicians and patients should be vigilant for appearance of signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, acholic stools, liver tenderness, hepatomegaly).¹ (See Hepatic Impairment under Cautions.)

Intracranial Hemorrhage

Intracranial hemorrhage (including some fatalities) reported.¹ ⁹ Other medical conditions or concomitant therapy may have caused or contributed to these events.¹ ⁹

Ritonavir-boosted tipranavir therapy generally not associated with abnormal coagulation parameters; abnormal coagulation parameters have not preceded intracranial hemorrhage.¹ ⁹

Manufacturer states that routine monitoring of coagulation parameters not necessary.¹

Interactions

Tipranavir must be used with low-dose ritonavir (ritonavir-boosted tipranavir).¹ Failure to administer with recommended low-dose ritonavir will result in subtherapeutic tipranavir concentrations and inadequate antiviral response.¹ Consider the usual cautions, precautions, and contraindications associated with ritonavir.¹

Concomitant use with certain drugs is not recommended or requires particular caution.¹ ²⁰⁰ (See Specific Drugs under Interactions.) Consider potential for drug interactions prior to and during ritonavir-boosted tipranavir therapy.¹ Review all drugs patient is receiving and monitor for adverse effects.¹

Effects on Platelets and Coagulation

Tipranavir inhibits platelet aggregation in vitro.¹

Caution advised in patients who may be at risk for increased bleeding from trauma, surgery, or other medical conditions; those receiving concomitant drugs known to increase the risk of bleeding (i.e., anticoagulants, antiplatelet agents); and those receiving high-dose vitamin E.¹

Vitamin E

Each mL of tipranavir oral solution contains 116 units of vitamin E.¹ Vitamin E content of usual dosages of this formulation exceeds recommended daily intake.¹

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.¹

Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.¹ (See Specific Drugs under Interactions.)

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii], reactivation of herpes simplex and herpes zoster); this may necessitate further evaluation and treatment.¹

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance.¹ Mechanism and long-term consequences of fat redistribution unknown; causal relationship not established.¹

Lipid Effects

Increased concentrations of total serum cholesterol and triglycerides reported.¹

Determine serum cholesterol and triglyceride concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.¹ (See HMG-CoA Reductase Inhibitors under Interactions.)

Hemophilia A and B

Spontaneous bleeding reported with HIV PIs;¹ causal relationship not established.¹

Use with caution in patients with history of hemophilia A or B.¹ Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.¹

HIV Resistance

Potential for cross-resistance with other HIV PIs not evaluated.¹ Effect of ritonavir-boosted tipranavir therapy on subsequent therapy with other HIV PIs unknown.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].¹ ²⁰²

Some experts state data insufficient to recommend routine use of ritonavir-boosted tipranavir for initial treatment in antiretroviral-naive pregnant women.²⁰²

Lactation

Not known whether distributed into milk.⁶ ²⁰²

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹

Adverse effects reported in children generally similar to those reported in adults;¹ rash reported more frequently in children than in adults.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Use with caution since tipranavir concentrations may be increased.¹

Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C).¹ ²⁰⁰

Risk for further elevations in hepatic enzyme concentrations or severe liver disease in HIV-infected patients with chronic HBV or HCV coinfection or increased AST or ALT concentrations prior to therapy.¹ (See Hepatic Effects under Cautions.)

Common Adverse Effects

Diarrhea, nausea, pyrexia, fatigue, vomiting, headache, abdominal pain.¹

Drug Interactions

Drug interaction studies were conducted using ritonavir-boosted tipranavir.¹

Tipranavir metabolized principally by CYP3A4.¹

Tipranavir with low-dose ritonavir inhibits CYP3A and 2D6.¹

Tipranavir is a P-glycoprotein (P-gp) substrate and is both a weak inhibitor and potent inducer of P-gp transport system.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 with possible alteration in metabolism of tipranavir, ritonavir, and/or other drug.¹

Drugs Affecting or Affected by P-glycoprotein Transport

Pharmacokinetic interactions likely with drugs that are P-gp inhibitors or inducers with possible altered metabolism of tipranavir or the other drug.¹

Specific Drugs

Drug	Interaction	Comments
Abacavir	Decreased abacavir AUC;¹ clinical importance unknown¹ In vitro evidence of additive antiretroviral effects ¹	Appropriate dosages for concomitant use with respect to safety and efficacy not established ¹ ²⁰⁰
Alfuzosin	Increased alfuzosin concentrations expected and risk of hypotension¹ ²⁰⁰	Concomitant use contraindicated¹ ²⁰⁰
Antacids	Decreased tipranavir concentrations and AUC¹	Administer ritonavir-boosted tipranavir 2 hours before or 1 hour after antacids²⁰⁰
Antiarrhythmic agents (amiodarone, disopyramide, dofetilide, dronedarone, flecainide, lidocaine, mexiletine, propafenone, quinidine)	Amiodarone, disopyramide, dofetilide, flecainide, lidocaine, mexiletine, propafenone, quinidine: Possible increased concentrations of antiarrhythmic agents¹ ²⁰⁰ Dronedarone: Increased dronedarone concentrations expected²⁰⁰	Amiodarone, flecainide, propafenone, quinidine: Concomitant use contraindicated¹ ²⁰⁰ Disopyramide, dofetilide, lidocaine, mexiletine: Experts state do not use concomitantly;²⁰⁰ consider alternative antiarrhythmic agent or antiretroviral²⁰⁰ Dronedarone: Experts state concomitant use contraindicated²⁰⁰
Anticoagulants, oral	Potential for increased risk of bleeding¹ Apixaban, rivaroxaban: Increased concentrations of the anticoagulant expected²⁰⁰ Betrixaban, dabigatran, edoxaban: Possible increased concentrations of the anticoagulant²⁰⁰ Warfarin: Possible altered warfarin concentrations;²⁰⁰ potential for serious and/or life-threatening bleeding¹	Apixaban: Experts state concomitant use not recommended, consider alternative antiretroviral or warfarin;²⁰⁰ if concomitant use necessary, reduce apixaban dosage by 50% and monitor for apixaban toxicity²⁰⁰ Betrixaban, edoxaban, rivaroxaban: Experts state concomitant use not recommended;²⁰⁰ consider alternative antiretroviral or warfarin²⁰⁰ Dabigatran: Experts state consider alternative antiretroviral or warfarin;²⁰⁰ if concomitant use necessary, administer dabigatran and ritonavir-boosted tipranavir at the same time²⁰⁰ Warfarin: Use with caution;¹ monitor INR, especially when initiating or discontinuing ritonavir-boosted tipranavir;¹ ²⁰⁰ adjust warfarin dosage as needed²⁰⁰
Anticonvulsants (carbamazepine, eslicarbazepine, ethosuximide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, valproic acid)	Carbamazepine: Possible increased carbamazepine concentrations; possible decreased tipranavir concentrations¹ ²⁰⁰ Eslicarbazepine, oxcarbazepine: Possible decreased tipranavir concentrations²⁰⁰ Ethosuximide: Possible increased ethosuximide concentrations²⁰⁰ Lamotrigine: Possible decreased lamotrigine concentrations²⁰⁰ Phenobarbital, phenytoin: Possible decreased tipranavir concentrations;¹ ²⁰⁰ possible decreased phenytoin concentrations²⁰⁰ Valproic acid: Possible decreased valproic acid concentrations¹ ²⁰⁰	Carbamazepine, phenobarbital, phenytoin: Use with caution;¹ consider alternative anticonvulsant;²⁰⁰ if used concomitantly, monitor anticonvulsant and tipranavir concentrations and virologic response²⁰⁰ Eslicarbazepine, oxcarbazepine: Experts state consider alterative anticonvulsant or antiretroviral;²⁰⁰ if concomitant use necessary, monitor virologic response and consider anticonvulsant and tipranavir concentration monitoring²⁰⁰ Ethosuximide: Monitor clinically for ethosuximide toxicities²⁰⁰ Lamotrigine: Experts state increased lamotrigine dosage may be needed;²⁰⁰ consider lamotrigine concentration monitoring or consider alternative anticonvulsant²⁰⁰ Valproic acid: Use concomitantly with caution;¹ monitor valproate concentrations and virologic response²⁰⁰
Antifungals, azoles	Fluconazole: Increased tipranavir concentrations and AUC;¹ ²⁰⁰ no clinically important effect on fluconazole concentrations¹ Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and altered tipranavir concentrations²⁰⁰ Itraconazole, ketoconazole: Increased antifungal concentrations¹ Posaconazole: Possible increased posaconazole and tipranavir concentrations²⁰⁰ Voriconazole: Altered voriconazole concentration¹ ²⁰⁰	Fluconazole: Fluconazole dosage adjustment not needed, but fluconazole dosage >200 mg daily not recommended;¹ ²⁰⁰ if high fluconazole dosage indicated, consider an alternative HIV PI or antiretroviral agent from another class²⁰⁰ Isavuconazonium: Monitor for tipranavir- and isavuconazole-associated adverse effects and virologic efficacy;²⁰⁰ consider monitoring isavuconazole concentrations²⁰⁰ Itraconazole: Use concomitantly with caution;¹ ²⁰⁰ itraconazole dosage >200 mg daily not recommended unless dosage guided by itraconazole concentration monitoring¹ ²⁰⁰ Ketoconazole: Use concomitantly with caution;¹ ketoconazole dosage >200 mg daily not recommended ¹ Posaconazole: Monitor for tipranavir-associated adverse effects;²⁰⁰ consider monitoring for posaconazole-associated adverse effects and consider posaconazole concentration monitoring²⁰⁰ Voriconazole: Do not use concomitantly unless potential benefits outweigh risks;²⁰⁰ if used, consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly²⁰⁰
Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)	Bedaquiline: Increased bedaquiline concentrations;²⁰⁰ clinical importance unknown²⁰⁰ Rifabutin: Increased rifabutin concentrations; no change in tipranavir concentrations²⁰⁰ ¹ Rifampin: Possible decreased tipranavir concentrations; possible decreased antiretroviral activity and increased risk of tipranavir resistance¹ ²⁰⁰ Rifapentine: Possible decreased tipranavir concentrations²⁰⁰	Bedaquiline: Use concomitantly with caution and monitor for QT_c interval prolongation and liver dysfunction²⁰⁰ Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 3 times weekly (further reduction may be needed); increase monitoring for adverse effects;¹ ²⁰⁰ monitor for antimycobacterial response and consider therapeutic drug monitoring²⁰⁰ Rifampin: Concomitant use contraindicated ¹ Rifapentine: Do not use concomitantly²⁰⁰
Antiplatelet agents	Potential for increased risk of bleeding¹ Ticagrelor, vorapaxar: Increased antiplatelet concentrations expected²⁰⁰	Use concomitantly with caution¹ Ticagrelor, vorapaxar: Concomitant use not recommended;²⁰⁰ experts state consider alternative antiretroviral²⁰⁰
Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)	Lurasidone: Increased lurasidone concentrations expected;²⁰⁰ potential for serious and/or life-threatening adverse effects¹ Perphenazine, risperidone, thioridazine: Possible increased concentrations of the antipsychotic²⁰⁰ Pimozide: Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)¹ Quetiapine: Increased quetiapine concentrations expected¹ ²⁰⁰	Lurasidone: Concomitant use contraindicated¹ Perphenazine, risperidone, thioridazine: Experts state initiate antipsychotic using lowest dosage, adjust maintenance dosage as needed, and monitor for antipsychotic-associated adverse effects²⁰⁰ Pimozide: Concomitant use contraindicated¹ Quetiapine: Consider alternative antiretroviral to avoid increased quetiapine exposures;¹ if concomitant use necessary, initiate quetiapine at lowest dosage and titrate as needed;²⁰⁰ if initiating ritonavir-boosted tipranavir in patient receiving quetiapine, reduce quetiapine to one-sixth of original dosage;¹ ²⁰⁰ monitor for quetiapine efficacy and adverse effects²⁰⁰
Atazanavir	Ritonavir-boosted tipranavir: Decreased atazanavir concentrations and AUC and increased tipranavir concentrations and AUC¹ In vitro evidence of additive to antagonistic antiretroviral effects¹	Atazanavir (with or without low-dose ritonavir): Concomitant use not recommended¹
Avanafil	Possible increased avanafil concentrations and increased risk of avanafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)¹ ²⁰⁰	Experts state concomitant use not recommended²⁰⁰
Benzodiazepines	Midazolam, triazolam: Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)¹ ²⁰⁰ Alprazolam, clonazepam, diazepam: Possible increased benzodiazepine concentrations²⁰⁰	Midazolam, triazolam: Concomitant use with oral midazolam or triazolam contraindicated;¹ some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation²⁰⁰ Alprazolam, clonazepam, diazepam: Consider alternative benzodiazepines with less potential for interaction (e.g., lorazepam, oxazepam, temazepam)²⁰⁰
β-Adrenergic blocking agents (atenolol, carvedilol, labetalol, metoprolol, nadolol, timolol, sotalol)	Carvedilol, metoprolol, timolol: Possible increased concentrations of the β-blocker²⁰⁰	Carvedilol, metoprolol, timolol: Clinical monitoring recommended and reduced dosage of the β-blocker may be needed;²⁰⁰ experts state consider use of alternatives not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol)²⁰⁰
Bosentan	Possible increased bosentan concentrations¹	In patients already receiving ritonavir-boosted tipranavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability¹ ²⁰⁰ In patients already receiving bosentan, discontinue bosentan for ≥36 hours prior to initiating ritonavir-boosted tipranavir; after ≥10 days of ritonavir-boosted tipranavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability¹ ²⁰⁰
Buprenorphine, buprenorphine and naloxone	Buprenorphine or fixed combination of buprenorphine and naloxone (buprenorphine/naloxone): Decreased tipranavir concentrations;¹ ²⁰⁰ no effect on clinical efficacy of buprenorphine/naloxone¹	Buprenorphine or buprenorphine/naloxone: Dosage adjustments cannot be recommended;¹ consider monitoring tipranavir concentrations²⁰⁰ If transmucosal buprenorphine is switched to buprenorphine implant, monitor to ensure buprenorphine effects are adequate and not excessive²⁰⁰
Bupropion	Decreased bupropion AUC²⁰⁰	Titrate bupropion dosage based on clinical response²⁰⁰
Buspirone	Increased buspirone concentrations expected²⁰⁰	Use low buspirone dosage with caution and titrate based on clinical response²⁰⁰
Calcifediol	Possible increased calcifediol concentrations²⁰⁰	Experts state calcifediol dosage adjustment may be required;²⁰⁰ closely monitor serum concentrations of 25-hydroxyvitamin D, intact parathyroid hormone, and calcium²⁰⁰
Calcium-channel blocking agents (e.g., diltiazem, felodipine, nicardipine, nisoldipine, verapamil)	Altered concentrations of calcium-channel blocking agents ¹ ²⁰⁰	Use concomitantly with caution; clinical monitoring recommended¹ ²⁰⁰
Colchicine	Increased colchicine concentrations¹	Patients with renal or hepatic impairment: Concomitant use with ritonavir-boosted tipranavir contraindicated¹ Patients with normal renal or hepatic function: Dosage adjustments recommended when used with ritonavir-boosted tipranavir¹ Colchicine for treatment of gout flares: In those receiving ritonavir-boosted tipranavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later¹ Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted tipranavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily¹ Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted tipranavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)¹
Cisapride	Potential for serious and/or life-threatening effects such as cardiac arrhythmias ¹	Concomitant use contraindicated¹
Clarithromycin	Slightly increased clarithromycin concentrations; decreased hydroxyclarithromycin concentrations; increased tipranavir concentrations¹ ²⁰⁰	Modification of usual dosage of clarithromycin or tipranavir not necessary in patients with normal renal function; reduce clarithromycin dosage by 50% if Cl_cr 30–60 mL/minute and reduce by 75% if Cl_cr <30 mL/minute¹ ²⁰⁰
Corticosteroids (beclomethasone, betamethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone)	Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected²⁰⁰ Budesonide, ciclesonide, fluticasone, mometasone (orally inhaled, intranasal): Increased corticosteroid concentrations possible;¹ ²⁰⁰ may result in adrenal insufficiency or Cushing's syndrome²⁰⁰ Betamethasone, methylprednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations possible;²⁰⁰ may result in adrenal insufficiency or Cushing's syndrome²⁰⁰ Betamethasone or budesonide (systemic): Decreased tipranavir concentrations possible;²⁰⁰ increased corticosteroid concentrations, which may result in adrenal insufficiency or Cushing's syndrome²⁰⁰ Dexamethasone (systemic): Possible decreased tipranavir concentrations and increased dexamethasone concentrations²⁰⁰ Prednisolone or prednisone (systemic): Increased corticosteroid concentrations possible;²⁰⁰ may result in adrenal insufficiency or Cushing's syndrome²⁰⁰	Beclomethasone (orally inhaled, intranasal): Dosage adjustments not necessary²⁰⁰ Budesonide, ciclesonide, fluticasone, mometasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of inhaled or intranasal corticosteroid outweigh risks of systemic corticosteroid adverse effects;¹ ²⁰⁰ consider alternative (e.g., beclomethasone)²⁰⁰ Betamethasone, methylprednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly²⁰⁰ Betamethasone or budesonide (systemic): Do not use concomitantly unless potential benefits outweigh risks of systemic corticosteroid adverse effects²⁰⁰ Dexamethasone (systemic): Consider alternative corticosteroid for long-term use;²⁰⁰ if concomitant use necessary, monitor virologic response²⁰⁰ Prednisolone or prednisone (systemic): Consider concomitant use only if potential benefits outweigh risks of systemic corticosteroid adverse effects;²⁰⁰ if concomitant use necessary, monitor for adrenal insufficiency, Cushing's syndrome, and other corticosteroid-associated adverse effects²⁰⁰
Daclatasvir	Data not available²⁰⁰
Darunavir	No in vitro evidence of antagonistic antiretroviral effects ²⁰⁴
Dasabuvir, ombitasvir, paritaprevir, and ritonavir	Fixed combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir (dasabuvir/ombitasvir/paritaprevir/ritonavir) or fixed combination of ombitasvir, paritaprevir, and ritonavir copackaged with dasabuvir (ombitasvir/paritaprevir/ritonavir with dasabuvir): Data not available²⁰⁰	Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): Experts state do not use concomitantly²⁰⁰
Delavirdine	In vitro evidence of additive antiretroviral effects ¹
Didanosine	Decreased didanosine concentrations and decreased tipranavir concentrations¹ In vitro evidence of additive antiretroviral effects ¹	For optimal absorption, administer didanosine at least 2 hours before or after tipranavir ¹ ²⁰⁰
Digoxin	Possible increased digoxin concentrations²⁰⁰	Use concomitantly with caution;²⁰⁰ titrate digoxin dosage and monitor digoxin concentrations²⁰⁰
Disulfiram	Potential pharmacokinetic interaction with alcohol contained in tipranavir capsules; possible disulfiram-like reaction¹
Dolutegravir	Decreased dolutegravir concentrations and AUC²⁰⁰ ²³⁶	In integrase strand transfer inhibitor-naive (INSTI-naive) patients, use dolutegravir 50 mg twice daily;¹ in INSTI-experienced patients with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted tipranavir whenever possible²³⁶
Dronabinol	Possible increased dronabinol concentrations²⁰⁰	Experts state monitor for dronabinol-associated adverse effects²⁰⁰
Dutasteride	Possible increased dutasteride concentrations²⁰⁰	Experts state adjust dutasteride dosage as needed based on clinical effects and endogenous hormone concentrations²⁰⁰
Elbasvir and grazoprevir	Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Increased grazoprevir concentrations expected;¹⁷⁷ ²⁰⁰ possible increased risk of ALT elevations¹⁷⁷ ²⁰⁰	Elbasvir/grazoprevir: Concomitant use contraindicated¹⁷⁷ ²⁰⁰
Eluxadoline	Increased eluxadoline concentrations expected²⁰⁰	Experts state use eluxadoline 75 mg twice daily and monitor for eluxadoline-associated adverse effects²⁰⁰
Eplerenone	Increased eplerenone concentrations expected²⁰⁰	Experts state concomitant use contraindicated²⁰⁰
Efavirenz	Decreased tipranavir concentrations and no change in efavirenz concentrations using tipranavir 500 mg twice daily and ritonavir 100 mg twice daily with efavirenz 600 mg once daily¹ In vitro evidence of additive antiretroviral effects ¹	Some experts state dosage adjustments not necessary²⁰⁰
Elvitegravir and cobicistat	Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF) or fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Possible altered or suboptimal concentrations of elvitegravir, cobicistat, and/or tipranavir²⁰⁰	EVG/c/FTC/TAF or EVG/c/FTC/TDF: Do not use concomitantly²⁰⁰
Emtricitabine	In vitro evidence of additive antiretroviral effects ¹
Enfuvirtide	Increased tipranavir trough concentrations¹ In vitro evidence of synergistic antiretroviral effects¹	Dosage adjustments not recommended¹
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)	Potential for serious or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)¹	Concomitant use contraindicated ¹ If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving tipranavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible²⁰²
Estrogens and progestins	Conjugated estrogens (equine or synthetic), estradiol: Possible decreased estrogen concentrations²⁰⁰ Drospirenone, medroxyprogesterone, progesterone: Possible increased progestin concentrations²⁰⁰ Ethinyl estradiol and norelgestromin (transdermal): Data not available²⁰⁰ Etonogestrel (subdermal implant): Data not available²⁰⁰ Oral contraceptives containing ethinyl estradiol and norethindrone: Decreased ethinyl estradiol concentrations; no effect on norethindrone concentrations¹ ²⁰⁰	Conjugated estrogens (equine or synthetic): Adjust estrogen dosage based on clinical effects²⁰⁰ Estradiol: Monitor for estrogen deficiency;¹ adjust estrogen dosage based on clinical effects and endogenous hormone concentrations²⁰⁰ Drospirenone, medroxyprogesterone, progesterone: Adjust progestin dosage as needed based on clinical effects²⁰⁰ Ethinyl estradiol and norelgestromin (transdermal): Consider alternative or additional contraceptive or alternative antiretroviral²⁰⁰ Etonogestrel (subdermal implant): Consider alternative or additional contraceptive or alternative antiretroviral²⁰⁰ Oral contraceptives containing ethinyl estradiol and norethindrone: Consider alternative nonhormonal or additional contraception methods¹ ²⁰⁰
Etravirine	Decreased etravirine concentrations and possible decreased antiretroviral efficacy; increased tipranavir concentrations²⁰⁰ ²¹⁴ No in vitro evidence of antagonistic antiretroviral effects²¹⁴	Do not used concomitantly²⁰⁰ ²¹⁴
Fentanyl	Possible increased fentanyl concentrations²⁰⁰	Carefully monitor for fentanyl therapeutic and adverse effects, including potentially fatal respiratory depression²⁰⁰
Finasteride	Pharmacokinetic interaction not expected²⁰⁰	Experts state dosage adjustment not necessary²⁰⁰
Flibanserin	Increased flibanserin concentrations expected²⁰⁰	Experts state concomitant use contraindicated²⁰⁰
Fosamprenavir	Possible decreased amprenavir concentrations¹	Concomitant use not recommended¹
Glecaprevir and pibrentasvir	Fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir): Increased glecaprevir and pibrentasvir concentrations expected²⁰⁰	Glecaprevir/pibrentasvir: Experts state do not use concomitantly²⁰⁰
Goserelin	Pharmacokinetic interaction not expected²⁰⁰	Experts state dosage adjustments not necessary²⁰⁰
HMG-CoA reductase inhibitors (statins)	Atorvastatin, lovastatin, rosuvastatin, simvastatin: Increased concentrations and AUCs of the antilipemic agent and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis¹ ¹⁸⁶ ²⁰⁰	Atorvastatin: Avoid concomitant use¹ ¹⁸⁶ ²⁰⁰ Lovastatin: Concomitant use contraindicated¹ ¹⁸⁶ ²⁰⁰ Pitavastatin: Dosage adjustments not necessary²⁰⁰ Rosuvastatin: Dosage adjustments not necessary²⁰⁰ Simvastatin: Concomitant use contraindicated¹ ¹⁸⁶ ²⁰⁰
Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)	Potential for altered or increased immunosuppressive agent concentrations¹ ²⁰⁰	Adjust dosage of immunosuppressive agent to account for potential increased concentrations and monitor for immunosuppressive agent-associated adverse effects;²⁰⁰ monitor plasma concentrations of immunosuppressive agent¹ ²⁰⁰
Ivabradine	Increased ivabradine concentrations expected²⁰⁰	Experts state concomitant use contraindicated²⁰⁰
Lamivudine	Pharmacokinetic interactions unlikely¹ In vitro evidence of additive antiretroviral effects¹
Ledipasvir and sofosbuvir	Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Decreased ledipasvir and sofosbuvir concentrations expected;¹⁸¹ ²⁰⁰ possible reduced HCV antiviral effects¹⁸¹	Ledipasvir/sofosbuvir: Concomitant use not recommended¹⁸¹ ²⁰⁰
Leuprolide	Pharmacokinetic interactions not expected²⁰⁰	Experts state dosage adjustments not necessary²⁰⁰
Loperamide	Decreased loperamide concentrations; no clinically important change in tipranavir concentrations¹
Lopinavir and ritonavir	Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Decreased lopinavir concentrations and AUC¹ In vitro evidence of additive to antagonistic or additive to synergistic antiretroviral effects¹	Lopinavir/ritonavir: Concomitant use not recommended¹ ²⁰⁰
Maraviroc	No clinically important effect on maraviroc pharmacokinetics²⁰⁰ ²²⁴ No in vitro evidence of antagonistic antiretroviral effects ²²⁴	Recommended maraviroc dosage is 300 mg twice daily when used with ritonavir-boosted tipranavir, provided regimen does not include a potent CYP3A inhibitor or inducer¹⁴ ²⁰⁰ ²²⁴
Meperidine	Potential for decreased meperidine concentrations, increased normeperidine concentrations ¹	Manufacturer of tipranavir does not recommend increasing meperidine dosage or concomitant long-term use because of potential for increased normeperidine concentrations and possible analgesic and CNS-stimulating activity (e.g., seizures) ¹
Methadone	Decreased methadone concentrations;¹ opiate withdrawal unlikely but may occur²⁰⁰	Methadone dosage adjustment may be necessary;¹ monitor for opioid withdrawal and increase methadone dosage as clinically indicated²⁰⁰
Metronidazole	Potential interaction with alcohol present in tipranavir capsules; possible disulfiram-like reaction¹
Nelfinavir	In vitro evidence of additive to antagonistic antiretroviral effects¹
Nevirapine	No clinically important effect on nevirapine concentrations;¹ ²⁰⁰ effect on tipranavir concentrations unknown²⁰⁰ In vitro evidence of additive antiretroviral effects ¹	Dosage adjustments not necessary²⁰⁰
Omeprazole	Decreased omeprazole concentrations; no change in tipranavir concentrations¹	Experts state concomitant use not recommended;²⁰⁰ if concomitant use necessary, consider increased omeprazole dosage based on clinical response¹ ²⁰⁰
Oral antidiabetic agents	Canagliflozin: Decreased canagliflozin concentrations expected²⁰⁰ Glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide: Potential for altered concentrations of antidiabetic agents¹ Saxagliptin or fixed combination of dapagliflozin and saxagliptin (dapagliflozin/saxagliptin): Increased saxagliptin concentrations expected²⁰⁰	Canagliflozin: If patient with estimated GFR >60 mL/minute per 1.73 m² receiving canagliflozin 100 mg daily requires additional glycemic control, experts state consider increasing canagliflozin dosage to 300 mg daily²⁰⁰ Glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide: Careful glucose monitoring warranted ¹ Saxagliptin or dapagliflozin/saxagliptin: Use saxagliptin dosage of 2.5 mg once daily;²⁰⁰ do not use dapagliflozin/saxagliptin since the fixed combination contains 5 mg of saxagliptin²⁰⁰
Oxycodone	Possible increased oxycodone concentrations²⁰⁰	Experts state monitor for oxycodone-associated adverse effects;²⁰⁰ oxycodone dosage reduction may be necessary²⁰⁰
Raltegravir	Decreased raltegravir concentrations and AUC¹	Raltegravir (Isentress): Dosage adjustments not needed¹ ²⁰⁰ Raltegravir 600-mg film-coated tablets (Isentress HD) : Concomitant use not recommended²⁰⁰ ²²⁵
Ranolazine	Increased ranolazine concentrations expected²⁰⁰	Experts state concomitant use contraindicated²⁰⁰
Rilpivirine	Possible increased rilpivirine concentrations; not expected to affect tipranavir concentrations¹ ²²⁶ No in vitro evidence of antagonistic antiretroviral effects ²²⁶	Dosage adjustments not necessary²⁰⁰
Ritonavir	Increased tipranavir concentrations and AUC;¹ ²⁰⁰ concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted tipranavir)¹
St. John’s wort (Hypericum perforatum)	Potential decreased tipranavir concentrations; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance¹	Concomitant use contraindicated¹
Salmeterol	Possible increased salmeterol concentrations and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia¹	Concomitant use not recommended¹
Saquinavir	Decreased saquinavir concentrations and AUC¹ In vitro evidence of additive to antagonistic antiretroviral effects¹	Concomitant use not recommended¹
Selective serotonin-reuptake inhibitors (SSRIs)	Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Specific data not available;²⁰⁰ possible increased SSRI concentrations¹ Fluvoxamine: Possible altered (increased or decreased) tipranavir concentrations²⁰⁰	Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Titrate SSRI dosage based on clinical response¹ ²⁰⁰ Fluvoxamine: Experts state consider alternative to fluvoxamine²⁰⁰
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)¹	Sildenafil for treatment of pulmonary arterial hypertension (PAH): Concomitant use with ritonavir-boosted tipranavir contraindicated¹ Sildenafil for treatment of erectile dysfunction: Do not exceed sildenafil dosage of 25 mg once every 48 hours; closely monitor for sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)¹
Simeprevir	Possible altered (increased or decreased) simeprevir concentrations due to CYP3A4 inhibition or induction by HIV PI¹⁸⁷	Concomitant use not recommended.¹⁸⁷ ²⁰⁰
Sofosbuvir	Decreased concentrations of sofosbuvir and metabolite (GS-331007) expected; may result in decreased sofosbuvir therapeutic effects ¹⁸⁸ ²⁰⁰	Concomitant use not recommended¹⁸⁸ ²⁰⁰
Sofosbuvir and velpatasvir	Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): Decreased sofosbuvir and velpatasvir concentrations expected¹⁷⁶ ²⁰⁰	Sofosbuvir/velpatasvir: Do not use concomitantly¹⁷⁶ ²⁰⁰
Sofosbuvir, velpatasvir, and voxilaprevir	Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): Decreased sofosbuvir and velpatasvir concentrations expected;¹⁷⁴ ²⁰⁰ effect on voxilaprevir not known¹⁷⁴ ²⁰⁰	Sofosbuvir/velpatasvir/voxilaprevir: Do not use concomitantly¹⁷⁴ ²⁰⁰
Spironolactone	Pharmacokinetic interaction not expected²⁰⁰	Experts state dosage adjustments not necessary²⁰⁰
Stavudine	Pharmacokinetic interaction unlikely¹ In vitro evidence of additive antiretroviral effects ¹
Suvorexant	Increased suvorexant concentrations expected²⁰⁰	Experts state concomitant use not recommended²⁰⁰
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)¹	Tadalafil for treatment of PAH in patients who have been receiving ritonavir-boosted tipranavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, may increase dosage to 40 mg once daily¹ Ritonavir-boosted tipranavir in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating ritonavir-boosted tipranavir; after ≥1 week of the antiretroviral agent, may resume tadalafil at dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily¹ Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection, syncope)¹ Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily²⁰⁰
Tenofovir	Decreased tenofovir concentrations and AUC; possible decreased tipranavir concentrations and AUC¹ ²⁰⁰ In vitro evidence of additive antiretroviral effects¹	Dosage adjustments not necessary²⁰⁰
Testosterone	Possible decreased testosterone concentrations²⁰⁰	Experts state adjust testosterone dosage as needed based on clinical effects and endogenous hormone concentrations²⁰⁰
Trazodone	Possible increased trazodone concentrations and AUC¹ ²⁰⁰ Increased risk of trazodone-associated adverse effects (e.g., nausea, dizziness, hypotension, syncope)¹	Use with caution;¹ consider reduced trazodone dosage;¹ use lowest possible trazodone dosage and monitor for CNS and cardiovascular adverse effects²⁰⁰
Tricyclic antidepressants (amitriptyline, doxepin, desipramine, imipramine, nortriptyline)	Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Possible increased concentrations of the tricyclic antidepressant¹ ²⁰⁰	Amitriptyline, imipramine, doxepin, nortriptyline: Use lowest possible antidepressant dosage; titrate antidepressant dosage based on clinical assessment and/or antidepressant concentrations²⁰⁰ Desipramine: Use reduced desipramine dosage and monitor plasma desipramine concentrations¹
Valacyclovir	No clinically important effect on tipranavir or acyclovir concentrations or AUC¹
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)¹	Vardenafil for treatment of erectile dysfunction: Do not exceed vardenafil dosage of 2.5 mg once every 72 hours; closely monitor for vardenafil-related adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)¹
Vitamin E	Potential for increased risk of bleeding with high-dose vitamin E¹	Use concomitantly with caution¹
Zidovudine	Decreased zidovudine AUC;¹ ²⁰⁰ clinical importance unknown¹ ²⁰⁰ In vitro evidence of additive antiretroviral effects¹	Appropriate dosage for concomitant use not established ¹ ²⁰⁰
Zolpidem	Possible increased zolpidem concentrations²⁰⁰	Experts state initiate zolpidem using low dosage;²⁰⁰ reduced dosage may be needed²⁰⁰

Tipranavir Pharmacokinetics

Absorption

Bioavailability

Tipranavir is administered concomitantly with low-dose ritonavir (ritonavir-boosted tipranavir).¹ Ritonavir decreases metabolism of tipranavir, resulting in increased tipranavir plasma concentrations.¹

Following >2 weeks of multiple oral doses given without regard to meals, peak plasma tipranavir concentrations attained approximately 3 hours after a dose.¹

Steady state attained in most patients after 7–10 days.¹ Steady-state trough concentrations are 70% lower than day 1, presumably due to intestinal P-gp induction.¹

Food

Compared with administration in the fasting state, administration of tipranavir (as capsules or oral solution) and ritonavir (as capsules) with a meal (500–682 kcal, 23–25% calories from fat) does not have a clinically important effect on tipranavir peak plasma concentrations or AUC.¹

Effect of food on administration of tipranavir (as capsules or oral solution) with ritonavir (as tablets) not evaluated.¹

Distribution

Extent

Not known whether distributed into CSF or semen.¹

Not known whether distributed into milk.¹ ²⁰²

Plasma Protein Binding

>99%.¹

Binds to albumin and α₁-acid-glycoprotein.¹

Elimination

Metabolism

Tipranavir extensively metabolized by CYP3A4.¹ Only minimal metabolism of tipranavir occurs when administered with ritonavir 200 mg.¹

Oral clearance of tipranavir decreased when administered with ritonavir; this may indicate decreased first-pass effect.¹

Elimination Route

Following administration of ritonavir-boosted tipranavir, eliminated principally in feces as unchanged tipranavir.¹ Approximately 82% of tipranavir dose excreted in feces and 4% excreted in urine.¹

Half-life

Effective mean elimination half-life at steady-state is 4.8–6 hours following administration of ritonavir-boosted tipranavir with a light meal.¹

Special Populations

Renal impairment: Pharmacokinetics not studied, but decreased total body clearance not expected since renal clearance of tipranavir is negligible.¹

Mild hepatic impairment (Child-Pugh class A): Increased plasma concentrations, but dosage adjustments not needed.¹

Moderate or severe impairment (Child-Pugh class B and C): Pharmacokinetics not evaluated.¹

Higher tipranavir concentrations reported in females compared with males; dosage adjustments not required.¹

Stability

Storage

Oral

Capsules

2–8°C prior to opening bottle;¹ after opening bottle, store at 25°C (may be exposed to 15–30°C) and use within 60 days.¹

Oral Solution

25°C (may be exposed to 15–30°C);¹ do not refrigerate or freeze.¹ After opening bottle, use within 60 days.¹

Actions and Spectrum

Tipranavir must be administered in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).¹
Tipranavir is extensively metabolized by CYP3A; ritonavir is a potent inhibitor of CYP3A.¹ Concomitant use of these drugs results in decreased metabolism and increased plasma concentrations of tipranavir.¹
Antiretroviral activity is due to tipranavir.¹
Active against HIV-1;¹ has some in vitro activity against HIV-2.¹³
Tipranavir inhibits replication of HIV-1 by interfering with HIV proteases.¹
Tipranavir-resistant HIV-1, including strains with decreased susceptibility to other HIV PIs, has been reported.¹

Advice to Patients

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.¹ Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.¹
Importance of using tipranavir with low-dose ritonavir (ritonavir-boosted tipranavir); importance of using these 2 drugs in conjunction with other antiretrovirals.¹
Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.¹ Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.¹
Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.²⁰⁰ Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.¹ ²⁰⁰
Importance of reading patient information provided by the manufacturer.¹
Importance of taking tipranavir at the same time as ritonavir.¹ If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.¹ If tipranavir is taken with ritonavir tablets, take the drugs with a meal.¹
Importance of swallowing tipranavir capsules whole; capsules should not be chewed.¹
If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.¹ If a dose is skipped, do not take a double dose to make up for the missed dose.¹
Importance of patient informing their clinician if they are allergic to sulfonamides.¹
Possibility of fatal or nonfatal intracranial hemorrhage.¹ Importance of informing clinician of unusual or unexplained bleeding.¹
Advise patients that severe liver disease (including fatalities) reported.¹ Importance of discontinuing ritonavir-boosted tipranavir and seeking medical attention if signs or symptoms of liver disease (fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, hepatomegaly) occur.¹
Need for periodic clinical and laboratory monitoring, including liver function tests, prior to and during treatment.¹ Importance of extra vigilance in HIV-infected patients with chronic HBV or HCV coinfection because of increased risk of hepatotoxicity.¹
Possibility of rash.¹ Importance of discontinuing ritonavir-boosted tipranavir and seeking medical attention if rash with or without joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or skin peeling occurs.¹
Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., vitamin E supplements) and herbal products (e.g., St. John’s wort), and any concomitant illnesses.¹
Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician.¹ Ritonavir-boosted tipranavir should not be used concomitantly with sildenafil used for treatment of pulmonary arterial hypertension (PAH).¹
Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.¹
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise HIV-infected women not to breast-feed.¹
Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tipranavir
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	250 mg	Aptivus	Boehringer Ingelheim
	Solution	100 mg/mL	Aptivus	Boehringer Ingelheim

References

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4. Croom KF, Keam SJ. Tipranavir: a ritonavir-boosted protease inhibitor. Drugs. 2005; 65:1669-77. http://www.ncbi.nlm.nih.gov/pubmed/16060700?dopt=AbstractPlus

5. MacGregor TR, Sabo JP, Norris SH et al. Pharmacokinetic characteristics of different dose combinations of coadministered tipranavir and ritonavir in healthy volunteers. HIV Clin Trials. 2004; 5:371-82. http://www.ncbi.nlm.nih.gov/pubmed/15682350?dopt=AbstractPlus

6. Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT: Personal communication.

7. Hicks C, RESIST-1 study team. RESIST-1: A phase 3, randomized, controlled, open-label, multicenter trial comparing tipranavir/ritonavir (TPV/r) to an optimized comparator protease inhibitor/r (CPI/r) regimen in antiretroviral (ARV) experienced patients: 2- week data. Proceedings of ICAAC, Washington, DC 2004. http://www.medadvocates.org

8. Cahn P, RESIST-2 study team. 24-week data from RESIST-2: Phase 3 study of the efficacy and safety of background therapy plus tipranavir/ritonavir (TPV/r) or optimized ritonavir-boosted standard-of-care (SOC) comparator PI (CPI) in a large randomized multicenter trial in treatment-experienced HIV+ patients. 7th International Congress on Drug Therapy in HIV Infection. Glasgow 2004 http://www.hivandhepatitis.com

9. Shepard KV. Dear Healthcare Professional: Important safety information regarding intracranial hemorrhage in patients receiving Aptivus (tipranavir) capsules. Ridgefield, CT: Boehringer Ingelheim; 2006 Jun 30.

12. Reddy SS. Dear healthcare professional letter. Results of pharmacokinetic study in healthy volunteers given Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. West Point, PA: Merck; 2012 Feb 6. http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf

13. Desbois D, Roquebert B, Peytavin G et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. 2008; 52:1545-8. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2292533&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/18227188?dopt=AbstractPlus

14. Pfizer, New York, NY: Personal communication regarding maraviroc.

17. Food and Drug Administration. FDA drug safety communication: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. 2012 Feb 8. From FDA website. Accessed 2012 Apr 23. http://www.fda.gov/Drugs/DrugSafety/ucm291119.htm

18. Food and Drug Administration. FDA drug safety communication: Updated information on drug interactions between Victrelis (boceprevir) and certain boosted HIV protease inhibitor drugs. 2012 Apr 26. From FDA website. Accessed 2012 Jul 9. http://www.fda.gov/Drugs/DrugSafety/ucm301616.htm

174. Gilead Sciences. Vosevi (sofosbuvir, velpatasvir, voxilaprevir) tablets prescribing information. Foster City, CA; 2017 Jul.

176. Gilead Sciences. Epclusa (sofosbuvir and velpatasvir) tablets prescribing information. Foster City, CA; 2017 Aug.

177. Merck & Co., Inc. Zepatier (elbasvir and grazoprevir) tablets prescribing information. Whitehouse Station, NJ; 2017 Feb.

181. Gilead Sciences. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2017 Apr.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm

187. Janssen Therapeutics. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2017 May.

188. Gilead Sciences Inc. Sovaldi (sofosbuvir) tablet prescribing information. Foster City, CA; 2017 Apr.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 17, 2017). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 27, 2017). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

202. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States (November 14, 2017). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

204. Janssen Therapeutics. Prezista (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2017 Jun.

214. Janssen Therapeutics. Intelence (etravirine) tablets prescribing information. Titusville, NJ; 2014 Aug.

224. ViiV Healthcare. Selzentry (maraviroc) tablets and oral solution prescribing information. Research Triangle Park, NC; 2016 Nov.

225. Merck & Co.. Isentress (raltegravir) film-coated tablets, chewable tablets, and for oral suspension and Isentress HD (raltegravir) film-coated tablets prescribing information. Whitehouse Station, NJ; 2017 May.

226. Janssen Therapeutics. Edurant (rilpivirine) tablets prescribing information. Titusville, NJ; 2015 Aug.

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2017 Mar.