Tipranavir

Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: 2-Pyridinesulfonamide, N - (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
Brands: Aptivus

• 
  

  Concomitant administration of tipranavir and low-dose ritonavir (200 mg) associated with intracranial hemorrhage, including some fatalities.¹

  
  


• 
  

  Concomitant administration of tipranavir and low-dose ritonavir (200 mg) associated with clinical hepatitis and hepatic decompensation, including some fatalities.¹

  
  


• 
  

  Extra vigilance warranted in HIV patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection because of increased risk of hepatotoxicity.¹

  
  

Introduction

Antiretroviral; HIV protease inhibitor (PI).^{1 4}

Uses for Tipranavir

Treatment of HIV Infection

Treatment of HIV infection.¹ Used in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretroviral agents.¹

Ritonavir-boosted tipranavir used in patients who are highly treatment-experienced or infected with HIV-1 resistant to multiple PIs.¹

Use of ritonavir-boosted tipranavir in conjunction with other active antiretroviral agents associated with greater likelihood of treatment response.¹

Use of ritonavir-boosted tipranavir should be guided by genotypic and phenotypic viral resistance testing and the individual’s prior antiretroviral treatment.¹

Prior to initiation of therapy, consider drug interaction potential of ritonavir-boosted tipranavir and patient factors that may increase risk of bleeding or hepatotoxicity.¹ (See Interactions and see Warnings and also Hepatic Impairment under Cautions.)

Use of ritonavir-boosted tipranavir not recommended in treatment-naive individuals.¹

Risks versus benefits of ritonavir-boosted tipranavir not established in pediatric patients <2 years of age.¹

Tipranavir Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).^{1 2} Do not use without low-dose ritonavir.^{1 2}

Take tipranavir and low-dose ritonavir at same time and with food.^{1 2}

Swallow tipranavir capsules whole; do not chew.³

Children: Oral solution can be used.¹ Alternatively, children who can reliably swallow a capsule may receive capsules.¹ To avoid medication errors, use extra care in calculating the dose, transcribing the medication order, and dispensing the prescription.¹

Dosage

Pediatric Patients

Treatment of HIV Infection

Oral

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 PIs.¹

Adults

Treatment of HIV Infection

Oral

500 mg twice daily boosted with low-dose ritonavir (200 mg twice daily).^{1 2}

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Do not exceed adult dosage.¹

Special Populations

Hepatic Impairment

Dosage adjustment not needed in mild hepatic impairment (Child-Pugh class A).¹ Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C).^{1 2}

Renal Impairment

Renal clearance of tipranavir negligible; decreased total body clearance not expected in renal impairment.¹ Some experts state dosage adjustment not necessary.²

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

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  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., certain antiarrhythmics, ergot alkaloids, cisapride, pimozide, oral midazolam, triazolam, lovastatin, simvastatin).¹ (See Specific Drugs under Interactions.)

  
  


• 
  

  Concomitant use with potent CYP3A inducers (e.g., rifampin, St. John’s wort) when such use may result in decreased plasma concentrations of tipranavir and possible loss of virologic response.¹

  
  

Warnings/Precautions

Warnings

Interactions

Tipranavir is administered concomitantly 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 and alters some drug interactions.¹ The usual cautions, precautions, and contraindications associated with ritonavir should be considered.¹

Concomitant use with certain drugs is not recommended or requires particular caution (e.g., sildenafil, tadalafil, vardenafil).^{1 2} (See Specific Drugs under Interactions.)

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 not associated with abnormal coagulation parameters; abnormal coagulation parameters have not preceded intracranial hemorrhage.^{1 9} Change in coagulation parameters (e.g., increased PT, increased aPTT, decreased vitamin K dependent factors) observed in rats given tipranavir; effects on these parameters increased in rats given concomitant vitamin E in the form of d-alpha-tocopherol polyethylene glycol 1000 succinate; changes in coagulation parameters not observed in other species (i.e., dogs) given tipranavir.¹ Manufacturer states that routine monitoring of coagulation parameters not necessary.¹

Effect 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

Hepatic Effects

Hepatitis and hepatic decompensation (including some fatalities) reported; 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 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.)

Hyperglycemic and Diabetogenic Effects

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

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

Sensitivity Reactions

Sulfonamide Sensitivity

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

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 receiving a single dose of ethinyl estradiol followed by ritonavir-boosted tipranavir.^{1 6} (See Estrogens/Progestins under Interactions.)

General Precautions

Hemophilia A and B

Spontaneous bleeding reported with PIs; 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

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

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.)

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 jiroveci [formerly P. carinii], reactivation of herpes simplex and herpes zoster); this may necessitate further evaluation and treatment.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state safety and pharmacokinetic data insufficient to recommend ritonavir-boosted tipranavir in pregnant women.¹⁰

Lactation

Not known whether distributed into milk.^{6 10}

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; 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 caution since tipranavir concentrations may be increased.¹

Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C).^{1 2}

Risk for further elevations in hepatic enzyme concentrations or severe liver disease in patients with chronic HBV or HCV 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

Interactions for Tipranavir

Drug interaction studies were conducted with ritonavir-boosted tipranavir (tipranavir 500 mg and ritonavir 200 mg).¹

Tipranavir metabolized principally by CYP3A4.¹

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

Tipranavir is a P-glycoprotein substrate and is both a weak inhibitor and potent inducer of P-glycoprotein 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

Inducers or Inhibitors of the P-glycoprotein Transport System

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

Specific Drugs

Drug	Interaction	Comments
Abacavir	Decreased abacavir AUC1 In vitro evidence of additive antiretroviral effects 1	Clinical importance unknown1 Appropriate dosages for concomitant use with respect to safety and efficacy not established 1 2
Antacids	Decreased tipranavir concentrations and AUC1	Administer ritonavir-boosted tipranavir 2 hours before or 1 hour after antacids2
Antiarrhythmic agents (amiodarone, flecainide, propafenone, quinidine)	Possible increased plasma concentrations of antiarrhythmic agents1	Concomitant use contraindicated1
Anticoagulants	Altered warfarin concentrations1 Potential for increased risk of bleeding1	Monitor INR 1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin, valproic acid)	Phenobarbital, phenytoin: Possible decreased tipranavir concentrations1 2 Carbamazepine: Possible increased carbamazepine concentrations; possible decreased tipranavir concentrations1 2 Valproic acid: Possible decreased concentrations of valproic acid1	Phenobarbital, phenytoin, valproic acid: Caution1 Carbamazepine: Caution; 1 consider use of an alternative anticonvulsant; monitor anticonvulsant concentrations and tipranavir concentrations if used concomitantly2
Antifungals (fluconazole, itraconazole, ketoconazole, voriconazole)	Fluconazole: Increased tipranavir concentrations1 Itraconazole or ketoconazole: Increased antifungal concentrations1 Voriconazole: Altered voriconazole concentration1 2	Fluconazole: No dosage adjustment needed; fluconazole dosage >200 mg daily not recommended1 Itraconazole or ketoconazole: Use concomitantly with caution; antifungal dosage >200 mg daily not recommended 1 2 Voriconazole: Concomitant use not recommended unless benefit outweighs risk2
Antimycobacterials, rifamycins (rifabutin, rifampin)	Rifabutin: Increased rifabutin concentrations; no change in tipranavir concentrations1 2 Rifampin: Possible decreased tipranavir concentrations; possible decreased antiretroviral activity and increased risk of tipranavir resistance1 2	Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 3 times weekly (further reduction may be needed); increase monitoring for adverse effects1 2 Rifampin: Concomitant use contraindicated 1 Rifapentine: Concomitant use not recommended2
Antiplatelet agents	Potential for increased risk of bleeding1
Atazanavir	Decreased atazanavir concentrations and increased tipranavir concentrations with ritonavir-boosted atazanavir1 In vitro evidence of additive or antagonistic antiretroviral effects1	Concomitant use not recommended1
Benzodiazepines	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	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 sedation2
Calcium-channel blocking agents (e.g., diltiazem, felodipine, nicardipine, nisoldipine, verapamil)	Altered concentrations of calcium-channel blocking agents 1	Use concomitantly with caution; clinical monitoring recommended1
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 2	Modification of usual dosage of clarithromycin or tipranavir not necessary in patients with normal renal function; reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute and reduce by 75% if Clcr <30 mL/minute 1 2
Corticosteroids (fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with ritonavir-boosted tipranavir resulting in decreased cortisol concentrations1 2	Fluticasone nasal spray/oral inhalation: Concomitant use with ritonavir-boosted tipranavir not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 2
Darunavir		Concomitant use of ritonavir-boosted darunavir not recommended12
Delavirdine	In vitro evidence of additive antiretroviral effects 1
Didanosine	Decreased didanosine concentrations and decreased tipranavir concentrations1 2 In vitro evidence of additive antiretroviral effects 1	For optimal absorption, administer didanosine at least 2 hours before or after tipranavir 1 2
Disulfiram	Potential pharmacokinetic interaction with alcohol contained in tipranavir capsules; possible disulfiram-like reaction1
Efavirenz	Decreased tipranavir concentrations; no change in efavirenz concentrations1 In vitro evidence of additive antiretroviral effects 1	Dosage adjustment not necessary2
Emtricitabine	In vitro evidence of additive antiretroviral effects 1
Enfuvirtide	In vitro evidence of synergistic antiretroviral effects1
Ergot alkaloids (dihydroergotamine, ergonovine, 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 possible10
Estrogens/Progestins	Hormonal contraceptives: Decreased ethinyl estradiol concentrations with oral contraceptive preparations1 2	Use alternative nonhormonal or additional contraception methods1 2 Hormone replacement: Monitor for signs of estrogen deficiency1 2
Etravirine	Decreased etravirine concentrations and increased tipranavir concentrations2 15	Concomitant use not recommended2
Fosamprenavir	Possible decreased amprenavir concentrations1 2	Concomitant use not recommended;1 2 appropriate dosages for concomitant use with respect to safety and efficacy not established2
HMG-CoA reductase inhibitors	Possible decreased clearance and increased plasma concentrations of some HMG-CoA reductase inhibitors (i.e., atorvastatin, lovastatin, simvastatin, rosuvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1 2	Concomitant use with lovastatin or simvastatin contraindicated1 2 If used with atorvastatin or rosuvastatin, use lowest possible initial dose of the HMG-CoA reductase inhibitor with careful monitoring1 2 Consider using HMG-COA reductase inhibitors with low potential for interaction (e.g., fluvastatin, pravastatin)1
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for altered immunosuppressive agent concentrations1	Monitor plasma concentrations of immunosuppressive agent if used concomitantly1
Indinavir	Data not available regarding pharmacokinetic interaction2 In vitro evidence of additive or antagonistic antiretroviral effects1	Concomitant use not recommended; appropriate dosages for concomitant use with respect to safety and efficacy not established2
Lamivudine	Pharmacokinetic interactions unlikely1 In vitro evidence of additive antiretroviral effects1
Loperamide	Decreased loperamide concentrations; no clinically important change in tipranavir concentrations1
Lopinavir	Decreased lopinavir concentrations1 2 In vitro evidence of additive or antagonistic antiretroviral effects1	Concomitant use not recommended; 1 2 appropriate dosages for concomitant use with respect to safety and efficacy not established2
Maraviroc	Pharmacokinetic interaction unlikely2 13 14	Recommended dosage of maraviroc is 300 mg twice daily, provided regimen does not include a CYP3A inhibitor or inducer2 13 14
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 concentrations1	Increased maintenance dosage of methadone may be needed 1 2
Metronidazole	Potential interaction with alcohol present in tipranavir capsules; possible disulfiram-like reaction1
Nelfinavir	Data not available regarding pharmacokinetic interaction1 In vitro evidence of additive or antagonistic antiretroviral effects1	Concomitant use not recommended; appropriate dosages for concomitant use with respect to safety and efficacy not established2
Nevirapine	Pharmacokinetic interactions unlikely 1 2 In vitro evidence of additive antiretroviral effects 1
Omeprazole	Decreased omeprazole concentrations; no change in tipranavir concentrations1 2	Consider increasing omeprazole dosage1 2
Oral antidiabetic agents (glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide)	Potential for altered plasma concentrations of antidiabetic agents1	Careful glucose monitoring warranted 1
Psychotherapeutic agents	Pimozide: Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)1 Desipramine: Possible increased desipramine concentrations1 SSRIs: Possible increased concentrations of fluoxetine, paroxetine, or sertraline1	Pimozide: Concomitant use contraindicated1 Desipramine: Consider reduction of usual desipramine dosage; monitor plasma desipramine concentrations1 SSRIs: Consider dosage adjustment of SSRI 1
Ritonavir	Increased tipranavir plasma concentrations and AUC;1 2 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted tipranavir)1 In vitro evidence of additive or antagonistic antiretroviral effects1
St. John’s wort (Hypericum perforatum)	Potential decreased tipranavir concentration; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Concomitant use contraindicated1
Saquinavir	Decreased saquinavir concentrations1 2 In vitro evidence of additive or antagonistic antiretroviral effects1	Concomitant use not recommended;1 2 appropriate dosages for concomitant use with respect to safety and efficacy not established2
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1	Do not exceed sildenafil dosage of 25 mg every 48 hours; closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 2
Stavudine	Pharmacokinetic interaction unlikely1 In vitro evidence of additive antiretroviral effects 1
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1	Use initial tadalafil dose of 5 mg; do not exceed a dosage of 10 mg once every 72 hours; closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 2
Tenofovir	Decreased tenofovir concentrations; decreased tipranavir concentrations1 2 In vitro evidence of additive antiretroviral effects1	Clinical importance unknown2
Trazodone	Possible increased trazodone concentrations1 Increased risk of trazodone-associated adverse effects (e.g., nausea, dizziness, hypotension, syncope)1	Caution; reduced trazodone dosage may be needed1
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1	Do not exceed vardenafil dosage of 2.5 mg every 72 hours; closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 2
Vitamin E	Potential for increased risk of bleeding with high-dose vitamin E1
Zidovudine	Decreased zidovudine AUC1 2 In vitro evidence of additive antiretroviral effects1	Clinical importance unknown1 2 Appropriate dosage for concomitant use not established 1 2

Tipranavir Pharmacokinetics

Absorption

Bioavailability

Tipranavir 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-glycoprotein induction.¹

Food

Compared with administration in the fasting state, administration of ritonavir-boosted tipranavir with a high-fat meal (868 kcal, 53% calories from fat) increases extent of absorption, but has minimal effect on peak plasma concentrations.¹

Distribution

Extent

Not known whether distributed into CSF or semen.¹

Not known whether distributed into milk.¹

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 Pharmacokinetics in moderate and severe impairment (Child-Pugh class B and C) 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

Actions and SpectrumActions

• 
  

  Tipranavir is 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-1¹

  
  


• 
  

  Tipranavir inhibits replication of HIV-1 by interfering with HIV proteases.¹

  
  


• 
  

  Tipranavir-resistant HIV-1, including strains with decreased susceptibility to other PIs, has been reported.¹

  
  

Advice to Patients

• 
  

  Critical nature of compliance with HIV therapy.¹ Importance of using tipranavir with low-dose ritonavir; importance of using these 2 drugs in conjunction with other antiretrovirals.¹

  
  


• 
  

  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


• 
  

  Importance of reading patient information provided by manufacturer.¹

  
  


• 
  

  Importance of taking tipranavir with food and at the same time as ritonavir.^{1 3} Importance of swallowing tipranavir capsules whole; capsules should not be chewed.³

  
  


• 
  

  If a dose is missed, take the next dose as soon as possible.^{3 6} Do not take a double dose to make up for the missed dose.³

  
  


• 
  

  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) has occurred.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 patients with chronic HBV or HCV coinfection because of increased risk of hepatotoxicity.¹

  
  


• 
  

  Possibility of rash.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).¹

  
  


• 
  

  Advise patients receiving selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE inhibitor-associated adverse effects (e.g., hypotension, visual changes, priapism) and that any symptoms should be promptly reported to their clinician.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

  
  


• 
  

  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.

Tipranavir

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	250 mg	Aptivus (with alcohol, polyoxyl 35 castor oil, and propylene glycol)	Boehringer Ingelheim
	Solution	100 mg/mL	Aptivus	Boehringer Ingelheim

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aptivus 250MG Capsules (BOEHRINGER INGELHEIM): 120/$1138.02 or 360/$3366.83

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2008 Jun.

2. Panel on Clinical Practices for Treatment of HIV infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ().