Tipranavir (Monograph)

Brand name: Aptivus
Drug class: HIV Protease Inhibitors

Medically reviewed by Drugs.com on Feb 10, 2025. Written by ASHP.

Introduction

Antiretroviral; HIV protease inhibitor (PI).

Uses for Tipranavir

Treatment of HIV Infection

Treatment of HIV-1 infection in adult and pediatric patients weighing ≥36 kg. Must be used in combination with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretrovirals.

Used in patients who are antiretroviral-experienced and infected with HIV-1 resistant to >1 HIV protease inhibitors (PIs).

Should not be used in antiretroviral-naive patients.

Tipranavir was previously used in combination with ritonavir (ritonavir-boosted) as part of a fully suppressive antiretroviral regimen. Current guidelines do not recommend its use due to inferior virological efficacy and toxicities. Consult guidelines for the most current information on recommended regimens. Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.

Tipranavir Dosage and Administration

General

Pretreatment Screening

• Perform liver function testing (e.g., serum AST, ALT, bilirubin).

• Use genotype or phenotype testing and consider treatment history to guide the use of ritonavir-boosted tipranavir. Ritonavir-boosted tipranavir should not be used in antiretroviral-naive patients.

• Evaluate serum triglyceride and cholesterol concentrations; manage lipid disorders as clinically appropriate.

Patient Monitoring

• Monitor liver function (e.g., serum AST, ALT, bilirubin) frequently during treatment and monitor for signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, hepatomegaly).

• Monitor for bleeding in patients with hemophilia.

• Monitor for persistent hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus. It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).

• Monitor serum triglyceride and cholesterol concentrations periodically during therapy with ritonavir-boosted tipranavir; manage lipid disorders as clinically appropriate.

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.

Other General Considerations

• Use of other antiretroviral agents active against HIV-1 with ritonavir-boosted tipranavir is associated with a greater likelihood of treatment response.

• Use ritonavir-boosted tipranavir with caution in patients with elevated AST or ALT, in the presence of hepatitis B or C co-infection, and in patients with mild hepatic impairment (Child-Pugh Class A).

• Use ritonavir-boosted tipranavir with caution in patients with known hypersensitivity to sulfonamide-containing drugs.

• Use ritonavir-boosted tipranavir with caution in patients at an increased risk for bleeding, or in those receiving concomitant medications that increase bleeding risk.

Administration

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

Take tipranavir and low-dose ritonavir at same time with a meal.

Swallow tipranavir capsules whole; do not open or chew. Assess children for ability to swallow capsules before prescribing.

Dosage

Pediatric Patients

Treatment of HIV Infection

Oral

Antiretroviral-experienced children weighing ≥36 kg: 500 mg twice daily with low-dose ritonavir (200 mg twice daily).

Adults

Treatment of HIV Infection

Oral

Antiretroviral-experienced: 500 mg twice daily with low-dose ritonavir (200 mg twice daily).

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not necessary. Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. Select dosage with caution.

Cautions for Tipranavir

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).

• 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).

• 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.

Warnings/Precautions

Warnings

Hepatotoxicity

Hepatitis and hepatic decompensation (including some fatalities) reported; causal relationship not established (see Boxed Warning). Hepatotoxicity generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs. Increased concentrations of serum hepatic transaminases (grade 3 and 4) reported.

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

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.

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).

Intracranial Hemorrhage

Intracranial hemorrhage (including some fatalities) reported (see Boxed Warning). Other medical conditions or concomitant therapy may have caused or contributed to these events. Ritonavir-boosted tipranavir therapy generally not associated with abnormal coagulation parameters; abnormal coagulation parameters have not preceded intracranial hemorrhage. Manufacturer states that routine monitoring of coagulation parameters not necessary.

Other Warnings/Precautions

Rash

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

Discontinue drug and administer appropriate treatment if severe rash occurs. Concomitant estrogen-containing oral contraceptives or estrogens for hormone replacement therapy may increase risk for developing non-serious rash.

Concomitant estrogen-containing oral contraceptives or estrogens for hormone replacement therapy may increase risk for developing non-serious rash.

Sulfonamide Allergy

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

Importance of Co-administration with Ritonavir

Tipranavir must be used with low-dose ritonavir (ritonavir-boosted tipranavir) and administered with a meal to achieve adequate antiviral response. Failure to administer with recommended low-dose ritonavir and meals will result in subtherapeutic tipranavir concentrations and inadequate antiviral response.

Consider the usual cautions, precautions, and contraindications associated with ritonavir.

Risk of Serious Adverse Reactions Due to Drug Interactions

Concomitant use with certain drugs is not recommended or requires particular caution or dosage adjustments.

Consider potential for drug interactions prior to and during ritonavir-boosted tipranavir therapy. Review all drugs patient is receiving and monitor for adverse effects.

Effects on Platelet Aggregation and Coagulation

Tipranavir inhibits platelet aggregation in vitro. 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.

Diabetes Mellitus/Hyperglycemia

Hyperglycemia (potentially persistent), new-onset diabetes mellitus or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred. Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.

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.

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.

Fat Redistribution

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

Elevated Lipids

Increased concentrations of total serum cholesterol and triglycerides reported. Determine serum cholesterol and triglyceride concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.

Patients with Hemophilia

Spontaneous bleeding reported with HIV PIs; causal relationship not established. Use with caution in patients with history of hemophilia A or B. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.

Resistance/Cross-resistance

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

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry available at 800-258-4263 or [Web]. Data insufficient to adequately assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Lactation

Not known whether distributed into human milk or if drug has any effects on breastfed infant or milk production; distributed into milk in rats.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

Females and Males of Reproductive Potential

Potential for reduced efficacy of concomitantly administered estrogen-containing oral contraceptives.

Advise patients receiving an estrogen-based oral contraceptive to use additional or alternative nonhormonal contraceptives.

Pediatric Use

Safety and efficacy established in children weighing ≥36 kg who are antiretroviral-experienced with HIV-1 strains resistant to >1 protease inhibitor. Adverse effects reported in children ≥36 kg generally similar to those reported in adults; rash reported more frequently in children than in adults.

Safety and efficacy established in children ≥2 years of age weighing <36 kg. Not recommended in this population due to lack of suitable pediatric formulation of the drug.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Use with caution since tipranavir concentrations may be increased. Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C). 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.

Renal Impairment

Pharmacokinetics not evaluated in renal impairment. Renal clearance is negligible; decreased clearance not expected in patients with renal impairment.

Common Adverse Effects

Adverse effects (>4%) in adults receiving ritonavir-boosted tipranavir in conjunction with other antiretroviral agents: diarrhea, nausea, pyrexia, fatigue, vomiting, headache, abdominal pain.

Adverse effects reported in pediatric patients were generally similar to those observed in adults, except for the incidence of rash, which occurred more frequently in pediatric patients.

Drug Interactions

Drug interaction studies were conducted using ritonavir-boostedtipranavir.

Tipranavir metabolized principally by CYP3A4.

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

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

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.

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.

Specific Drugs

Tipranavir Pharmacokinetics

Absorption

Bioavailability

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

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

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

Food

Effect of food on administration of tipranavir with ritonavir (as tablets) not evaluated.

Distribution

Extent

Not known whether distributed into CSF or semen.

Not known whether distributed into human milk; distributed into animal milk.

Plasma Protein Binding

>99%.

Binds to albumin and α₁-acid-glycoprotein.

Elimination

Metabolism

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

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

Elimination Route

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

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.

Special Populations

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

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

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

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

Stability

Storage

Oral

Capsules

2–8°C prior to opening bottle; after opening bottle, store at 20–25°C (excursions permitted to 15–30°C) and use within 60 days.

Actions

• Tipranavir is administered in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir). Tipranavir is extensively metabolized by CYP3A and ritonavir is a potent inhibitor of CYP3A. Concomitant use of these drugs results in decreased metabolism and increased plasma concentrations of tipranavir.

• Antiretroviral activity is due to tipranavir.

• Active against HIV-1.

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

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

Advice to Patients

• Advise patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Stress importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

• Use tipranavir with low-dose ritonavir (ritonavir-boosted tipranavir); stress importance of using these 2 drugs in conjunction with other antiretrovirals.

• Advise patients to take tipranavir at the same time as ritonavir with a meal.

• If a dose is missed, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time. If a dose is skipped, a double dose should not be taken to make up for the missed dose.

• Stress importance of patients informing their clinician if they are allergic to sulfonamides.

• Possibility of fatal or nonfatal intracranial hemorrhage. Stress importance of informing clinician if unusual or unexplained bleeding develops.

• Advise patients that severe liver disease (including fatalities) has been reported. Stress 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.

• Need for periodic clinical and laboratory monitoring, including liver function tests, prior to and during treatment. Stress importance of extra vigilance in patients with chronic HBV or HCV coinfection because of increased risk of hepatotoxicity.

• Possibility of rash. Stress 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.

• Inform patients that redistribution/accumulation of body fat may occur with antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., PDE5 inhibitors) and over-the-counter (OTC) drugs (e.g., vitamin E supplements) and herbal products (e.g., St. John’s wort), and any concomitant illnesses.

• Advise women to use a reliable nonhormonal (e.g., barrier) method of contraception due to the potential interaction with estrogen-based hormonal contraceptives.

• Stress importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed. Inform patients that an antiretroviral pregnancy registry is available that monitors fetal outcomes of infants exposed to tipranavir. Providers can register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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