Tipranavir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Aptivus: 250 mg

Solution, Oral:

Aptivus: 100 mg/mL (95 mL) [contains polyethylene glycol, propylene glycol, tocophersolan; buttermint-butter toffee flavor]

Pharmacology

Mechanism of Action

Binds to the site of HIV-1 protease activity and inhibits cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV. This results in the formation of immature, noninfectious viral particles.

Pharmacokinetics/Pharmacodynamics

Absorption

Incomplete (percentage not established)

Distribution

V_d:

Children 2 to <6 years: 4 L

Children 6 to <12 years: 4.7 L

Children and Adolescents 12 to 18 years: 5.3 L

Adults: 7.7 to 10.2 L

Metabolism

Hepatic, via CYP3A4 (minimal when coadministered with ritonavir)

Excretion

Feces (82.3%); urine (4.4%); primarily as unchanged drug (when coadministered with ritonavir)

Time to Peak

Children and Adolescents 2 to 18 years: 2.5 to 2.7 hours; Adults: 3 hours

Half-Life Elimination

Children 2 to <6 years of age: ~8 hours, 6 to <12 years of age: ~7 hours, 12 to 18 years: ~5 hours; Adults: Males: 6 hours; Females: 5.5 hours

Protein Binding

>99.9% (albumin, alpha-1 acid glycoprotein)

Use in Specific Populations

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection in combination with ritonavir and other antiretroviral agents; limited to treatment-experienced, multiprotease inhibitor-resistant patients.

Contraindications

Coadministration of tipranavir/ritonavir with drugs highly dependent upon CYP3A for clearance or potent CYP3A inducers, including alfuzosin, amiodarone, bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, lovastatin, lurasidone, midazolam (oral), pimozide, propafenone, quinidine, rifampin, sildenafil (for pulmonary arterial hypertension [eg, Revatio]), simvastatin, St John’s wort, and triazolam; moderate-to-severe hepatic impairment (Child-Pugh class B or C)

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to tipranavir or any component of the product, concurrent therapy with colchicine, astemizole (not available in Canada), terfenadine (not available in Canada), or quetiapine.

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: 500 mg twice daily; Note: Coadministration with ritonavir (200 mg twice daily) is required.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Gene mutation and antiretroviral (ARV) resistance patterns should be evaluated (refer to https://www.iasusa.org/ for more information) when necessary.

HIV-1 infection, treatment: Note: Although FDA approved, tipranavir is no longer recommended for use in the treatment of HIV (HHS [pediatric] 2019). Use in combination with other ARV agents. Not recommended for treatment-naive patients. Coadministration with ritonavir is required; the ritonavir boosting dose with tipranavir is higher than doses used with other protease inhibitors.

Children ≥2 years and Adolescents:

Weight-directed dosing: Oral: Tipranavir 14 mg/kg (maximum: 500 mg) plus ritonavir 6 mg/kg (maximum: 200 mg) twice daily.

If intolerance or toxicity develops and virus is not resistant to multiple protease inhibitors: May decrease dose to: Tipranavir 12 mg/kg plus ritonavir 5 mg/kg twice daily; do not exceed adult doses.

BSA-directed dosing: Oral: Tipranavir 375 mg/m² (maximum: 500 mg) plus ritonavir 150 mg/m² (maximum: 200 mg) twice daily.

If intolerance or toxicity develops and virus is not resistant to multiple protease inhibitors: May decrease dose to: Tipranavir 290 mg/m²plus ritonavir 115 mg/m² twice daily; do not exceed adult doses.

Dosing: Adjustment for Toxicity

Asymptomatic patients:

AST or ALT 5 to 10 times ULN and total bilirubin >2.5 times ULN: Discontinue therapy.

AST or ALT >10 times ULN: Discontinue therapy.

Administration

Oral: Swallow tipranavir capsules whole; do not open or chew. Tipranavir must be coadministered with ritonavir. When using with ritonavir tablets, administer with food (HHS [adult] 2017). When using with ritonavir capsules or solution, administer without regard to meals (HHS [adult] 2017).

Dietary Considerations

Capsule contains dehydrated ethanol. Oral solution formulation contains vitamin E; additional vitamin E supplements should be avoided.

Storage

Capsule: Prior to opening bottle, store at 2°C to 8°C (36°F to 46°F). After bottle is opened, may be stored at 25°C (77°F) (excursions permitted to 15°C to 30°C [59°F to 86°F]) for up to 60 days.

Oral solution: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). After bottle is open, use within 60 days. Do not refrigerate or freeze oral solution.

Drug Interactions

Abacavir: Protease Inhibitors may decrease the serum concentration of Abacavir. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Tipranavir may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Monitor therapy

Alfuzosin: Protease Inhibitors may increase the serum concentration of Alfuzosin. Avoid combination

Amiodarone: Tipranavir may increase the serum concentration of Amiodarone. Avoid combination

Amphetamines: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amphetamines. Monitor therapy

Anticoagulants: Tipranavir may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Consider therapy modification

AtorvaSTATin: Tipranavir may increase the serum concentration of AtorvaSTATin. Avoid combination

Benzhydrocodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Benzhydrocodone. Monitor therapy

Bepridil: Tipranavir may increase the serum concentration of Bepridil. Avoid combination

Bosentan: May decrease the serum concentration of Tipranavir. Tipranavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking tipranavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting tipranavir/ritonavir; wait at least 10 days before restarting bosentan. Consider therapy modification

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder. Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated. Consider therapy modification

CarBAMazepine: May increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Consider therapy modification

Cholic Acid: BSEP/ABCB11 Inhibitors may decrease the excretion of Cholic Acid. Avoid combination

Cisapride: Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Avoid combination

Clarithromycin: Protease Inhibitors may diminish the therapeutic effect of Clarithromycin. Specifically, certain protease inhibitors may decrease formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness vs. H. influenzae and other non-MAC infections. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed. Clarithromycin may increase the serum concentration of Protease Inhibitors. Management: Saquinavir is contraindicated with clarithromycin. Avoid clarithromycin adult doses over 1000 mg/day with a protease inhibitor. Further dose reductions may be needed with impaired renal function. Consider alternative antimicrobial for a non-MAC infection. Consider therapy modification

CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of Tipranavir. However, the magnitude of this change is unclear, and dosing recommendations for this combination are not available. Avoid combination

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification

Colchicine: Tipranavir may increase the serum concentration of Colchicine. Management: Colchicine should not be used with tipranavir in patients with impaired renal or hepatic function. In those with normal renal and hepatic function, reduced colchicine doses (as directed) are required if used with tipranavir. Consider therapy modification

Cyclophosphamide: Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Monitor therapy

CycloSPORINE (Systemic): Protease Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors. Consider therapy modification

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Strong) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Ajmaline; Dapoxetine; Indoramin; Metoprolol; Tamoxifen; Timolol (Ophthalmic); Tropisetron. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Delavirdine: Protease Inhibitors may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Protease Inhibitors. Consider therapy modification

Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification

Dextromethorphan: Tipranavir may increase the serum concentration of Dextromethorphan. Management: Consider avoiding dextromethorphan in patients taking tipranavir. If combined, monitor closely for increased dextromethorphan effects/toxicities. Consider therapy modification

Didanosine: Tipranavir may decrease the serum concentration of Didanosine. Management: It is recommended that didanosine be administered at least 2 hours apart from tipranavir in order to minimize any potential dosage form-related interaction. Consider therapy modification

Disulfiram: May enhance the adverse/toxic effect of Tipranavir. Consider therapy modification

Dolutegravir: Tipranavir may decrease the serum concentration of Dolutegravir. Specifically, Tipranavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Tipranavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir dose to 50 mg twice daily in patients receiving tipranavir/ritonavir. Seek alternatives to tipranavir/ritonavir in INSTI experienced patients with suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Eluxadoline: Tipranavir may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with tipranavir and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Enfuvirtide: Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline; Nicergoline; Pergolide. Avoid combination

Estrogen Derivatives: May enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification

Etravirine: Tipranavir may decrease the serum concentration of Etravirine. Avoid combination

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Flecainide: Tipranavir may increase the serum concentration of Flecainide. Avoid combination

Fluconazole: May increase the serum concentration of Tipranavir. Management: Limit fluconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Consider therapy modification

Fluticasone (Oral Inhalation): Tipranavir may increase the serum concentration of Fluticasone (Oral Inhalation). Avoid combination

FluvoxaMINE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluvoxaMINE. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Fosphenytoin. Consider therapy modification

Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Monitor therapy

Garlic: May decrease the serum concentration of Protease Inhibitors. Management: Concurrent use of garlic supplements with protease inhibitors is not recommended. If this combination is used, monitor closely for altered serum concentrations/effects of protease inhibitors, and particularly for signs/symptoms of therapeutic failure. Consider therapy modification

Grazoprevir: Tipranavir may increase the serum concentration of Grazoprevir. Avoid combination

HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor. Consider therapy modification

Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Monitor therapy

Itraconazole: Tipranavir may increase the serum concentration of Itraconazole. Management: Limit itraconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): Tipranavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit ketoconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Consider therapy modification

Ledipasvir: Tipranavir may decrease the serum concentration of Ledipasvir. Avoid combination

Levomethadone: Tipranavir may decrease the serum concentration of Levomethadone. Monitor therapy

Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Monitor therapy

Lomitapide: Tipranavir may increase the serum concentration of Lomitapide. Avoid combination

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lovastatin: Protease Inhibitors may increase the serum concentration of Lovastatin. Avoid combination

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination

Methadone: Tipranavir may decrease the serum concentration of Methadone. More specifically, the combination of Tipranavir and Ritonavir may decrease Methadone serum concentrations. Monitor therapy

Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: Reduce metoclopramide dose to 5 mg 4 times daily (30 minutes before each meal and at bedtime) and limit the maximum daily dose to 20 mg if combined with strong CYP2D6 inhibitors. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Monitor therapy

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Tipranavir. A disulfiram-like reaction may occur due to the alcohol contained in tipranavir capsules. Monitor therapy

MetroNIDAZOLE (Topical): May enhance the adverse/toxic effect of Tipranavir. Monitor therapy

Midazolam: Protease Inhibitors may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy

Nefazodone: Protease Inhibitors may increase the serum concentration of Nefazodone. Management: Consider alternatives to, or reduced doses of, nefazodone in patients treated with HIV protease inhibitors. Monitor patients receiving these combinations closely for toxic effects of nefazodone. Consider therapy modification

Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy

Obeticholic Acid: BSEP/ABCB11 Inhibitors may increase serum concentrations of the active metabolite(s) of Obeticholic Acid. Management: Avoid concomitant use of obeticholic acid and bile salt efflux pump (BSEP) inhibitors if possible. If concomitant therapy is necessary, monitor patients for elevated liver transaminases and elevated bilirubin. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of PHENobarbital. Consider therapy modification

Phenytoin: May decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Phenytoin. Consider therapy modification

Pimozide: Protease Inhibitors may increase the serum concentration of Pimozide. Avoid combination

Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Consider therapy modification

Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. Management: Monitor for signs and symptoms of possible treatment failure with primaquine in patients who are taking strong CYP2D6 inhibitors. If efficacy of primaquine is compromised, may consider adjusting therapies. Consider therapy modification

Progestins (Contraceptive): Tipranavir may increase the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Propafenone: Tipranavir may increase the serum concentration of Propafenone. Avoid combination

Protease Inhibitors: Tipranavir may decrease the serum concentration of Protease Inhibitors. Exceptions: Ritonavir. Avoid combination

Protease Inhibitors: May increase the serum concentration of other Protease Inhibitors. Management: Atazanavir--indinavir combination contraindicated. Tipranavir/ritonavir or atazanavir/ritonavir not recommended with other protease inhibitors (PI). Darunavir/cobicistat not recommended with PI that require boosting.Other combos may require dose changes. Consider therapy modification

Proton Pump Inhibitors: Tipranavir may decrease the serum concentration of Proton Pump Inhibitors. These data are derived from studies with Ritonavir-boosted Tipranavir. Monitor therapy

QuiNIDine: Tipranavir may increase the serum concentration of QuiNIDine. Avoid combination

Raltegravir: Tipranavir may decrease the serum concentration of Raltegravir. Management: Concurrent use of tipranavir/ritonavir with once-daily raltegravir (Isentress HD) is not recommended. Monitor therapy

Rifabutin: Tipranavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Tipranavir may increase the serum concentration of Rifabutin. Management: Reduce rifabutin doses. Tipranavir US labeling recommends a decrease of at least 75%, to 150 mg every other day or 3 times per week for adults. Clinical guidelines recommend 150 mg daily or 300 mg 3 times per week when used with tipranavir/ritonavir. Consider therapy modification

RifAMPin: May decrease the serum concentration of Tipranavir. Avoid combination

Riociguat: Protease Inhibitors may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

Rosuvastatin: Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details. Consider therapy modification

Salmeterol: Tipranavir may increase the serum concentration of Salmeterol. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sildenafil: Protease Inhibitors may increase the serum concentration of Sildenafil. Management: Erectile dysfunction: sildenafil max = 25 mg/48 hrs with ritonavir, atazanavir, or darunavir; starting dose = 25 mg with other protease inhibitors (adult doses). Contraindicated if sildenafil being used for pulmonary arterial hypertension. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. Avoid combination

Simvastatin: Protease Inhibitors may increase the serum concentration of Simvastatin. Avoid combination

Sofosbuvir: Tipranavir may decrease the serum concentration of Sofosbuvir. Avoid combination

St John's Wort: May decrease the serum concentration of Tipranavir. Avoid combination

Tacrolimus (Systemic): Protease Inhibitors may decrease the metabolism of Tacrolimus (Systemic). Consider therapy modification

Tacrolimus (Topical): Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Tadalafil: Tipranavir may increase the serum concentration of Tadalafil. Avoid combination

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Avoid combination

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy

Temsirolimus: Protease Inhibitors may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification

Tenofovir Alafenamide: Tipranavir may decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tenofovir Disoproxil Fumarate: May decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Tetrabenazine adult dose should be reduced by 50% when starting a strong CYP2D6 inhibitor. Maximum tetrabenazine adult dose is 50 mg/day when used with a strong CYP2D6 inhibitor. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

TraMADol: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Tricyclic Antidepressants: Protease Inhibitors may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy

Tropisetron: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tropisetron. Monitor therapy

Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Monitor therapy

Valproate Products: Protease Inhibitors may decrease the serum concentration of Valproate Products. Monitor therapy

Vitamin E (Systemic): Tipranavir may enhance the adverse/toxic effect of Vitamin E (Systemic). Management: Patients taking tipranavir oral solution are advised to avoid taking additional vitamin E, beyond the amounts contained in a multivitamin product. This interaction does not apply to tipranavir capsules. Consider therapy modification

Vortioxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Consider therapy modification

Zidovudine: Protease Inhibitors may decrease the serum concentration of Zidovudine. Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Skin rash (children: 21%; adults: 3% to 10%)

Endocrine & metabolic: Hypertriglyceridemia (>400 mg/dL: 61%), hypercholesterolemia (>300 mg/dL: 22%)

Gastrointestinal: Diarrhea (15%; children: 4%)

Hepatic: Increased serum transaminases (>2.5 x ULN: 26% to 32%; grades 3/4: 10% to 20%)

Neuromuscular & skeletal: Increased creatine phosphokinase (children, grades 3/4: 11%)

1% to 10%:

Central nervous system: Fatigue (6%), headache (5%), dizziness, drowsiness, insomnia, intracranial hemorrhage, malaise, peripheral neuropathy, sleep disorder

Dermatologic: Pruritus

Endocrine & metabolic: Increased amylase (grade 3: 6% to 8%), weight loss (3%), dehydration (2%), increased gamma-glutamyl transferase (2%), diabetes mellitus, hyperglycemia, lipodystrophy (acquired), lipohypertrophy

Gastrointestinal: Nausea (5% to 9%), vomiting (6%), abdominal pain (4%), abdominal distension, anorexia, decreased appetite, dyspepsia, flatulence, gastroesophageal reflux disease, increased serum lipase, pancreatitis

Hematologic & oncologic: Hemorrhage (children: 8%), decreased white blood cell count (grade 3: 5%), anemia (3%), neutropenia (2%), thrombocytopenia

Hepatic: Increased serum ALT (2%, grades 3/4: 10%), increased serum AST (grades 3/4: 6%), hepatic failure, hepatitis, hyperbilirubinemia, liver steatosis

Hypersensitivity: Hypersensitivity reaction

Immunologic: Immune reconstitution syndrome

Neuromuscular & skeletal: Myalgia (2%), amyotrophy (facial), lipoatrophy, muscle cramps

Renal: Renal insufficiency

Respiratory: Cough (children: 6%), dyspnea (2%), epistaxis (children: 4%), flu-like symptoms

Miscellaneous: Fever (6% to 8%), drug toxicity (mitochondrial damage)

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution/accumulation of fat (eg, central obesity, buffalo hump, peripheral wasting, facial wasting, breast enlargement, cushingoid appearance).
• Hepatotoxicity: [US Boxed Warning]: Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Patients with chronic hepatitis B or C coinfection have an increased risk; use with caution. Reactions generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications. Assess liver function tests at baseline and frequently throughout treatment. Monitor patients closely, especially those with chronic hepatitis B or C coinfection; discontinue use if signs or symptoms of hepatotoxicity occur (eg, fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly) or if asymptomatic AST/ALT elevations >10 times ULN or AST/ALT elevations >5 to 10 times ULN concurrently with total bilirubin >2.5 times ULN occur.
• Hyperlipidemia: With coadministered ritonavir, increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• Intracranial hemorrhage: [US Boxed Warning]: Use has been associated with fatal and nonfatal intracranial hemorrhage. Events often occurred in patients with medical conditions (eg, CNS lesions, head trauma, recent neurosurgery, coagulopathy, alcohol abuse) or concurrent medications which may have influenced these events. No abnormal pattern of coagulation parameters has been observed in patients in general, or preceding intracranial hemorrhage development.
• Skin reactions: Has been associated with a variety of skin reactions including rash (urticarial or maculopapular) and possible photosensitivity. In some cases rash was accompanied by joint pain or stiffness, throat tightness or generalized pruritus. Rash (mild to moderate) may be more frequent in pediatric patients. Discontinue treatment if severe skin rash develops.
• Sulfonamide allergy: Use with caution in patients with sulfonamide allergy; contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir is unknown.

Disease-related concerns:

• Diabetes: Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, DKA, and new-onset diabetes mellitus have been reported in HIV-1 infected patients receiving protease inhibitors.
• Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding (including spontaneous skin hematomas and hemarthrosis) during protease inhibitor therapy has been reported.
• Hepatic impairment: Use with caution in patients with Child-Pugh class A (mild) hepatic impairment; contraindicated in Child-Pugh class B or C (moderate-to-severe) impairment.
• Platelet aggregation: May impair platelet aggregation, resulting in bleeding; use with caution in patients who may be at risk for increased bleeding (trauma, surgery, other medical conditions, or taking antiplatelet agents, anticoagulants, or supplemental high doses of vitamin E).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Ethanol: Capsules contain dehydrated alcohol 7% w/w (0.1 g per capsule).
• Vitamin E: Oral solution contains vitamin E 116 units/mL.

Monitoring Parameters

Triglycerides and total cholesterol at baseline and during therapy. Liver function tests (including bilirubin) at baseline and frequently throughout therapy; patients with chronic hepatitis B or C coinfection should be monitored closely. Monitor for symptoms of hepatotoxicity (eg, fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, acholic stools, liver tenderness or hepatomegaly). Monitor viral load, CD4, and serum glucose as clinically indicated.

Pregnancy

Pregnancy Considerations

Tipranavir crosses the placenta.

Outcome information specific to tipranavir use in pregnancy is no longer being reviewed and updated in the Health and Human Services (HHS) perinatal guidelines. Maternal antiretroviral therapy (ART) may be associated with adverse pregnancy outcomes, including preterm delivery, stillbirth, low birth weight, and small-for-gestational-age infants. Actual risks may be influenced by maternal factors such as disease severity, gestational age at initiation of therapy, and specific ART regimen, therefore close fetal monitoring is recommended. Because there is clear benefit to appropriate treatment, maternal ART should not be withheld due to concerns for adverse neonatal outcomes. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children without HIV but who were exposed to ART in utero and develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction. Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with protease inhibitors; it is not clear if pregnancy increases this risk. Consider performing the standard glucose screening test earlier in pregnancy in women who initiated protease inhibitor therapy prior to conception.

Based on the HHS perinatal HIV guidelines, tipranavir is not one of the recommended antiretroviral agents for use during pregnancy or females who are trying to conceive.

In general, ART is recommended for all pregnant females living with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. Therapy should be individualized following a discussion of the potential risks and benefits of treatment during pregnancy. Monitoring of pregnant females is more frequent than in nonpregnant adults. ART should be continued postpartum for all females living with HIV and can be modified after delivery.

Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com). Health care providers caring for pregnant females living with HIV and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2019).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, loss of strength and energy, abdominal pain, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), severe headache, bruising, bleeding, muscle pain, joint pain, joint stiffness, change in body fat, or signs of infection (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.