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Tipranavir

Pronunciation

(tip RA na veer)

Index Terms

  • PNU-140690E
  • TPV

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]

Brand Names: U.S.

  • Aptivus

Pharmacologic Category

  • Antiretroviral, Protease Inhibitor (Anti-HIV)

Pharmacology

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.

Absorption

Incomplete (percentage not established)

Distribution

Vd:

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 L

Metabolism

Hepatic, via CYP3A4 (minimal when coadministered with ritonavir)

Excretion

Feces (82%); urine (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% (albumin, alpha-1 acid glycoprotein)

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

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

Contraindications

Concurrent therapy of tipranavir/ritonavir with drugs highly dependent upon CYP3A for clearance or are potent CYP3A inducers, including alfuzosin, amiodarone, bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, lovastatin, 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.

Dosing: Adult

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection: Children ≥2 years and Adolescents: Oral: Canadian labeling does not approve of use in patients <18 years.

US labeling: 14 mg/kg or 375 mg/m2 (maximum: 500 mg/dose) twice daily. Note: Coadministration with ritonavir (6 mg/kg or 150 mg/m2 [maximum: 200 mg/dose] twice daily) is required.

If intolerance or toxicity develops and virus is not resistant to multiple protease inhibitors: May decrease dose to 12 mg/kg or 290 mg/m2 twice daily. Note: Coadministration with ritonavir (5 mg/kg or 115 mg/m2 twice daily) is required.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, dosage adjustment not expected since renal clearance is negligible. Guidelines state that dosage adjustment is not required (HHS [adult] 2015).

Dosing: Hepatic Impairment

Child-Pugh class A (mild impairment): There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Child-Pugh class B or C (moderate-to-severe impairment): Use is contraindicated

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: Tipranavir must be coadministered with ritonavir. When using ritonavir tablets, administer with food (HHS [adult] 2015; (HHS [pediatric] 2014). When using ritonavir capsules or solution, administer with food for pediatric patients (HHS [pediatric] 2014); may be administered without regard to meals for adult patients (HHS [adult] 2015). Canadian labeling states that adults should take with food.

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) 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

Afatinib: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of P-gp inducers, increase afatinib dose by 10mg as tolerated; reduce to original afatinib dose 2-3 days after stopping P-gp inducers. Per Canadian labeling: avoid combination if possible. Consider therapy modification

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

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

ALPRAZolam: Protease Inhibitors may increase the serum concentration of ALPRAZolam. Management: Seek alternatives to alprazolam in patients treated with HIV protease inhibitors. Concurrent use of alprazolam with indinavir is contraindicated. All patients receiving such a combination should be monitored closely for excessive response to alprazolam. Consider therapy modification

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

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

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

Boceprevir: Tipranavir may decrease the serum concentration of Boceprevir. Boceprevir may decrease the serum concentration of Tipranavir. 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

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor; this recommendation does not apply if treating major depressive disorder. Reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor. 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 (Clinically Relevant) 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. 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: Avoid clarithromycin adult doses greater than 1000 mg/day when used with a protease inhibitor. Further dose reductions may be needed in patients with impaired renal function. Consider alternative antimicrobial for any non-MAC infection. Consider therapy modification

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

Contraceptives (Progestins): Tipranavir may increase the serum concentration of Contraceptives (Progestins). 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

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: CYP2D6 Inhibitors (Strong) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Dapoxetine; Tamoxifen. Consider therapy modification

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

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

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with p-glycoprotein inducers when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering p-glycoprotein inducers, particularly strong inducers. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

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

Digoxin: Protease Inhibitors may increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade. Monitor therapy

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): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inducers in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. 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. 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

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline. 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 (Nasal): Tipranavir may increase the serum concentration of Fluticasone (Nasal). Avoid combination

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

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

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

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

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: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Avoid combination

Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

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

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

Meperidine: Protease Inhibitors may enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased. Consider therapy modification

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

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

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. 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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

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. 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

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. 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: P-glycoprotein/ABCB1 Inducers 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

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

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 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

Theophylline Derivatives: Protease Inhibitors may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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

TraZODone: Tipranavir may increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with tipranavir. Consider therapy modification

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

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

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

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin E: Tipranavir may enhance the adverse/toxic effect of Vitamin E. This interaction only applies to tipranavir oral solution. 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

Vitamin E (Oral): Tipranavir may enhance the adverse/toxic effect of Vitamin E (Oral). 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: Rash (children 21%; adults 3% to 10%)

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

Gastrointestinal: Diarrhea (15%)

Hepatic: Transaminases increased (>2.5 x ULN: 26% to 32%; grade 3/4: 10% to 20%)

Neuromuscular & skeletal: CPK increased (grade 3/4: children 11%)

2% to 10%:

Central nervous system: Fever (6% to 8%), fatigue (6%), headache (5%)

Endocrine & metabolic: Dehydration (2%)

Gastrointestinal: Nausea (5% to 9%), amylase increased (grade 3: 6% to 8%), vomiting (6%), abdominal pain (4%), diarrhea (children 4%), weight loss (3%)

Hematologic: Bleeding (children 8%), WBC decreased (grades 3: 5%), anemia (3%), neutropenia (2%)

Hepatic: ALT increased (2%, grades 3/4: 10%), AST increased (grades 3/4: 6%), GGT increased (2%)

Neuromuscular & skeletal: Myalgia (2%)

Respiratory: Cough (children 6%), dyspnea (2%), epistaxis (children 4%)

<2% (Limited to important or life-threatening): Abdominal distension, anorexia, appetite decreased, diabetes mellitus, dizziness, dyspepsia, exanthem, facial wasting, flatulence, flu-like syndrome, gastroesophageal reflux, hepatic failure, hepatic steatosis, hepatitis, hyperbilirubinemia, hyperglycemia, hypersensitivity, immune reconstitution syndrome, insomnia, intracranial hemorrhage, lipase increased, lipoatrophy, lipodystrophy (acquired), lipohypertrophy, malaise, mitochondrial toxicity, muscle cramp, neuropathy (peripheral), pancreatitis, pruritus, renal insufficiency, sleep disorder, somnolence, thrombocytopenia

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C coinfection, as these patients have an increased risk of hepatotoxicity.

Intracranial hemorrhage:

Both fatal and nonfatal intracranial hemorrhage have been reported.

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hepatotoxicity: [US Boxed Warning]: In combination with ritonavir, clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. May exacerbate pre-existing hepatic dysfunction (causal relationship not established); patients with chronic hepatitis B or C coinfection have an increased risk. 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 toxicity occur (eg, fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, 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. Treatment experienced patients with chronic hepatitis B or C coinfection or elevated transaminases are at ~2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation.

• 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.

• Increased cholesterol: With coadministered ritonavir, increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

• Intracranial hemorrhage: [US Boxed Warning]: Use in combination with ritonavir has been associated with rare reports of fatal and nonfatal intracranial hemorrhage; causal relationship not established. 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. Risk of rash increases in patients with lower CD4 counts. 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).

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 also for symptoms of hepatotoxicity (eg, fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, 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 the ULN (discontinue if occurs). Monitor viral load, CD4, and serum glucose as clinically indicated

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies; data collected by the antiretroviral pregnancy registry is insufficient to evaluate human teratogenic risk. Tipranavir has a moderate level of transfer across the human placenta (based on one case). A small increased risk of preterm birth has been associated with maternal use of protease inhibitor-based combination antiretroviral (ARV) therapy during pregnancy; however, the benefits of use generally outweigh this risk and protease inhibitors (PIs) should not be withheld if otherwise recommended. Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with PIs; it is not clear if pregnancy increases this risk. The HHS Perinatal HIV Guidelines note that there are insufficient data to recommend tipranavir for use in antiretroviral-naive pregnant women; however, if use is required due to resistance to other agents, tipranavir must be given with low-dose ritonavir boosting. Available pharmacokinetic data is insufficient to make dosing recommendations.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually-transmitted diseases.

Women receiving estrogen (as hormonal contraception or replacement therapy) may have an increased incidence of rash during therapy with tipranavir.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2015).

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 diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, 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, trouble speaking or thinking, change in balance, or change in eyesight), severe abdominal pain, severe nausea, vomiting, severe headache, bruising, bleeding, loss of strength and energy, urinary retention, change in amount of urine passed, dizziness, tachycardia, flu-like symptoms, muscle pain, joint pain, numbness or tingling, shortness of breath, 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 healthcare 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.

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