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Tipranavir

Medically reviewed by Drugs.com. Last updated on May 23, 2020.

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 10.2 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)

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. Note: Tipranavir is no longer recommended for use in the initial treatment of HIV (HHS [adult] 2019).

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.

Dosing: Adult

HIV-1 infection, treatment: Oral: 500 mg twice daily; Note: Coadministration with ritonavir (200 mg twice daily) is required. Tipranavir is no longer recommended for use in the initial treatment of HIV (HHS [adult] 2019).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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/m2 plus ritonavir 115 mg/m2 twice daily; do not exceed adult doses.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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. When using with ritonavir capsules or solution, administer without regard to meals (HHS [adult] 2019).

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 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) for up to 60 days.

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

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

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

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

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

Amphetamines: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a strong CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs. 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: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. 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: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. 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: Protease Inhibitors may increase the serum concentration of Bosentan. Management: Dose adjustment of bosentan and increased monitoring for bosentan toxicities is necessary when these agents are combined. See full drug interaction monograph for details. Consider therapy modification

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate 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

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

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

Cholic Acid: BSEP/ABCB11 Inhibitors may decrease the excretion of Cholic Acid. Management: Avoid the use of bile salt efflux pump inhibitors with cholic acid. If such a combination cannot be avoided, monitor serum transaminases (eg, AST, ALT) and bilirubin closely. Consider therapy modification

Cisapride: Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Avoid combination

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

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. Monitor therapy

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

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 concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. 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

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

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

Didanosine: Tipranavir may decrease the serum concentration of Didanosine. Management: Separate didanosine and tipranavir administration by at least 2 hours to minimize any potential dosage form-related interaction. Monitor antiviral response closely in patients receiving didanosine in combination with tipranavir/ritonavir. Consider therapy modification

Disulfiram: May enhance the adverse/toxic effect of Tipranavir. Avoid combination

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 to 50 mg twice/day in adults. Increase weight based dose to twice daily in pediatric patients. See interaction monograph for details. Not recommended with Dovato or Juluca combo products. Seek alternatives if INSTI resistance. Consider therapy modification

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

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

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

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: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. 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. 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: Consider alternative, non-hormonal forms of contraception. If used as hormone replacement therapy, monitor for estrogen deficiency. Monitor all patients using tipranavir/ritonavir and ethinyl estradiol/norethindrone for dermatologic adverse effects. Consider therapy modification

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

Fesoterodine: CYP2D6 Inhibitors (Strong) 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

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

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

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. Monitor therapy

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

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

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

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

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 and monitor for increased iloperidone toxicities, including QTc interval prolongation and arrhythmias. Consider therapy modification

Imipramine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Imipramine. The concentrations of desipramine may be increased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Imipramine. Monitor therapy

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

Letermovir: May increase the serum concentration of UGT1A1 Inducers. Avoid combination

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

Lofepramine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Lofepramine. The active metabolite of lofepramine is desipramine. 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

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

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

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: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for EPS when combined. 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

Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. 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

Nortriptyline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nortriptyline. 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

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

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

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

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

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

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

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

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

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

Primidone: May decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Primidone. Monitor therapy

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

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

Protease Inhibitors: Tipranavir may decrease the serum concentration of Protease Inhibitors. 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

Protriptyline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Protriptyline. 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

RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Consider therapy modification

Rosuvastatin: Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Limit rosuvastatin to 10 mg daily in patients receiving atazanavir/ritonavir or lopinavir/ritonavir. Patients receiving fosamprenavir/ritonavir or tipranavir/ritonavir do not require dose adjustments if rosuvastatin is used concomitantly. Consider therapy modification

Sacituzumab Govitecan: UGT1A1 Inducers may decrease serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Avoid combination

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). Management: Tacrolimus dose reductions may be required when starting or altering a protease inhibitor. Some patients may require less than 1 mg/week of tacrolimus during coadministration with a protease inhibitor. Monitor plasma concentrations and response. Consider therapy modification

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

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. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Consider therapy modification

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

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: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Consider therapy modification

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

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

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

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

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

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

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

Trimipramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Trimipramine. 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. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Consider therapy modification

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

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

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>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)

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/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).

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.

Reproductive Considerations

Based on the Health and Humans Services perinatal HIV guidelines, tipranavir is not one of the recommended antiretroviral agents for use in females who are trying to conceive.

Females living with HIV not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. Consult drug interactions database for more detailed information specific to use of tipranavir and specific contraceptives.

For males and females living with HIV and planning a pregnancy, maximum viral suppression below the limits of detection with antiretroviral therapy (ART), modification of therapy (if needed), optimization of the woman's health, and a discussion of the potential risks and benefits of ART therapy during pregnancy are recommended prior to conception (HHS [perinatal] 2019).

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.

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

What is this drug used for?

• It is used to treat HIV infection.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Headache

• Vomiting

• Loss of strength and energy

• Abdominal pain

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Bruising

• Bleeding

• Muscle pain

• Joint pain

• Joint stiffness

• Change in body fat

• Infection

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.