Tipranavir Interactions

HMG-CoA Reductase Inhibitors: Atorvastatin Rosuvastatin ↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites ↑ Rosuvastatin Avoid co-administration with atorvastatin.

Source: FDA drug label - tipranavir

Tipranavir Fosamprenavir Administered with rifampin 300 mg daily Decrease AUC by 82% Saquinavir Decrease AUC by 70% Coadministration may result in severe hepatocellular toxicity.

Source: FDA drug label - rifampin

Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [ see Clinical Pharmacology (12.3)].

Source: FDA drug label - deferasirox

Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Voriconazole ↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution.

Source: FDA drug label - tipranavir

Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Voriconazole ↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution.

Source: FDA drug label - tipranavir

Voriconazole ↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution. ↕ Voriconazole (not studied) Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.

Source: FDA drug label - tipranavir

Nucleoside Reverse Transcriptase Inhibitors: Abacavir ↓ Abacavir AUC by approximately 40% Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.

Source: FDA drug label - tipranavir

Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir .

Source: FDA drug label - amlodipine and atorvastatin

Protease Inhibitors (co-administered with 200 mg of ritonavir): Fosamprenavir ↓ Amprenavir Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.

Source: FDA drug label - tipranavir

Lopinavir ↓ Lopinavir Saquinavir ↓ Saquinavir Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir ↓ Atazanavir ↑ Tipranavir Virus Integrase Strand Transfer Inhibitors (INSTI): Raltegravir ↓ Raltegravir No dose adjustment is needed for 400 mg twice daily dosing regimen of raltegravir.

Source: FDA drug label - tipranavir

Lopinavir ↓ Lopinavir Saquinavir ↓ Saquinavir Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir ↓ Atazanavir ↑ Tipranavir Virus Integrase Strand Transfer Inhibitors (INSTI): Raltegravir ↓ Raltegravir No dose adjustment is needed for 400 mg twice daily dosing regimen of raltegravir.

Source: FDA drug label - tipranavir

Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

Source: FDA drug label - atorvastatin calcium

Antimycobacterials: Clarithromycin ↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary. For patients with renal impairment the following dosage adjustments should be considered: For patients with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL CR <30 mL/min the dose of clarithromycin should be decreased by 75%.

Source: FDA drug label - tipranavir

Dolutegravir ↓ Dolutegravir For dosage recommendations, refer to dolutegravir prescribing information.

Source: FDA drug label - tipranavir

Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration ↓=Decrease Clinical Comment ↑= Increase Antiretroviral Agents: Protease Inhibitors (PI) tipranavir/ritonavir ↓ TAF Coadministration with DESCOVY is not recommended.

Source: FDA drug label - emtricitabine and tenofovir alafenamide

Human immunodeficiency virus (HIV) / Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors Significant changes in the plasma concentrations of the estrogen and /or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., efavirenz, nevirapine] or increase [e.g., etravirine]).

Source: FDA drug label - etonogestrel and ethinyl estradiol vaginal ring

nelfinavir (without ritonavir) ritonavir saquinavir/ritonavir tipranavir/ritonavir ↑ nelfinavir ↓ etravirine ↓ etravirine ↓ etravirine Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended.

Source: FDA drug label - etravirine

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

Source: FDA drug label - tipranavir

Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.

Source: FDA drug label - tipranavir

Protease Inhibitors (co-administered with 200 mg of ritonavir): Fosamprenavir ↓ Amprenavir Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.

Source: FDA drug label - tipranavir

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or some HCV protease inhibitors (e.g.

Source: FDA drug label - levonorgestrel and ethinyl estradiol

Lopinavir ↓ Lopinavir Saquinavir ↓ Saquinavir Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir ↓ Atazanavir ↑ Tipranavir Virus Integrase Strand Transfer Inhibitors (INSTI): Raltegravir ↓ Raltegravir No dose adjustment is needed for 400 mg twice daily dosing regimen of raltegravir.

Source: FDA drug label - tipranavir

HIV-1 Protease Inhibitor: tipranavir* ↓ lopinavir Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.

Source: FDA drug label - lopinavir and ritonavir

7 DRUG INTERACTIONS • Coadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of maraviroc.

Source: FDA drug label - maraviroc

Paradoxical Effects of Anti-Retroviral Agents on Methadone Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone.

Source: FDA drug label - methadone hydrochloride

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

Source: FDA drug label - tipranavir

A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). Benzodiazepines: Parenterally administered midazolam ↑ Midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration.

Source: FDA drug label - tipranavir

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

Source: FDA drug label - tipranavir

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

Source: FDA drug label - tipranavir

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Source: FDA drug label - norelgestromin and ethinyl estradiol

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors: Significant decreases in systemic concentrations of progestin have been noted in cases of co-administration with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz).

Source: FDA drug label - norethindrone

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Source: FDA drug label - norethindrone acetate and ethinyl estradiol

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Source: FDA drug label - norethindrone and ethinyl estradiol

Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and HIV/AIDS medications containing strong inhibitors or inducers of CYP3A Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of coadministration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]) or with HIV/AIDS medications containing strong inhibitors (e.g., cobicistat and ritonavir) or inducers of CYP3A.

Source: FDA drug label - norgestimate and ethinyl estradiol

A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). Proton Pump Inhibitors: Omeprazole ↓ Omeprazole, ↔ Tipranavir Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.

Source: FDA drug label - tipranavir

Lopinavir ↓ Lopinavir Saquinavir ↓ Saquinavir Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir ↓ Atazanavir ↑ Tipranavir Virus Integrase Strand Transfer Inhibitors (INSTI): Raltegravir ↓ Raltegravir No dose adjustment is needed for 400 mg twice daily dosing regimen of raltegravir. For all other dosing regimens of raltegravir, refer to current prescribing information for raltegravir.

Source: FDA drug label - tipranavir

Other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) ↑ rilpivirine ↔ boosted PI Concomitant use of EDURANT or EDURANT PED with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes).

Source: FDA drug label - rilpivirine hydrochloride

7 DRUG INTERACTIONS When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions. HIV-1 Protease Inhibitor: tipranavir ↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.

Source: FDA drug label - ritonavir

The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure.

Source: FDA drug label - rosuvastatin

The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure.

Source: FDA drug label - rosuvastatin calcium

Examples Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice a , idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole Strong CYP3A Inducers Clinical Impact Coadministration of RYDAPT with strong CYP3A inducers may decrease midostaurin concentrations [see Clinical Pharmacology (12.3)].

Source: FDA drug label - rydapt

tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.

Source: FDA drug label - sofosbuvir, velpatasvir, and voxilaprevir

Glimepiride Glipizide Glyburide Pioglitazone Repaglinide Tolbutamide ↔ Glimepiride (CYP2C9) ↔ Glipizide (CYP2C9) ↔ Glyburide (CYP2C9) ↕ Pioglitazone (CYP2C8 and CYP3A4) ↕ Repaglinide (CYP2C8 and CYP3A4) ↔ Tolbutamide (CYP2C9) The effect of TPV/ritonavir on CYP2C8 substrate is not known.

Source: FDA drug label - tipranavir

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3 .

Source: FDA drug label - warfarin sodium