Aptivus

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Aptivus

Classes

Protease Inhibitors

Administration
Oral Administration

Tipranavir should NOT be administered without ritonavir (see Dosage). Ritonavir coadministration is needed to assure appropriate tipranavir serum concentrations.
If co-administered with ritonavir tablets, tipranavir must be taken with a meal; however if co-administered with ritonavir capsules or solution, tipranavir may be taken with or without food.

Oral Solid Formulations

Capsules must be swallowed whole; DO NOT opened or chewed.

Oral Liquid Formulations

Administer the oral solution using using a calibrated dosing syringe or the 5 ml oral syringe that is provided.

Adverse Reactions
Severe

hepatic failure / Delayed / 0-2.0
intracranial bleeding / Delayed / 0-2.0
pancreatitis / Delayed / 0-2.0
hepatotoxicity / Delayed / Incidence not known

Moderate

hypertriglyceridemia / Delayed / 0-35.9
elevated hepatic enzymes / Delayed / 0-32.1
hypercholesterolemia / Delayed / 0-15.6
bleeding / Early / 7.5-12.0
hyperamylasemia / Delayed / 0-7.5
anemia / Delayed / 3.3-3.3
hyperlipidemia / Delayed / 2.5-2.5
dehydration / Delayed / 2.1-2.1
dyspnea / Early / 2.1-2.1
steatosis / Delayed / 0-2.0
hyperbilirubinemia / Delayed / 0-2.0
hepatitis / Delayed / 0-2.0
lipodystrophy / Delayed / 0-2.0
diabetes mellitus / Delayed / 0-2.0
hyperglycemia / Delayed / 0-2.0
neutropenia / Delayed / 2.0-2.0
thrombocytopenia / Delayed / 0-2.0
peripheral neuropathy / Delayed / 1.5-1.5
QT prolongation / Rapid / 0-1.0
erythema / Early / Incidence not known

Mild

rash / Early / 3.1-21.0
diarrhea / Early / 3.6-15.0
nausea / Early / 4.5-8.5
fever / Early / 6.5-7.5
vomiting / Early / 5.5-5.9
fatigue / Early / 5.7-5.7
cough / Delayed / 5.5-5.5
headache / Early / 5.2-5.2
abdominal pain / Early / 1.5-4.4
epistaxis / Delayed / 3.7-3.7
weight loss / Delayed / 3.1-3.1
myalgia / Early / 2.3-2.3
muscle cramps / Delayed / 0-2.0
malaise / Early / 0-2.0
influenza / Delayed / 0-2.0
pruritus / Rapid / 0-2.0
anorexia / Delayed / 0-2.0
dyspepsia / Early / 0-2.0
gastroesophageal reflux / Delayed / 0-2.0
flatulence / Early / 0-2.0
dizziness / Early / 0-2.0
drowsiness / Early / 0-2.0
insomnia / Early / 1.7-1.7
photosensitivity / Delayed / 10.0
maculopapular rash / Early / 10.0
urticaria / Rapid / Incidence not known
Cushingoid features / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known

Boxed Warning
Hepatic decompensation, hepatic disease, hepatitis, hepatitis B and HIV coinfection, hepatotoxicity, jaundice

Tipranavir is contraindicated in patients with moderate and severe hepatic disease (Child-Pugh B or C). The administration of tipranavir has been associated with the development of hepatotoxicity. Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Use tipranavir cautiously in patients with mild hepatic disease (Child-Pugh A), liver enzyme abnormalities (i.e., jaundice), hepatitis, or any other underlying hepatic impairment. Perform liver function tests (LFTs) prior to initiating therapy and frequently throughout the duration of treatment to monitor for hepatotoxicity. Treatment experienced patients with chronic hepatitis B or C or with elevations in hepatic enzymes are at approximately 2-fold risk for developing Grade 3 or 4 hepatic enzyme elevations or hepatic decompensation. In clinical trials with treatment-experienced patients, Grade 3 and 4 hepatic enzyme elevations were seen in approximately 10% of patients who received tipranavir for up to 48 weeks. In clinical trials with treatment-naive patients, Grade 3 or 4 hepatic enzyme elevations were seen in approximately 20% of patients who received tipranavir for up to 48 weeks. Discontinue tipranavir in any patient who develops signs or symptoms of hepatic insufficiency or hepatitis, in any asymptomatic patient who develops increases in AST or ALT that are 10-times the upper limit of normal (ULN), or in any asymptomatic patient who develops increases in AST or ALT that are 5- to 10-times ULN and total bilirubin 2.5-times ULN. It should also be noted that since tipranavir is metabolized in the liver, patients with mild hepatic impairment may be at risk for increased tipranavir concentrations. Patients presenting with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most patients with coinfection should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients with coinfection to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [46638] [34362]

Alcoholism, anticoagulant therapy, coagulopathy, head trauma, hypertension, intracranial bleeding, surgery

In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 patients with HIV who received tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, and alcoholism or alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, although tipranavir has been shown to inhibit platelet aggregation in vitro, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. Use with caution in patients who may be at risk for increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet or anticoagulant therapy. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH.

Common Brand Names

Aptivus

Dea Class

Rx

Description

Non-peptidic protease inhibitor (PI); must be "boosted" with ritonavir
Used to treat HIV-1 infection in treatment-experienced patients with strains resistant to more than 1 PI
Black Box Warnings regarding fatal and non-fatal hepatotoxicity and intracranial hemorrhage

Dosage And Indications
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in patients with evidence of HIV replication despite ongoing antiretroviral therapy who are either treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. Oral dosage Adults

500 mg (given with ritonavir 200 mg) PO twice daily.

Children >= 2 years and Adolescents

14 mg/kg PO given with ritonavir (6 mg/kg PO) twice daily OR 375 mg/m2 PO given with ritonavir (150 mg/m2 PO) twice daily. Maximum dose is 500 mg (with ritonavir 200 mg) PO twice daily. If intolerance or toxicity develops in patients who do NOT exhibit viral resistance to multiple protease inhibitors, consider decreasing the dose to 12 mg/kg (given with ritonavir 5 mg/kg) or 290 mg/m2 (given with ritonavir 115 mg/m2) PO twice daily.

Dosing Considerations
Hepatic Impairment

Tipranavir is metabolized by the liver and is associated with adverse hepatic reactions (see Adverse Reactions). Use caution and close monitoring when administering to patients with mild hepatic disease (Child-Pugh A), as increased concentrations may be seen and because worsening of hepatic disease may be seen. Use is contraindicated in patients with moderate and severe (Child-Pugh B or C) hepatic disease.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Abacavir: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
Abacavir; Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4. (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
Abacavir; Lamivudine, 3TC: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available. (Moderate) Concurrent administration of tipranavir and ritonavir with zidovudine results in decreased zidovudine concentrations. The clinical significance of this interaction has not been established, and no recommendations for zidovudine dosage adjustments are available.
Abciximab: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Abemaciclib: (Major) If coadministration with tipranavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If tipranavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of tipranavir. Abemaciclib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Abrocitinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with abrocitinib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and tipranavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Acetaminophen; Aspirin: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with tipranavir may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of tipranavir could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tipranavir is necessary. If tipranavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like tipranavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tipranavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and tipranavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A and P-gp inhibitor; tipranavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of tipranavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until tipranavir has cleared from the circulation (approximately 3 half-lives of tipranavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; tipranavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with tipranavir (boosted with ritonavir) is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of tipranavir/ritonavir). Afatinib is a P-glycoprotein (P-gp) substrate. When administered with ritonavir, P-gp is inhibited with the first dose of tipranavir followed by strong induction over time; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If the protease inhibitor is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like protease inhibitors can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If the protease inhibitor is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Concurrent use of alfuzosin and protease inhibitors is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with tipranavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and tipranavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alpha-glucosidase Inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Alprazolam: (Contraindicated) Coadministration of tipranavir boosted with ritonavir and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with tipranavir/ritonavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and tipranavir/ritonavir are strong CYP3A4 inhibitors. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Aluminum Hydroxide: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Amiodarone: (Contraindicated) Coadministration of tipranavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of amiodarone resulting in elevated amiodarone plasma concentrations.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir due to the increased risk of developing myopathy/rhabdomyolysis. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amoxapine: (Major) Because most cyclic antidepressants are partially metabolized by CYP2D6, caution is advisable during co-administration of amoxapine and potent CYP2D6 inhibitors such as tipranavir. Elevated plasma concentrations of amoxapine may result in more pronounced anticholinergic effects and the risk of seizures may be increased.
Amoxicillin; Clarithromycin; Omeprazole: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent.
Amphetamines: (Moderate) Warn patients that there are potentially serious drug interactions between tipranavir and prescription amphetamine therapy or illicit amphetamine use. The risk of amphetamine toxicity may be increased during concurrent use of potent CYP2D6 inhibitors such as tipranavir. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, discontinue both the amphetamine and CYP2D6 inhibitor and initiate appropriate medical treatment.
Antacids: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Antithrombin III: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Apalutamide: (Contraindicated) Tipranavir is contraindicated for use with apalutamide. Apalutamide is a CYP3A4 substrate and strong inducer. Tipranavir is a CYP3A4 substrate and strong inhibitor; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Exposure to apalutamide may also increase.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of tipranavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased tipranavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in tipranavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tipranavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Tipranavir is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tipranavir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Argatroban: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants or platelet inhibitors. In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH. While coadministration with warfarin does not result in altered warfarin concentrations, alterations in INR may still occur; close monitoring of the patient's INR is recommended. Patients should be advised to promptly report any signs or symptoms of bleeding.
Aripiprazole: (Major) Recommendations for managing aripiprazole and tipranavir vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), avoid concomitant use. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; tipranavir is a strong CYP2D6 and strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and tipranavir vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), no dosage adjustment is necessary for patients already tolerating 441 mg; avoid use in patients taking higher doses. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; tipranavir is a strong CYP2D6 and strong CYP3A inhibitor.
Artemether; Lumefantrine: (Moderate) Tipranavir is a substrate and a potent inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Tipranavir is a substrate and a potent inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with tipranavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor.
Aspirin, ASA: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Caffeine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Carisoprodol: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events. (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Dipyridamole: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Omeprazole: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Aspirin, ASA; Oxycodone: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tipranavir is necessary. If tipranavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like tipranavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tipranavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Contraindicated) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with atazanavir ('boosted' with ritonavir 100 mg) results in decreased atazanavir and increased tipranavir concentrations. These drugs should not be coadministered.
Atazanavir; Cobicistat: (Contraindicated) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with atazanavir ('boosted' with ritonavir 100 mg) results in decreased atazanavir and increased tipranavir concentrations. These drugs should not be coadministered. (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Atogepant: (Major) Avoid use of atogepant and tipranavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with tipranavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and tipranavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Dosage reduction of atomoxetine is recommended in patients receiving tipranavir due to the potential for increased atomoxetine exposure and related adverse effects. In children and adolescents up to 70 kg receiving tipranavir, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving tipranavir, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. Tipranavir is a strong CYP2D6 inhibitor; atomoxetine is a CYP2D6 substrate. Coadministration of a strong CYP2D6 inhibitor and atomoxetine in extensive metabolizers of CYP2D6, increased atomoxetine steady-state plasma concentrations by approximately 6 to 8-fold. This increase is similar to exposures observed in poor metabolizers. Concurrent use of a strong CYP2D6 inhibitor with atomoxetine in poor metabolizers is not expected to increase atomoxetine exposure.
Atorvastatin: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir due to the increased risk of developing myopathy/rhabdomyolysis. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Atorvastatin; Ezetimibe: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir due to the increased risk of developing myopathy/rhabdomyolysis. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of tipranavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors including tipranavir, should not take avanafil.
Avapritinib: (Major) Avoid coadministration of avapritinib with tipranavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with tipranavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after tipranavir is discontinued. Axitinib is a CYP3A4/5 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and tipranavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Barbiturates: (Moderate) Monitor for decreased efficacy of tipranavir if coadministered with barbiturates. Concurrent use may decrease the plasma concentrations of tipranavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Tipranavir is a CYP3A substrate and barbiturates are CYP3A inducers.
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as tipranavir boosted with ritonavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, tipranavir/ritonavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with tipranavir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of tipranavir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If tipranavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6.
Berotralstat: (Major) Use of berotralstat with tipranavir is not recommended. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. The exposure of tipranavir may also be increased. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; tipranavir is a CYP3A4 substrate and P-gp inducer.
Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Consider using an alternative treatment to betametasone, such as a corticosteroid less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly if long term use is indicated. Tipranavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Tipranavir must be administered with low-dose ritonavir, which is strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid the coadministration of betrixaban and tipranavir. Concomitant administration of betrixaban and tipranavir results in decreased plasma concentrations of betrixaban that may be insufficient to achieve the intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate and tipranavir is a P-gp inducer.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Bivalirudin: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants or platelet inhibitors. In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH. While coadministration with warfarin does not result in altered warfarin concentrations, alterations in INR may still occur; close monitoring of the patient's INR is recommended. Patients should be advised to promptly report any signs or symptoms of bleeding.
Bortezomib: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for cytochrome P450 3A4. Agents that inhibit CYP3A4, such as tipranavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with CYP3A4 inhibitors should be closely monitored for potential toxicity.
Bosentan: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and tipranavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as tipranavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Tipranavir is a strong inhibitor of both CYP3A4 and CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with tipranavir if possible due to increased plasma exposure of brigatinib which may result in an increase in brigatinib-related adverse reactions; tipranavir exposure may also increase. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of tipranavir, resume the brigatinib dose that was tolerated prior to initiation of tipranavir. Brigatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with tipranavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; tipranavir is a strong inhibitor of CYP3A4.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination

dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine; Lidocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Buprenorphine: (Minor) Although no significant effects have been noted, buprenorphine AUC, Cmax, and Cmin may be decreased by about 80% when coadministered with tipranavir plus ritonavir. Tipranavir trough concentrations may be decreased by 19 to 40% and serum concentration monitoring may be warranted.
Buprenorphine; Naloxone: (Minor) Although no significant effects have been noted, buprenorphine AUC, Cmax, and Cmin may be decreased by about 80% when coadministered with tipranavir plus ritonavir. Tipranavir trough concentrations may be decreased by 19 to 40% and serum concentration monitoring may be warranted.
Buspirone: (Moderate) When buspirone is administered with an inhibitor of CYP3A4 like tipranavir, a lower dose of buspirone is recommended. Dose adjustment of either drug should be based on clinical assessment.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events. (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with tipranavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and tipranavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with tipranavir 2 to 3 days after discontinuation of tipranavir. Cabozantinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Calcium Carbonate: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Calcium Carbonate; Simethicone: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Calcium; Vitamin D: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Canagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Canagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Cannabidiol: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with cannabidiol is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with tipranavir is necessary. Capmatinib is a CYP3A substrate and P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibition of P-gp may increase tipranavir exposure.
Carbamazepine: (Major) Carbamazepine increases the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. Coadministration of tipranavir with carbamazepine is expected to result in decreased tipranavir concentrations, an alternative anticonvulsant should be considered when possible. Treatment failures have been reported with other protease inhibitors when carbamazepine was used concomitantly. In addition, tipranavir boosted with ritonavir is a potent CYP3A inibitor and coadministration may result in increased serum concentrations of carbamazepine. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and carbamazepine are unknown. If used concomitantly, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or carbamazepine toxicity.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as tipranavir, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
Carvedilol: (Moderate) Altered concentrations of tipranavir and/or carvedilol may occur during coadministration. Carvedilol and tipranavir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
Ceritinib: (Major) Avoid concomitant use of ceritinib with tipranavir due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions; exposure to tipranavir may also increase. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After tipranavir is discontinued, resume the dose of ceritinib taken prior to initiating tipranavir. Both drugs are CYP3A substrates and strong CYP3A4 inhibitors. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chlordiazepoxide: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chlordiazepoxide; Amitriptyline: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chlordiazepoxide; Clidinium: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with tipranavir may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of tipranavir could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Cidofovir: (Moderate) Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with protease inhibitors and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased the cilostazol AUC by 117%. Coadministration with a moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of tipranavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Cisapride: (Contraindicated) Concomitant use of protease inhibitors and cisapride is contraindicated; use increases cisapride exposure and the risk for cisapride-related adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concomitant use of cisapride with CYP3A inhibitors also is disallowed under the Propulsid Limited Access Program.
Clarithromycin: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with protease inhibitors; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Clorazepate: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: (Moderate) Caution is advisable during concurrent use of tipranavir and clozapine. Clozapine is a substrate for CYP1A2, CYP2D6, and CYP3A4; tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, and a moderate inducer of CYP1A2. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Use with a CYP1A2 inducer may result in a loss of effectiveness of clozapine. According to the manufacturer, patients receiving clozapine in combination with inhibitors or inducers of CYP2D6, CYP3A4, or CYP1A2 should be monitored for adverse reactions or loss of effectiveness, respectively. Consideration should be given to adjusting the clozapine dose as clinically warranted.
Cobicistat: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with tipranavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro; tipranavir is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with tipranavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of tipranavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tipranavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and tipranavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Tipranavir can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken tipranavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: (Contraindicated) Coadministration of conivaptan and tipranavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase tipranavir exposure and risk for tipranavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A and P-gp inhibitor; tipranavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Bazedoxifene: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Medroxyprogesterone: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. In addition, coadministration of medroxyprogesterone, a CYP3A substrate with tipranavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and tipranavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; tipranavir boosted with ritonavir is a strong CYP3A inhibitor.
Cranberry, Vaccinium macrocarpon Ait.: (Major) Tipranavir should be used with caution in patients who may be at risk of increased bleeding, such as in patients taking high doses of vitamin E. In vitro, tipranavir was observed to inhibit human platelet aggregation at concentrations consistent with human exposure at regular doses. In rats, coadministration with vitamin E increased the bleeding effects of tipranavir.
Crizotinib: (Major) Avoid concomitant use of tipranavir and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; exposure to tipranavir may also increase. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of tipranavir. Crizotinib is a CYP3A substrate and moderate inhibitor. Tipranavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
Cyclosporine: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Dabigatran: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as tipranavir, a mild inducer. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and tipranavir; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of tipranavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; tipranavir is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as tipranavir boosted with ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of tipranavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
Dapagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Saxagliptin: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as tipranavir boosted with ritonavir. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Daridorexant: (Major) Avoid concomitant use of daridorexant and tipranavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with tipranavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Dasatinib: (Major) Avoid coadministration of dasatinib and tipranavir due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to tipranavir with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of tipranavir is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If tipranavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with tipranavir. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; tipranavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Desipramine: (Major) Concomitant use of tipranavir boosted with ritonavir and desipramine may result in elevated desipramine concentrations and serious adverse events. During coadministration, consider dosage reduction and concentration monitoring of desipramine.
Desirudin: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants or platelet inhibitors. In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH. While coadministration with warfarin does not result in altered warfarin concentrations, alterations in INR may still occur; close monitoring of the patient's INR is recommended. Patients should be advised to promptly report any signs or symptoms of bleeding.
Desogestrel; Ethinyl Estradiol: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor. Tipranavir is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions and a decrease in tipranavir efficacy if concomitant use of dexamethasone and tipranavir is necessary. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may increase dexamethasone concentrations and decrease tipranavir exposure. Dexamethasone is a CYP3A substrate and CYP3A inducer; tipranavir is a CYP3A substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Bupropion: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Quinidine: (Contraindicated) Concurrent use of quinidine and tipranavir is contraindicated due to the potential for serious and/or life-threatening cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of quinidine, resulting in elevated quinidine serum concentrations. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Didanosine, ddI: (Moderate) Concurrent administration of tipranavir and ritonavir with didanosine, ddI results in decreased didanosine concentrations. For optimal absorption, tipranavir and ritonavir should not be administered within 2 hours of buffered didanosine.
Dienogest; Estradiol valerate: (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Diethylstilbestrol, DES: (Moderate) Tipranavir increases the metabolism of estrogens. If coadministration is necessary, monitor for decreased effect of diethylstilbestrol.
Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Diltiazem: (Moderate) Tipranavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of tipranavir.
Dipyridamole: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Disopyramide: (Major) Tipranavir can inhibit CYP3A4, an isoenzyme that is partially responsible for the metabolism of disopyramide. Although no definitive clinical data have yet confirmed this interaction, the concurrent use of these agents should be approached with caution due to the potential for serious disopyramide toxicity.
Disulfiram: (Major) The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Docetaxel: (Major) Avoid coadministration of docetaxel with tipranavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of CYP3A4 inhibitors, such as tipranavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
Dolutegravir: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4.
Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions o r clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4.
Dolutegravir; Rilpivirine: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4. (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Donepezil: (Moderate) In theory, co-administration of tipranavir and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
Donepezil; Memantine: (Moderate) In theory, co-administration of tipranavir and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
Doravirine: (Minor) Coadministration of doravirine and tipranavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tipranavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available. (Minor) Coadministration of doravirine and tipranavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tipranavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with tipranavir. Tipranavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxercalciferol: (Moderate) Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if these drugs are administered together.
Doxorubicin Liposomal: (Major) Tipranavir is a potent CYP2D6 and CYP3A4 inhibitor; it is also a potent inducer of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Inducers of P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of tipranavir and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
Doxorubicin: (Major) Tipranavir is a potent CYP2D6 and CYP3A4 inhibitor; it is also a potent inducer of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Inducers of P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of tipranavir and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
Dronabinol: (Major) Use caution if coadministration of dronabinol with tipranavir is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Tipranavir is a strong inhibitor of CYP3A4, and is contraindicated with sensitive drugs that are highly dependent on CYP3A4/5 for clearance. Dronabinol is a CYP2C9 and 3A4 substrate; concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) The concomitant use of dronedarone and tipranavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Tipranavir is a strong inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of tipranavir have not been described, although an increase in tipranavir serum concentrations is possible.
Drospirenone: (Major) Tipranavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipanavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with PIs that include ritonavir as a booster to use an additional method of contraception to protect against unwanted pregnancy. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as tipranavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
Drospirenone; Estetrol: (Major) Tipranavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipanavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with PIs that include ritonavir as a booster to use an additional method of contraception to protect against unwanted pregnancy. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as tipranavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
Drospirenone; Estradiol: (Major) Tipranavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipanavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with PIs that include ritonavir as a booster to use an additional method of contraception to protect against unwanted pregnancy. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as tipranavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Drospirenone; Ethinyl Estradiol: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. (Major) Tipranavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipanavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with PIs that include ritonavir as a booster to use an additional method of contraception to protect against unwanted pregnancy. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as tipranavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. (Major) Tipranavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipanavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with PIs that include ritonavir as a booster to use an additional method of contraception to protect against unwanted pregnancy. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as tipranavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
Duloxetine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with tipranavir. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Tipranavir is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Dutasteride: (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity of both drugs when coadministered with tipranavir. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; tipranavir is a sensitive substrate and strong inhibitor of CYP3A. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as tipranavir.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Edoxaban: (Moderate) Coadministration of edoxaban and tipranavir may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tipranavir is a mild P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of tipranavir; monitor for decreased efficacy of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Elacestrant: (Major) Avoid concomitant use of elacestrant and tipranavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. The exposure of tipranavir may also be increased. Elacestrant is a CYP3A substrate and P-gp inhibitor and tipranavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and tipranavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and tipranavir to 6 months. Monitor for elagolix-related side effects and reduced response to tipranavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; tipranavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease tipranavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and tipranavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and tipranavir to 6 months. Monitor for elagolix-related side effects and reduced response to tipranavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; tipranavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease tipranavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with tipranavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Tipranavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity.
Elexacaftor; tezacaftor; ivacaftor: (Major) If tipranavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in tipranavir-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase tipranavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and tipranavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with tipranavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; tipranavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with tipranavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); tipranavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Contraindicated) Coadministration of tipranavir and eliglustat is contraindicated. Tipranavir is a strong CYP2D6 and CYP3A inhibitor and P-glycoprotein (P-gp) substrate; its use is contraindicated with other drugs that are highly dependent on CYP3A for metabolic clearance. Eliglustat is a CYP2D6 and CYP3A substrate and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of tipranavir and eliglustat may result in significantly increased plasma concentrations eliglustat, increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). In addition, the inhibition of P-gp transport caused by eliglustat may result in increased plasma concentration of tipranavir.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as tipranavir, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
Eluxadoline: (Major) When administered concurrently with tipranavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); tipranavir is an OATP1B1 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Moderate) Coadministration of tipranavir boosted with ritonavir and elvitagravir results in an unknown effect on the plasma concentrations of elvitegravir. The recommended dosing regimen for these drugs used in combination is: elvitegravir 150 mg PO once daily with tipranavir/ritonavir 500/200 mg PO twice daily. No data are available for use of other dosage.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Moderate) Coadministration of tipranavir boosted with ritonavir and elvitagravir results in an unknown effect on the plasma concentrations of elvitegravir. The recommended dosing regimen for these drugs used in combination is: elvitegravir 150 mg PO once daily with tipranavir/ritonavir 500/200 mg PO twice daily. No data are available for use of other dosage. (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Empagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin: (Major) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of p-glycoprotein (e.g.,tipranavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin; Metformin: (Major) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of p-glycoprotein (e.g.,tipranavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Enasidenib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and tipranavir/ritonavir due to increased encorafenib exposure. Increased or decreased tipranavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of tipranavir/ritonavir. If tipranavir/ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of tipranavir/ritonavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor; tipranavir is a sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Enfuvirtide: (Moderate) Phase 3 trials showed that the coadministration of enfuvirtide increases tipranavir trough concentrations by 45%; however, the mechanism for this increase is unknown. The manufacturer of tipranavir states that tipranavir dosage adjustments are not recommended.
Entrectinib: (Major) Avoid coadministration of entrectinib with tipranavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If tipranavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of tipranavir. Entrectinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Contraindicated) Tipranavir is contraindicated for use with enzalutamide. Enzalutamide is a strong CYP3A4 inducer and tipranavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Eplerenone: (Contraindicated) Coadministration of tipranavir and eplerenone is contraindicated. Tipranavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Eptifibatide: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and tipranavir due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If tipranavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
Ergoloid Mesylates: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Erlotinib: (Major) Avoid coadministration of erlotinib with tipranavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Ertugliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Ertugliflozin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Estazolam: (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression).
Esterified Estrogens: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Esterified Estrogens; Methyltestosterone: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Estradiol: (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Levonorgestrel: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Norethindrone: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Norgestimate: (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Progesterone: (Major) Tipranavir can increase or decrease the metabolism of hormones. Concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. The metabolism of progesterone may also be inhibited by tipranavir, a strong inhibitor of the CYP3A4 hepatic enzyme. For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of excess hormones. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estropipate: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethinyl Estradiol; Norelgestromin: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norethindrone Acetate: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norgestrel: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethosuximide: (Moderate) Tipranavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
Ethotoin: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Etonogestrel: (Major) Etonogestrel is not recommended for women who require the chronic use of drugs that are potent inducers of hepatic enzymes, as contraceptive efficacy is likely to be reduced. Several of the anti-retroviral protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean area under the curve (AUC) of the estrogen and progestin have been noted in some cases. The efficacy and safety of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors; it is unknown whether this applies to etonogestrel. Healthcare providers should refer to the labeling of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Hormonal contraceptives may decrease the serum concentrations of amprenavir and fosamprenavir, which could lead to loss of virologic response and possible viral resistance; thus, etonogestrel should not be administered with amprenavir or fosamprenavir.
Etonogestrel; Ethinyl Estradiol: (Major) Etonogestrel is not recommended for women who require the chronic use of drugs that are potent inducers of hepatic enzymes, as contraceptive efficacy is likely to be reduced. Several of the anti-retroviral protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean area under the curve (AUC) of the estrogen and progestin have been noted in some cases. The efficacy and safety of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors; it is unknown whether this applies to etonogestrel. Healthcare providers should refer to the labeling of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Hormonal contraceptives may decrease the serum concentrations of amprenavir and fosamprenavir, which could lead to loss of virologic response and possible viral resistance; thus, etonogestrel should not be administered with amprenavir or fosamprenavir. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Etravirine: (Major) Etravirine should not be coadministered with tipranavir. Concomitant use may cause a significant decrease in etravirine plasma concentration and, thus, a loss of therapeutic effect.
Everolimus: (Major) Avoid coadministration of everolimus with tipranavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Tipranavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Fedratinib: (Major) Avoid coadministration of fedratinib with tipranavir as concurrent use may increase fedratinib exposure; tipranavir exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If tipranavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; tipranavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and protease inhibitors should be approached with caution and conservative dosing of felodipine due to the potential for s ignificant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concurrent use of a strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. Concurrent use of a moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fenfluramine: (Major) Do not exceed a maximum dose of fenfluramine 20 mg per day if coadministered with tipranavir; for patients also receiving stiripentol plus clobazam, do not exceed a maximum dose of fenfluramine 17 mg per day. Concomitant use may increase fenfluramine plasma concentrations and the risk of adverse reactions. Fenfluramine is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased fenfluramine overall exposure by 81% and decreased norfenfluramine overall exposure by 13%.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Finasteride; Tadalafil: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of tipranavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of tipranavir therapy. Stop tadalafil at least 24 hours prior to starting tipranavir. After at least 1 week of tipranavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and tipranavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Finerenone: (Contraindicated) Concomitant use of finerenone and tipranavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Major) Tipranavir should be used with caution in patients who may be at risk of increased bleeding, such as in patients taking high doses of vitamin E. In vitro, tipranavir was observed to inhibit human platelet aggregation at concentrations consistent with human exposure at regular doses. In rats, coadministration with vitamin E increased the bleeding effects of tipranavir.
Flecainide: (Contraindicated) When administered in the FDA approved dosage regimen, tipranavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as flecainide, should be expected with concurrent use. Coadministration of tipranavir and flecainide is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as tipranavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Moderate) Tipranavir concentrations are increased when coadministered with fluconazole; however, no dose adjustments are required if fluconazole dose is less than 200 mg PO daily. Fluconazole doses greater than 200 mg per day are not recommended to be given with tipranavir.
Fluoxetine: (Moderate) Use caution when coadministering tipranavir and ritonavir with selective serotonin reuptake inhibitors, as increased SSRI concentrations may be seen. Patients should be monitored for increased SSRI adverse effects and the SSRI dose should be adjusted if necessary.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and tipranavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with tipranavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and tipranavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and tipranavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and tipranavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluvastatin: (Moderate) Concurrent use of tipranavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Tipranavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, saquinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
Fondaparinux: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Food: (Major) Advise patients to avoid cannabis use during protease inhibitor treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and protease inhibitors are strong CYP3A inhibitors. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Concomitant administration of tipranavir and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with tipranavir long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Fosamprenavir: (Major) Avoid concurrent use of fosamprenavir and tipranavir. Concomitant use may decrease the exposure of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Coadministration with tipranavir decreased the exposure of fosamprenavir by 44%.
Fosphenytoin: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; tipranavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Futibatinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; futibatinib is a P-gp inhibitor.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with tipranavir is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. Based on in vitro data, gefitinib is also metabolized to O-desmethyl gefitinib by CYP2D6 and tipranavir is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Gilteritinib: (Major) Consider an alternative to tipranavir during treatment with gilteritinib. Concurrent use may increase gilteritinib and/or tipranavir exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib and tipranavir adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate and a P-gp inhibitor; tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Consider an alternative to tipranavir during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and tipranavir as coadministration may decrease serum concentrations of glecaprevir and/or increase serum concentrations of tipranavir. This may result in decreased efficacy of glecaprevir and/or increased tipranavir-related adverse effects. Glecaprevir is a substrate and inhibitor of P-glycoprotein (P-gp); tipranavir is a substrate and inducer of P-gp. (Moderate) Caution is advised with the coadministration of pibrentasvir and tipranavir as coadministration may decrease serum concentrations of pibrentasvir and/or increase serum concentrations of tipranavir. This may result in decreased efficacy of pibrentasvir and/or increased tipranavir-related adverse effects. Pibrentasvir is a substrate and inhibitor of P-glycoprotein (P-gp); tipranavir is a substrate and inducer of P-gp.
Glipizide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glyburide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Guanfacine: (Major) Tipranavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If tipranavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and tipranavir is a strong CYP3A4 inhibitor.
Haloperidol: (Moderate) Tipranavir is a potent inhibitor of CYP2D6 and CYP3A4, the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
Heparin: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Hydantoins: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with tipranavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and tipranavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tipranavir is necessary. If tipranavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like tipranavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tipranavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Concomitant use of idelalisib, a CYP3A4 substrate, and tipranavir, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. Additionally, idelalisib is a strong CYP3A inhibitor while tipranavir is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and tipranavir.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with tipranavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Tipranavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with tipranavir. If tipranavir is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 and CYP2D6 substrate. Tipranavir is a strong inhibitor of both CYP3A4 and CYP2D6. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. A strong CYP2D6 inhibitor increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Drugs that inhibit both CYP3A4 and CYP2D6 do not add to the effect of either inhibitor given alone.
Imatinib: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended.
Incretin Mimetics: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Infigratinib: (Major) Avoid concomitant use of infigratinib and tipranavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Irinotecan Liposomal: (Major) Avoid administration of tipranavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tipranavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of tipranavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tipranavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with tipranavir is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; tipranavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated tipranavir concentrations may also be seen with coadministration, as tipranavir is a substrate and isavuconazole is an inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) The coadministration of tipranavir and rifampin is contraindicated. Rifampin induces CYP isoenzymes, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90%. Loss of antiretroviral efficacy and the potential for viral resistance is expected during concurrent use.
Isoniazid, INH; Rifampin: (Contraindicated) The coadministration of tipranavir and rifampin is contraindicated. Rifampin induces CYP isoenzymes, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90%. Loss of antiretroviral efficacy and the potential for viral resistance is expected during concurrent use.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with protease inhibitors is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with tipranavir as istradefylline exposure and adverse effects may increase. Tipranavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Both tipranavir boosted with ritonavir and itraconazole are inhibitors of CYP3A4. Additionally, both drugs are CYP3A4 substrates. Based on expected CYP drug interactions, tipranavir (in the FDA approved dosage regimen) should be used cautiously with itraconazole; high doses (i.e., > 200 mg) of itraconazole should be avoided.
Ivabradine: (Contraindicated) Coadministration of ivabradine and tipranavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; tipranavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If tipranavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in tipranavir-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase tipranavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and tipranavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with tipranavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; tipranavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of tipranavir. If tipranavir is discontinued, wait at least 5 half-lives of tipranavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Tipranavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and tipranavir due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Major) Avoid tipranavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and tipranavir are CYP3A substrates and strong CYP3A inhibitors.
Lacosamide: (Moderate) Use caution during concurrent use of lacosamide and tipranavir, particularly in patients with renal or hepatic impairment. Lacosamide is a CYP3A4 substrate; tipranavir is a potent inhibitor of CYP3A4. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadminsitered with a strong CYP3A4 inhibitor. Dosage reduction of lacosamide may be necessary in this population.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concurrent administration of tipranavir and ritonavir with zidovudine results in decreased zidovudine concentrations. The clinical significance of this interaction has not been established, and no recommendations for zidovudine dosage adjustments are available.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent.
Lapatinib: (Major) Avoid coadministration of lapatinib with tipranavir due to increased plasma concentrations of lapatinib; exposure to tipranavir may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If tipranavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold. Inhibitors of P-gp may increase plasma concentrations of tipranavir.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with tipranavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If tipranavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of tipranavir. Larotrectinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lasmiditan: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with lasmiditan is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with tipranavir boosted with ritonavir. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
Lefamulin: (Major) Avoid coadministration of lefamulin with tipranavir/ritonavir due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; tipranavir boosted with ritonavir is both a strong inhibitor of CYP3A4 and P-gp inducer. The net effect on lefamulin concentrations is unclear.
Lemborexant: (Major) Avoid coadministration of lemborexant and tipranavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Major) Concurrent use of lenacapavir and tipranavir is not recommended due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. The exposure of tipranavir may also be increased. Tipranavir is a CYP3A and P-gp substrate; lenacapavir is a CYP3A substrate and moderate CYP3A and P-gp inhibitor.
Leniolisib: (Major) Avoid concomitant use of leniolisib and tipranavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Letermovir: (Major) Concurrent administration of letermovir and tipranavir is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Tipranavir is a strong P-gp inducer. Also, concurrent administration may increase plasma concentrations of tipranavir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Tipranavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor, however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide; Norethindrone: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levoketoconazole: (Major) Avoid tipranavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and tipranavir are CYP3A substrates and strong CYP3A inhibitors.
Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Tipranavir is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
Levonorgestrel: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Levonorgestrel; Ethinyl Estradiol: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Lidocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
Lidocaine; Epinephrine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
Lidocaine; Prilocaine: (Moderate) Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
Linagliptin: (Major) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of p-glycoprotein (e.g.,tipranavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
Linagliptin; Metformin: (Major) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of p-glycoprotein (e.g.,tipranavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and tipranavir. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Lomitapide: (Contraindicated) Concomitant use of tipranavir boosted with ritonavir and lomitapide is contraindicated. If treatment with tipranavir boosted with ritonavir is unavoidable, lomitapide should be stopped during the course of treatment. Tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and tipranavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor. Tipranavir is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Moderate) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with loperamide results in decreased loperamide concentrations (30% reduction in AUC) and decreased tipranavir Cmin (26% reduction). The clinical significance of this interaction has not been established, and no recommendations for dosage adjustments are available.
Loperamide; Simethicone: (Moderate) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with loperamide results in decreased loperamide concentrations (30% reduction in AUC) and decreased tipranavir Cmin (26% reduction). The clinical significance of this interaction has not been established, and no recommendations for dosage adjustments are available.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with tipranavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of tipranavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If tipranavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of tipranavir. Lorlatinib is a CYP3A substrate and moderate inducer. Tipranavir is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Lovastatin: (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
Low Molecular Weight Heparins: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Lumacaftor; Ivacaftor: (Major) If tipranavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in tipranavir-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase tipranavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and tipranavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of tipranavir; avoid concurrent use if possible. If concomitant use of tipranavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when tipranavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking tipranavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking tipranavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Tipranavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of tipranavir and decrease its therapeutic efficacy. Although tipranavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, tipranavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of tipranavir; avoid concurrent use if possible. If concomitant use of tipranavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when tipranavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking tipranavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking tipranavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Tipranavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of tipranavir and decrease its therapeutic efficacy. Although tipranavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, tipranavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of tipranavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; tipranavir must be administered with ritonavir, which is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as tipranavir, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and tipranavir due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macitentan: (Major) Avoid concurrent use of macitentan and tipranavir. Tipranavir is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with tipranavir is necessary.
Magnesium Hydroxide: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Maribavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with maribavir is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; maribavir is a P-gp inhibitor.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with tipranavir due to risk of heart failure due to systolic dysfunction and risk for reduced mavacamten efficacy. Concomitant use may increase or decrease mavacamten exposure and decrease plasma concentrations of tipranavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a CYP2C19 substrate and substrate and moderate inducer of CYP3A and tipranavir is a moderate CYP2C19 inhibitor and substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Medroxyprogesterone: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. In addition, coadministration of medroxyprogesterone, a CYP3A substrate with tipranavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Tipranavir is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
Meperidine: (Moderate) Coadministration of tipranavir with meperidine should be avoided when possible. Tipranavir increases the metabolism of meperidine resulting in decreased pain control but elevated concentrations of the neurotoxic metabolite, normeperidine. Meperidine dosage increase or long-term use is not recommended.
Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Rosiglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor tr eatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Saxagliptin: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as tipranavir boosted with ritonavir. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Methadone: (Moderate) Protease inhibitors may interact with methadone to varying degrees. Most of the protease inhibitors reduce the metabolism of methadone, and there is a potential for excessive methadone-related side effects.
Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Metoclopramide: (Major) Due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor, the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor, the recommended dose of metoclopramide is 5 mg PO four times daily times daily. Metoclopramide is a substrate of CYP2D6 and tipranavir is a strong CYP2D6 inhibitor.
Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. In the presence of a moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. In the presence of a moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
Metronidazole: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Midazolam: (Major) Protease inhibitors may increase midazolam concentrations; the risk for midazolam-related adverse effects varies by midazolam dosage form and route of administration. Oral midazolam use is contraindicated. Intranasal midazolam should be avoided when possible. Additional monitoring and a dosage reduction may be necessary with parenteral midazolam. Midazolam is a CYP3A substrate and protease inhibitors are CYP3A inhibitors. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and tipranavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Caution is advised when administering tipranavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with tipranavir should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving tipranavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with tipranavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with tipranavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with tipranavir is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with tipranavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and tipranavir are substrates and strong inhibitors of CYP3A4.
Miglitol: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Mirtazapine: (Moderate) Concurrent administration of mirtazapine and tipranavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of tipranavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with tipranavir due to increased risk of adverse reactions. Coadministration increases mitapivat and may increase tipranavir exposure. Mitapivat is a CYP3A substrate and P-gp inhibitor and tipranavir is a strong CYP3A inhibitor and P-gp substrate. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Contraindicated) Tipranavir is contraindicated for use with mitotane. Mitotane is a strong CYP3A4 inducer and tipranavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and tipranavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Mometasone: (Moderate) Concomitant administration of tipranavir and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with tipranavir long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with tipranavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with tipranavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as tipranavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with tipranavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Nateglinide: (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together.
Nebivolol: (Major) Avoid the concomitant use of nebivolol and tipranavir. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as tipranavir, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and tipranavir. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as tipranavir, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
Nefazodone: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
Neratinib: (Major) Avoid concomitant use of tipranavir with neratinib due to an increased risk of neratinib-related toxicity; tipranavir exposure may also increase. Neratinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Tipranavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as tipranavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Niacin; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Nicardipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Nifedipine: (Moderate) Tipranavir may interact with certain calcium-channel blockers. Tipranavir may interact with calcium-channel blockers that undergo significant metabolism via CYP3A4, including nifedipine. Cautious dose titration of these calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and tipranavir. If coadministration is required, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Additionally, monitor patients closely for prolongation of the QT interval and for adverse reactions associated with nilotinib or tipranavir. If tipranavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and tipranavir is a sensitive substrate and strong inhibitor of CYP3A4.
Nimodipine: (Moderate) Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with protease inhibitors due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Norethindrone: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms.
Norethindrone; Ethinyl Estradiol: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Norgestimate; Ethinyl Estradiol: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Norgestrel: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Olanzapine; Fluoxetine: (Moderate) Use caution when coadministering tipranavir and ritonavir with selective serotonin reuptake inhibitors, as increased SSRI concentrations may be seen. Patients should be monitored for increased SSRI adverse effects and the SSRI dose should be adjusted if necessary.
Olaparib: (Major) Avoid coadministration of olaparib with tipranavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after tipranavir is discontinued. Olaparib is a CYP3A substrate and tipranavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Olopatadine; Mometasone: (Moderate) Concomitant administration of tipranavir and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with tipranavir long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and tipranavir. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole; Amoxicillin; Rifabutin: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with tipranavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with tipranavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and tipranavir/ritonavir is a strong CYP3A inhibitor. Coadministration with tipranavir/ritonavir increased the AUC of rifabutin by approximately 2.9-fold.
Oritavancin: (Major) Tipranavir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of tipranavir may be reduced if these drugs are administered concurrently.
Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osimertinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with osimertinib is necessary. Tipranavir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with protease inhibitors is necessary. Oxybutynin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tipranavir is necessary. If tipranavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like tipranavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tipranavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with tipranavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Tipranavir exposure may also increase. Pacritinib is a CYP3A substrate and a P-gp inhibitor; tipranavir is a strong CYP3A inhibitor and a P-gp substrate.
Palbociclib: (Major) Avoid coadministration of tipranavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of tipranavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If tipranavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of tipranavir) to the dose used before initiation of tipranavir. Palbociclib is primarily metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A and tipranavir is a sensitive CYP3A4 substrate.
Paliperidone: (Major) Avoid using a strong inducer of P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong P-gp inducer such as tipranavir is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp.
Palovarotene: (Major) Avoid concomitant use of palovarotene and tipranavir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with tipranavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor.
Pazopanib: (Major) Avoid administering pazopanib with strong CYP3A4 inhibitors, such as tipranavir. If co-administration with a strong CYP3A4 inhibitor is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4 and P-glycoprotein (P-gp) substrate, and tipranavir, a strong CYP3A4 inhibitor, a CYP3A4 and P-gp substrate, and a P-gp inducer, may result in altered pazopanib and/or tipranavir concentrations.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and tipranavir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If tipranavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of tipranavir. Pemigatinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentosan: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Perampanel: (Moderate) Concurrent use of perampanel with tipranavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Tipranavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and tipranavir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease tipranavir plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If tipranavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of tipranavir. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; tipranavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenytoin: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as tipranavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
Pimozide: (Contraindicated) Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP.
Pioglitazone; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and tipranavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of tipranavir may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of tipranavir use. Resume the previous dose of pirtobrutinib after tipranavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and P-gp inhibitor and tipranavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking tipranavir; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If tipranavir is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of tipranavir/ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ponatinib: (Major) Avoid coadministration of ponatinib and tipranavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tipranavir and consider alternative therapy. After tipranavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tipranavir. Ponatinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Posaconazole: (Major) Posaconazole and tipranavir should be coadministered with caution due to an increased potential for adverse events. Both posaconazole and tipranavir are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of tipranavir. Further, tipranavir is an inducer and substrates of the drug efflux protein, P-glycoprotein, for which posaconazole is an inhibitor and also a substrate. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and tipranavir, ultimately resulting in an increased risk of adverse events.
Pralsetinib: (Major) Avoid concomitant use of tipranavir and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and tipranavir is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Pramlintide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Pretomanid: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with pretomanid is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; pretomanid is a P-gp inhibitor.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and tipranavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Tipranavir can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken tipranavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Progesterone: (Major) Tipranavir can increase or decrease the metabolism of hormones. Concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. The metabolism of progesterone may also be inhibited by tipranavir, a strong inhibitor of the CYP3A4 hepatic enzyme. For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of excess hormones. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Propafenone: (Contraindicated) Coadminsitration of tipranavir with propafenone is contraindicated due to the potential for serious and/or life-threatening cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of propafenone resulting in elevated propafenone plasma concentrations.
Proton pump inhibitors: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Tipranavir markedly induces the hepatic cytochrome P-450 enzyme CYP2C19, an enzyme responsible for the metabolism of PPIs. However, since tipranavir is not given unless it is co-prescribed with ritonavir, a known marked enzyme inhibitor, a reduction in PPI metabolism may be unlikely to occur. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If tipranavir and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Quazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed.
Quetiapine: (Major) Avoid concurrent use of quetiapine and tipranavir. Tipranavir boosted with ritonavir may inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If administration of tipranavir is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose and monitor for quetiapine-related adverse events. If tipranavir is discontinued, increase the quetiapine dose by 6-fold.
Quinidine: (Contraindicated) Concurrent use of quinidine and tipranavir is contraindicated due to the potential for serious and/or life-threatening cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of quinidine, resulting in elevated quinidine serum concentrations.
Quinine: (Major) Anti-retroviral protease inhibitors can inhibit the metabolism of CYP3A4 substrates such as quinine. In theory, this interaction could potentially result in drug accumulation and quinine toxicity. Monitor for potential quinine toxicity and decrease quinine dosage if needed.
Quizartinib: (Major) Avoid concomitant use of tipranavir with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Raltegravir: (Major) Coadministration of tipranavir plus ritonavir with raltegravir administered as a once daily dose (high dose regimen) is not recommended, as concurrent use results in decreased raltegravir concentrations. Tipranavir/ritonavir may be given with other dosage regimens of raltegravir with no dose adjustments necessary. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; tipranavir given with ritonavir is a UGT1A1 inducer. In drug interaction studies, tipranavir; ritonavir had no clinically meaningful effect on the pharmacokinetics of raltegravir 400 mg twice daily.
Ramelteon: (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
Ranolazine: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, tipranavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, tipranavir may decrease the absorption of ranolazine via P-glycoprotein induction.
Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended.
Regorafenib: (Major) Avoid coadministration of regorafenib with tipranavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix; Estradiol; Norethindrone acetate: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. (Moderate) Tipranavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as tipranavir boosted with ritonavir, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: (Contraindicated) Coadministration of ribociclib with tipranavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to tipranavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; tipranavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
Ribociclib; Letrozole: (Contraindicated) Coadministration of ribociclib with tipranavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to tipranavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; tipranavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
Rifabutin: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with tipranavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with tipranavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and tipranavir/ritonavir is a strong CYP3A inhibitor. Coadministration with tipranavir/ritonavir increased the AUC of rifabutin by approximately 2.9-fold.
Rifampin: (Contraindicated) The coadministration of tipranavir and rifampin is contraindicated. Rifampin induces CYP isoenzymes, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90%. Loss of antiretroviral efficacy and the potential for viral resistance is expected during concurrent use.
Rifapentine: (Major) Avoid coadministration of protease inhibitors and rifapentine as concurrent use may result in significant decreases in the plasma concentrations of the antiretroviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Riluzole: (Moderate) Coadministration of riluzole with tipranavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and tipranavir is a CYP1A2 inducer.
Riociguat: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Tipranavir is a potent inhibitor of CYP3A4. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Ripretinib: g> (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with tipranavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Moderate) Monitor for an increase in risperidone-related adverse effects if concomitant use with tipranavir is necessary and reduce risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, an anticipatory dosage decrease may be considered prior to initiation of tipranavir. Concomitant use may increase risperidone exposure. Risperidone is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with other strong CYP2D6 inhibitors increased risperidone overall exposure by 2.5- to 9-fold.
Ritlecitinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with ritlecitinib is necessary. Concomitant use may increase the plasma concentrations of tipranavir. Tipranavir is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and tipranavir may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Tipranavir is a potent inhibitor CYP3A4 and mild inducer of P-gp, and rivaroxaban is a substrate of CYP3A4 and P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Roflumilast: (Moderate) Coadminister tipranavir and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Tipranavir is a strong inhibitor of CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving one of several CYP3A4 inhibitors, including cimetidine, enoxacin, erythromycin, fluvoxamine, or ketoconazole, resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Romidepsin: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and tipranavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
Rosuvastatin: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when tipranavir is given in combination with most HMG-CoA reductase inhibitors. If rosuvastatin is to be used concomitantly with tipranavir (in the FDA approved dosage regimen), use the lowest possible dose with careful monitoring, or consider an alternative HMG-CoA reductase inhibitor that is less significantly metabolized by CYP3A4 (i.e., fluvastatin, pravastatin).
Rosuvastatin; Ezetimibe: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when tipranavir is given in combination with most HMG-CoA reductase inhibitors. If rosuvastatin is to be used concomitantly with tipranavir (in the FDA approved dosage regimen), use the lowest possible dose with careful monitoring, or consider an alternative HMG-CoA reductase inhibitor that is less significantly metabolized by CYP3A4 (i.e., fluvastatin, pravastatin).
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with tipranavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of tipranavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with tipranavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Contraindicated) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with saquinavir results in decreased saquinavir concentrations (76% reduction in AUC). It is recommended that these drugs not be coadministered.
Saxagliptin: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as tipranavir boosted with ritonavir. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Segesterone Acetate; Ethinyl Estradiol: (Major) Segesterone is not recommended for women who require the chronic use of drugs that are potent inducers of hepatic enzymes, as contraceptive efficacy is likely to be reduced. Several of the anti-retroviral protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean area under the curve (AUC) of the estrogen and progestin have been noted in some cases. The efficacy and safety of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors; it is unknown whether this applies to segesterone. Healthcare providers should refer to the labeling of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Hormonal contraceptives may decrease the serum concentrations of amprenavir and fosamprenavir, which could lead to loss of virologic response and possible viral resistance; thus, segesterone should not be administered with amprenavir or fosamprenavir. (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Selpercatinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with selpercatinib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; selpercatinib is a P-gp inhibitor.
Sertraline: (Moderate) Use caution when coadministering sertraline with a combination of tipranavir plus ritonavir because increased sertraline concentrations may occur. Tipranavir and ritonavir are potent CYP3A4 inhibitors and sertraline is a substrate of CYP3A4. Patients should be monitored for sertraline-induced adverse effects, including nausea, vomiting, diarrhea, and QT prolongation.
Sildenafil: (Major) Sildenafil is contraindicated for use with tipranavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Major) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as anti-retroviral protease inhibitors may cause significant increases in silodosin plasma concentrations.
Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Siponimod: (Moderate) Concomitant use of siponimod and tipranavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with taurursodiol is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; taurursodiol is a P-gp inhibitor.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
Solifenacin: (Major) If coadministered with tipranavir do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. The plasma concentrations of solifenacin may be elevated when administered concurrently with tipranavir. Monitor for excessive anticholinergic effects. Solifenacin is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid concomitant use of sonidegib and tipranavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Tipranavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sorafenib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with sorafenib is necessary. Tipranavir is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotorasib: (Moderate) Monitor for decreased efficacy or increased toxicity of tipranavir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of tipranavir. Tipranavir is a CYP3A and P-gp substrate; sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Sparsentan: (Major) Avoid concomitant use of sparsentan and tipranavir. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. Sparsentan is a CYP3A substrate and P-gp inhibitor and tipranavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Stiripentol: (Moderate) Consider a dose adjustment of tipranavir when coadministered with stiripentol. Coadministration may alter plasma concentrations of tipranavir resulting in an increased risk of adverse reactions and/or decreased efficacy. Tipranavir is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if protease inhibitors must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If protease inhibitors is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a CYP3A inhibitor like protease inhibitors can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If protease inhibitors is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfonylureas: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sunitinib: (Major) Avoid coadministration of tipranavir with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and tipranavir is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Tipranavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with tipranavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and a protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tipranavir is a strong CYP3A4 inhibitor.
Tadalafil: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of tipranavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of tipranavir therapy. Stop tadalafil at least 24 hours prior to starting tipranavir. After at least 1 week of tipranavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and tipranavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with tipranavir is necessary. Talazoparib is a P-gp substrate and tipranavir is a P-gp inhibitor.
Tamoxifen: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with tipranavir is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Tipranavir is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as tipranavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with tipranavir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Major) Avoid coadministration of tipranavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); tipranavir exposure may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of tipranavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Tipranavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tipranavir.
Tenofovir Alafenamide: (Major) Administering tenofovir alafenamide concurrently with tipranavir boosted with ritonavir is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp); tipranavir boosted with ritonavir is an inducer of P-gp.
Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Tepotinib: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with tepotinib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; tepotinib is a P-gp inhibitor.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with tipranavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C19, and CYP3A4; tipranavir is an inducer of CYP1A2 and CYP2C19, and an inhibitor of CYP3A4. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Tetrabenazine: (Major) The primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Increased alpha-HTBZ and beta-HTBZ serum concentrations may occur during coadministration with tipranavir, leading to an increased risk of tetrabenazine-related adverse reactions. When tetrabenazine is given with a strong inhibitor of CYP2D6, such as tipranavir, the maximum single dose of tetrabenazine should not exceed 25 mg and the daily dose should not exceed 50 mg.
Tezacaftor; Ivacaftor: (Major) If tipranavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in tipranavir-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase tipranavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and tipranavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with tipranavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); tipranavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thiazolidinediones: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and tipranavir if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; tipranavir is a strong CYP3A4 inhibitor.
Thrombin Inhibitors: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants or platelet inhibitors. In clinical trials, there have been 14 reports of intracranial bleeding (intracranial hemorrhage, ICH), including 8 fatalities, in 13 out of 6,840 HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. The median time to onset of an ICH event was 525 days on tipranavir treatment. In general, there have been no reported patterns of abnormal coagulation parameters in patients receiving tipranavir, or preceding the development of ICH. Routine measurement of coagulation parameters does not appear to be indicated. An increased risk of ICH has previously been observed in patients with advanced HIV disease or AIDS; further investigations are ongoing to assess the role of tipranavir in ICH. While coadministration with warfarin does not result in altered warfarin concentrations, alterations in INR may still occur; close monitoring of the patient's INR is recommended. Patients should be advised to promptly report any signs or symptoms of bleeding.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as tipranavir. Although not studied, ticagrelor is a substrate of CYP3A4/5 and concomitant use with tipranavir may increase ticagrelor exposure which may increase the bleeding risk.
Ticlopidine: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Tirofiban: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with tipranavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tipranavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with tipranavir. Tipranavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with tipranavir. Concurrent use may increase tolterodine exposure. Tipranavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and tipranavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; tipranavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Toremifene: (Major) Avoid coadministration of tipranavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with tipranavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Trandolapril; Verapamil: (Moderate) Verapamil is a substrate and inhibitor of CYP3A4, is a substrate of Pgp, and can prolong the PR interval; both pharmacokinetic and pharmacodynamic interactions may occur with tipranavir. Cautious dose titration of verapamil should be considered.
Trazodone: (Major) Avoid coadministration of trazodone with tipranavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Tipranavir may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as protease inhibitors, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects.
Tucatinib: (Moderate) Coadministration of tipranavir with tucatinib may result in increased tipranavir exposure, leading to an increase in tipranavir-related adverse effects. Tipranavir is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Ulipristal: (Minor) Concomitant use of ulipristal and tipranavir may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Upadacitinib: (Major) During concomitant use of upadacitinib and tipranavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, and consideration of a dose reduction, based on tolerability, is recommended in patients taking a strong CYP2D6 inhibitor. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of valbenazine and its active metabolite may be higher in patients taking a strong CYP3A4 or CYP2D6 inhibitor and QT prolongation may become clinically significant. Because tipranavir is both a strong CYP3A4 and CYP2D6 inhibitor, the potential increase in effects of such a combination with valbenazine are unknown.
Valproic Acid, Divalproex Sodium: (Major) Coadministration of tipranavir and valproic acid, divalproex sodium may result in decreased valproic acid concentrations. Monitor valproic acid concentrations and efficacy.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with tipranavir boosted with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and tipranavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with tipranavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of tipranavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of tipranavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
Verapamil: (Moderate) Verapamil is a substrate and inhibitor of CYP3A4, is a substrate of Pgp, and can prolong the PR interval; both pharmacokinetic and pharmacodynamic interactions may occur with tipranavir. Cautious dose titration of verapamil should be considered.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as tipranavir. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with tipranavir is necessary. Vinblastine is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vincristine: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with tipranavir is necessary. Vinorelbine is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
Vitamin D: (Major) Tipranavir should be used with caution in patients who may be at risk of increased bleeding, such as in patients taking high doses of vitamin E. In vitro, tipranavir was observed to inhibit human platelet aggregation at concentrations consistent with human exposure at regular doses. In rats, coadministration with vitamin E increased the bleeding effects of tipranavir.
Vitamin E: (Major) Tipranavir should be used with caution in patients who may be at risk of increased bleeding, such as in patients taking high doses of vitamin E. In vitro, tipranavir was observed to inhibit human platelet aggregation at concentrations consistent with human exposure at regular doses. In rats, coadministration with vitamin E increased the bleeding effects of tipranavir.
Vitamin E: (Major) Tipranavir should be used with caution in patients who may be at risk of increased bleeding, such as in patients taking high doses of vitamin E. In vitro, tipranavir was observed to inhibit human platelet aggregation at concentrations consistent with human exposure at regular doses. In rats, coadministration with vitamin E increased the bleeding effects of tipranavir.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and tipranavir is contraindicated as use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Concomitant use may also increase tipranavir exposure and adverse effects. Voclosporin is a sensitive CYP3A4 substrate and P-gp inhibitor and tipranavir is a strong CYP3A4 inhibitor and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and tipranavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with tipranavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) There is a potential for a bi-directional inhibition between voriconazole and protease inhibitors, such as tipranavir. Coadministration of tipranavir boosted with ritonavir and voriconazole has not been studied; however, their concurrent use is not recommended unless the benefit outweighs the risk.
Vortioxetine: (Major) Concurrent use of tipranavir and vortioxetine may result in increased plasma concentrations of vortioxetine due to CYP2D6 inhibition by tipranavir. Because the primary isoenzyme involved in the metabolim of vortioxetine is CYP2D6, the manufacturer recommends a reduction in the vortioxetine dose by one-half during co-administration with strong inhibitors of CYP2D6. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
Voxelotor: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with voxelotor is necessary. Concomitant use may increase the plasma concentrations of tipranavir. Tipranavir is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with tipranavir; concurrent use may increase the risk of bleeding or reduce efficacy. Tipranavir is a CYP3A4 inhibitor as well as CYP1A2 inducer. Warfarin is a substrate of CYP3A4 and CYP1A2.
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as tipranavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with tipranavir/ritonavir. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of tipranavir/ritonavir, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Zidovudine, ZDV: (Moderate) Concurrent administration of tipranavir and ritonavir with zidovudine results in decreased zidovudine concentrations. The clinical significance of this interaction has not been established, and no recommendations for zidovudine dosage adjustments are available.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and tipranavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

How Supplied

Aptivus Oral Cap: 250mg
Aptivus Oral Sol: 1mL, 100mg

Maximum Dosage
Adults

1000 mg/day PO.

Geriatric

1000 mg/day PO.

Adolescents

28 mg/kg/day or 750 mg/m2/day, not to exceed 1000 mg/day PO.

Children

 >= 2 years: 28 mg/kg/day or 750 mg/m2/day, not to exceed 1000 mg/day PO.
 < 2 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Tipranavir inhibits HIV protease, an enzyme involved in the replication of HIV. Tipranavir flexibly binds to the active site of HIV protease and inhibits the virus-specific processing of the viral gag and gag-pol polyproteins in HIV infected cells, thus preventing the formation of mature virions. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages). In vitro, tipranavir produces additive to antagonistic antiviral effects when combined with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The drug generally has additive antiviral effects when combined with NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine), and the HIV fusion inhibitor enfuvirtide.[31320]
 
Resistance to tipranavir does occur. Experiments with site-directed mutations of HIV in vitro showed that the presence of 6 protease mutations (I13V, V32I, L33F, K45I, V82L, I84V) conferred greater than 10-fold reduced susceptibility to tipranavir. While cross-resistance among protease inhibitors has been observed, tipranavir displays a less than 4-fold decreased susceptibility against 90% of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses that emerged in vitro had decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, and ritonavir, but remained sensitive to saquinavir.[31320]

Pharmacokinetics

Tipranavir is administered orally. To achieve effective plasma concentrations, each dose is coadministered (boosted) with 200 mg of ritonavir. Coadministration with ritonavir increases tipranavir concentrations by almost 29-fold, presumably by inhibiting hepatic CYP3A metabolism and intestinal P-glycoprotein (P-gp) efflux pump. Tipranavir is extensively bound (more than 99.9%) to plasma proteins, specifically albumin and alpha1-acid glycoprotein; the unbound fraction appears to be independent of total drug concentration. Approximately 80% of a tipranavir dose, at steady state, is excreted in the feces; renal excretion is minimal, with approximately 4% recovered in the urine. The effective mean elimination half-life of tipranavir, when administered with ritonavir, is approximately 6 hours at steady state.[31320]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, CYP3A5, P-gp
Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state; even though, when given alone, ritonavir is a P-gp inhibitor. Tipranavir is predominantly metabolized by CYP3A4, and when administered with ritonavir, a CYP3A4 inhibitor, the metabolism is minimal. When administered with ritonavir, tipranavir has many effects on the CYP isoenzyme system. It is a potent inhibitor of hepatic and intestinal CYP3A4, hepatic and intestinal CYP3A5, and CYP2D6. Marked induction of CYP2C19 and moderate induction of CYP1A2 is also seen. Tipranavir has no net effect on CYP2C9.[31320]

Oral Route

Tipranavir oral absorption is limited. Administration of tipranavir with ritonavir capsules and a meal (500 to 682 Kcal, 25% fat) had no clinically significant effect on tipranavir maximum plasma concentration (Cmax) or systemic exposure (AUC) when compared to fasted conditions. The effect of food on tipranavir, when administered with ritonavir tablets, has not been evaluated. Steady-state concentrations are attained after 7 to 10 days of twice-daily dosing in most patients. Trough concentrations at steady-state are approximately 70% lower than those on Day 1, presumably due to intestinal P-gp induction.[31320]

Pregnancy And Lactation
Pregnancy

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend against the use of tipranavir-containing regimens during pregnancy. According to the guidelines, patients who become pregnant while taking tipranavir should be switched to an alternative treatment regimen. Available data from the Antiretroviral Pregnancy Registry (APR) are insufficient to make conclusions regarding potential of tipranavir to cause birth defects. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. It is strongly recommended that health care providers report cases of antenatal antiretroviral drug exposure. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tipranavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263; or fax: 1-800-800-1052.

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding tipranavir use during breast-feeding and excretion into human breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.