PAXLOVID (nirmatrelvir/ritonavir)

There are 46 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Selected Protease Inhibitors/Amiodarone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ritonavir-boosted nirmatrelvir(1) or tipranavir(2); ritonavir-boosted or unboosted indinavir(3); or nelfinavir (4) may inhibit the metabolism of amiodarone at CYP3A4. CLINICAL EFFECTS: The concurrent administration of amiodarone with ritonavir-boosted nirmatrelvir(1) or tipranavir(2); ritonavir-boosted or unboosted indinavir(3); or nelfinavir (4) may result in increased levels, clinical effects, and toxicity of amiodarone. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent administration of amiodarone with ritonavir-boosted nirmatrelvir(1) or tipranavir(2); ritonavir-boosted or unboosted indinavir(3); or nelfinavir (4) is contraindicated by the manufacturers of these drugs. DISCUSSION: Indinavir has been shown to inhibit CYP3A4. Therefore, the manufacturer of indinavir states that the concurrent administration of indinavir with amiodarone, which is metabolized by CYP3A4, is contraindicated.(3) Nelfinavir has been shown to inhibit CYP3A4. Therefore, the manufacturer of nelfinavir states that the concurrent administration of nelfinavir with amiodarone, which is metabolized by CYP3A4, is contraindicated.(4) Protease inhibitors linked to this monograph include: indinavir, nelfinavir, nirmatrelvir, and tipranavir. Ritonavir is always used with another protease inhibitor as a pharmacokinetic booster and is captured as part of the protease inhibitor regimen.	AMIODARONE HCL, AMIODARONE HCL-D5W, NEXTERONE, PACERONE
Nirmatrelvir-Ritonavir; Tipranavir/Flecainide; Propafenone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Ritonavir-boosted nirmatrelvir and tipranavir may inhibit the metabolism of flecainide by CYP2D6, and of propafenone by CYP2D6 and CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent administration may result in increased levels and clinical effects of flecainide and propafenone, including serious and/or life-threatening effects like QT prolongation and torsades de pointes.(1) PREDISPOSING FACTORS: The interaction with tipranavir may be more severe in patients who are CYP2D6 extensive or intermediate metabolizers. Renal and hepatic impairment may increase risk for excessive QTc prolongation as flecainide and propafenone are both renally and hepatically eliminated. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The concurrent administration of ritonavir-boosted nirmatrelvir or tipranavir and flecainide or propafenone is contraindicated.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: The combination of tipranavir coadministered with ritonavir has been shown to inhibit CYP2D6 and CYP3A4 in vitro and in vivo. Agents that are extensively metabolized by CYP2D6 and CYP3A4 and have high first pass metabolism, like flecainide and propafenone, may be the most susceptible to large increases when coadministered with tipranavir coadministered with ritonavir.(1)	FLECAINIDE ACETATE, PROPAFENONE HCL, PROPAFENONE HCL ER
Protease Inhibitors/Oral Midazolam; Triazolam SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of the benzodiazepines midazolam and triazolam at CYP3A4.(1-30) CLINICAL EFFECTS: Concurrent administration may result in increased levels and clinical effects of the benzodiazepines, which may result in profound sedation, respiratory depression, coma, and/or death.(1-30) Higher triazolam levels may increase risk for anterograde amnesia, "sleep driving" and other complex behavior disorders.(30) PREDISPOSING FACTORS: The elderly are particularly sensitive to increased plasma concentrations of triazolam.(30) PATIENT MANAGEMENT: The manufacturers of the protease inhibitors and US guidelines on use of antiretroviral agents (31) state that concurrent administration of triazolam or oral midazolam with ritonavir-boosted(1-3) darunavir,(4-6) lopinavir,(7-9) nirmatrelvir,(10) paritaprevir,(11) saquinavir,(12-14) or tipranavir (15-17); ritonavir-boosted or unboosted amprenavir,(18-19) atazanavir,(20-21) fosamprenavir,(22-23) indinavir,(24-26); or nelfinavir,(27-29) is contraindicated. Midazolam may be administered by the intravenous route in patients with close clinical monitoring for respiratory depression and/or prolonged sedation. Caution should be exercised and dosage adjustments should be considered if these effects occur. DISCUSSION: In an open-label, randomized study in 14 subjects, lopinavir/ ritonavir (400/100 mg twice daily) decreased the metabolism of single doses of oral and intravenous midazolam (0.025 mg/kg and 5 mg, respectively) by 77% and 92%, respectively.(32) In a double-blind, randomized, cross-over study in 12 subjects, concurrent administration of saquinavir base with oral midazolam increased the bioavailability of oral midazolam from 41% to 90%. The midazolam maximum concentration (Cmax) and area-under-curve (AUC) increased two-fold and five-fold, respectively. The concurrent administration of saquinavir base with intravenous midazolam resulted in a decrease in midazolam clearance by 56% and increased the midazolam half-life from 4.1 hours to 9.5 hours.(33) In a study in 6 healthy subjects, saquinavir base (1200 mg twice daily) increased the AUC and Cmax of a single dose of midazolam (7.5 mg) by 514% and 235%, respectively.(12) In a study in 16 healthy subjects, saquinavir/ritonavir (1000/100 mg twice daily) increased the AUC and Cmax of a single dose of midazolam (7.5 mg) by 1144% and 327%, respectively.(14) In a double-blind study, ritonavir (four doses of 200 mg) decreased the clearance of a single dose of triazolam (0.125 mg) by 96%.(34) Amprenavir,(35), lopinavir,(36) and ritonavir(33,34) have been shown to inhibit triazolam metabolism in vitro in human liver microsomes. In a clinical trial of 13 healthy patients patients receiving concurrent midazolam (3mg) and ritonavir (100 mg three times daily), midazolam AUC increased by a factor of 28.4 +/- 4.2 and oral clearance was reduced to 4.2% of normal.(37) Protease inhibitors linked to this monograph include: amprenavir, atazanavir, fosamprenavir, darunavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir, and tipranavir. Ritonavir, as a pharmacokinetic booster, will alert through the primary protease inhibitor.	HALCION, MIDAZOLAM, MIDAZOLAM HCL, TRIAZOLAM
Selected Protease Inhibitors; Cobicistat/Pimozide SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Protease inhibitors(1-13,15) and cobicistat(14) may inhibit the metabolism of pimozide at CYP3A4. CLINICAL EFFECTS: Concurrent administration may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1-15) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(17) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(17) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(18) PATIENT MANAGEMENT: The concurrent use of pimozide and the protease inhibitors amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5) indinavir,(6,7) nelfinavir,(6,8) nirmatrelvir coadministered with ritonavir,(15) and tipranavir coadministered with ritonavir(13) and cobicistat(14) is contraindicated. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: An in vitro study indicates that pimozide is metabolized at CYP3A4.(15) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(6) Selected CYP3A inhibitors linked include: amprenavir, atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, nelfinavir, nirmatrelvir, paritaprevir, and tipranavir.	PIMOZIDE
Protease Inhibitors/Ergot Alkaloids SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of the ergot alkaloids by CYP3A4, including dihydroergotamine, ergotamine, ergonovine, and methylergonovine. (1-13) CLINICAL EFFECTS: The concurrent administration of a protease inhibitor with an ergot alkaloid may result in elevated levels, clinical effects, and adverse effects of the ergot alkaloids.(1-13) Signs of ergotism may include peripheral vasospasm and ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent administration of ergot alkaloids with amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5) indinavir, (6) the combination of lopinavir and ritonavir,(7) nelfinavir,(8) nirmatrelvir coadministered with ritonavir,(25) ritonavir, (12) saquinavir,(9,10) and tipranavir coadministered with ritonavir(11) is contraindicated. The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as protease inhibitors.(13) Protease inhibitors linked include: amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, ritonavir, saquinavir, and tipranavir. DISCUSSION: There have been several case reports of ergotism developing in patients receiving concurrent ergotamine derivatives with indinavir,(14) nelfinavir,(15) or ritonavir.(16-23) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	DIHYDROERGOTAMINE MESYLATE, ERGOLOID MESYLATES, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, METHYLERGONOVINE MALEATE, METHYSERGIDE MALEATE, MIGERGOT, MIGRANAL, TRUDHESA
Selected Protease Inhibitors/Quinidine SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Boceprevir; nelfinavir; and ritonavir-boosted nirmatrelvir and tipranavir are strong inhibitors of CYP3A4. Quinidine, an antiarrhythmic with a narrow therapeutic range, is metabolized by CYP3A4.(1-5) CLINICAL EFFECTS: Quinidine causes dose-dependent QTc prolongation. Concurrent use with strong inhibitors of CYP3A4 are expected to increase systemic exposure to quinidine, increasing risk for an abnormally long QT interval. Prolongation of the QT interval may lead to life-threatening ventricular arrhythmias, including torsades de pointes.(6) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(6) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(6) PATIENT MANAGEMENT: The concurrent administration of quinidine with either boceprevir; nelfinavir; or ritonavir-boosted nirmatrelvir or tipranavir is contraindicated.(2-5) The manufacturer of a low-dose quinidine combination product(dextromethorphan 20 mg/quinidine 10 mg) makes the following recommendations for patients receiving concomitant treatment with strong-moderate inhibitors of CYP3A4: - Correct hypokalemia and hypomagnesemia prior to initiating therapy and monitor during treatment. - Perform a baseline ECG evaluation, then repeat ECG 3 to 4 hours after the first dose. Product is contraindicated in patients with a prolonged QT interval. - reevaluate ECG if risk factors for arrhythmia change during treatment - Instruct patients to report symptoms consistent with cardiac arrhythmia, e.g. syncope or palpitations. If reported, discontinue treatment and evaluate patient.(7) DISCUSSION: Boceprevir; nelfinavir; and ritonavir-boosted nirmatrelvir and tipranavir(2-5) inhibit CYP3A4 at clinically relevant concentrations. Selected protease inhibitors linked to this monograph include: boceprevir, nelfinavir, nirmatrelvir, and tipranavir. Ritonavir is always used with another protease inhibitor as a pharmacokinetic booster and is captured as part of the protease inhibitor regimen.	NUEDEXTA, QUINIDINE GLUCONATE, QUINIDINE SULFATE
Lovastatin; Simvastatin/Selected CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of HMG-CoA reductase inhibitors that are metabolized by CYP3A4. CLINICAL EFFECTS: Concurrent administration may result in elevated HMG levels, which may increase the risk of myopathy, including rhabdomyolysis.(1-18) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Do not use simvastatin with protease inhibitors,(1-3) with or without cobicistat(2,3) or ritonavir. The manufacturer of simvastatin states that the concurrent use of strong CYP3A4 inhibitors is contraindicated. The manufacturer of lovastatin states that the concurrent use of strong CYP3A4 inhibitors is contraindicated, including protease inhibitors, with or without cobicistat or ritonavir.(4, 25) The manufacturers of atazanavir,(5) cobicistat,(18) darunavir,(6) fosamprenavir,(7) indinavir,(8) the combination of lopinavir with ritonavir,(9) the combination of nirmatrelvir with ritonavir,(17) saquinavir,(11) and tipranavir(12) state that concurrent use of lovastatin or simvastatin is contraindicated. The manufacturer of nirmatrelvir/ritonavir recommends discontinuing use of lovastatin and simvastatin at least 12 hours prior to initiation of nirmatrelvir/ritonavir and holding statin therapy until 5 days after completing nirmatrelvir/ritonavir therapy.(17) The manufacturers of amprenavir(13) and nelfinavir(14) state that lovastatin and simvastatin should not be used with these agents. It would be prudent to utilize fluvastatin in patients treated with protease inhibitors who require HMG-CoA reductase therapy. DISCUSSION: A study in 15 subjects found that darunavir/ritonavir (300/100 mg twice daily) decreased the maximum concentration (Cmax) and area-under curve (AUC) of atorvastatin (10 mg daily) by 64% and 15%, when compared to atorvastatin (40 mg daily) administered alone. Atorvastatin minimum concentration (Cmin) increased by 81% during concurrent therapy.(6) A study in 16 subjects found that fosamprenavir increased atorvastatin Cmax and AUC by 304% and 130%, respectively. Atorvastatin Cmin decreased by 10%.(7) A study in 12 subjects found that lopinavir increased atorvastatin Cmax, AUC, and Cmin by 4.67-fold, 5.88-fold, and 2.28-fold, respectively. Atorvastatin had no clinically significant effect on lopinavir pharmacokinetics.(9) A study in 12 subjects found that lopinavir increased pravastatin Cmax and AUC by 1.26-fold and 1.33-fold, respectively. Pravastatin had no clinically significant effect on lopinavir pharmacokinetics.(9) A randomized, controlled trial in healthy subjects examined the effects of a combination of ritonavir and saquinavir on the pharmacokinetics of atorvastatin, pravastatin, and simvastatin and the effects of pravastatin on nelfinavir pharmacokinetics. The combination of ritonavir and saquinavir decreased pravastatin levels by 50% and increased atorvastatin and simvastatin levels by 79% and 3059%, respectively. Pravastatin had no statistically significant effect on nelfinavir pharmacokinetics.(14) An open-label study in healthy subjects examined the effects of nelfinavir on atorvastatin and simvastatin pharmacokinetics. Nelfinavir increased atorvastatin AUC, Cmax, and Cmin by 74%, 122%, and 39%, respectively. Nelfinavir increased simvastatin AUC and Cmax by 505% and 517%, respectively. There was no effect on nelfinavir pharmacokinetics when compared to historical controls.(14,16) A study in 14 healthy HIV-seronegative adults found that nelfinavir decreased median pravastatin AUC by 46.5%. Nelfinavir also decreased median pravastatin Cmax by 40.1%.(19) In a study of 25 HIV-positive patients, 13 patients were treated with pravastatin and 12 patients were treated with fluvastatin. Within the 25 patients, 8 patients were also on concomitant indinavir-containing highly active antiretroviral therapy (HAART). Indinavir plasma levels were not significantly influenced by pravastatin or fluvastatin therapy.(20) Rhabdomyolysis has been reported during concurrent use of simvastatin and nelfinavir(21) or ritonavir.(22) Lovastatin was tested in a single dose, open-labeled, randomized crossover study of ten healthy volunteers. Grapefruit juice increased Cmax of lovastatin 12-fold, and the area under the AUC 15-fold. Likewise, the active metabolite lovastatin acid demonstrated a 4-fold increase in Cmax and a 5-fold increase in AUC. Lovastatin and lovastatin acid concentrations and AUC increased in each subject.(23) A study found that itraconazole (200 mg for 4 days) increased lovastatin (40 mg on day 4)Cmax by greater than 25-fold and lovastatin acid AUC and Cmax by greater than 20-fold and 13-fold. A study found that itraconazole (100 mg for 4 days) increased lovastatin (40 mg on day 4) AUC and Cmax by greater than 14.8-fold and lovastatin acid AUC and Cmax by 15.4 and 11.5-fold.(25) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	ALTOPREV, EZETIMIBE-SIMVASTATIN, FLOLIPID, LOVASTATIN, SIMVASTATIN, VYTORIN, ZOCOR
Eletriptan/Selected Protease Inhibitors; Cobicistat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Cobicistat or protease inhibitors which are strong inhibitors of CYP3A4 may reduce the CYP3A4 mediated metabolism of eletriptan.(1-6) CLINICAL EFFECTS: Concurrent use of eletriptan with strong inhibitors of CYP3A4(1-7) may result in elevated levels of and adverse effects from eletriptan.(1-6) Agents linked to this monograph are: atazanavir, boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir, telaprevir, and tipranavir. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of potent inhibitors of CYP3A4.(2) The UK manufacturer of eletriptan states that eletriptan should not be used together with indinavir, nelfinavir, or ritonavir.(1) If migraine treatment is needed during protease inhibitor therapy, use triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or zolmitriptan.(8-11) DISCUSSION: In a clinical trial, another strong CYP3A4 inhibitor ketoconazole 400 mg, increased the eletriptan maximum concentration (Cmax) and exposure (area-under-curve, AUC) by 2.7-fold and 5.9-fold, respectively. The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1) In another trial, a high dose of a moderate to strong CYP3A4 inhibitor, erythromycin (1000 mg), increased the eletriptan Cmax and AUC by 2-fold and 3.6-fold, respectively. The half-life of eletriptan increased from 4.6 hours to 7.1 hours.(2)	ELETRIPTAN HBR, RELPAX
Irinotecan/Strong CYP3A4 Inhibitors; Darunavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of SN-38, the active metabolite of irinotecan. Strong CYP3A4 inhibitors and darunavir may prevent the breakdown of SN-38 to its inactive metabolites APC, NPC, M2, M3, and M4.(1,2) CLINICAL EFFECTS: Coadministration of irinotecan with a strong CYP3A4 inhibitor may result in increased irinotecan plasma concentration, and therefore increased exposure to its active metabolite SN-38. Increased SN-38 exposure may lead to serious toxicity, including severe neutropenia, interstitial pulmonary disease, and even death.(3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of irinotecan and strong CYP3A4 inhibitors or darunavir is contraindicated.(2-4) Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting irinotecan.(4) The US manufacturer of itraconazole states that concomitant administration with irinotecan is contra-indicated during and two weeks after itraconazole treatment.(5) If concurrent therapy is warranted, consider a four-fold reduction in irinotecan dose.(3) Patients receiving concurrent therapy should be closely monitored for toxicity. DISCUSSION: A randomized cross-over study involving seven patients was performed in which each was given irinotecan 350 mg/m2 IV alone for 90 minutes and followed 3 weeks later by irinotecan 100 mg/m2 given with ketoconazole 200 mg orally 1 hour before or 23 hours after the infusion of irinotecan, or both cycles were given vice versa. With ketoconazole coadministration, the conversion of irinotecan to its inactive metabolite was reduced by 87%, whereas the relative exposure to the active prodrug was increased by 109%. Both hematologic (degree of myelosuppression; percent decrease in neutrophil count) and nonhematologic (nausea, vomiting, and diarrhea) parameters were similar between the courses, despite a 3.5 fold reduced irinotecan dose when given in combination with ketoconazole. The authors concluded that the coadministration of various CYP3A4 inhibitors could potentiate a fatal outcome.(3) A prospective, open-label, randomized study was conducted to determine the pharmacokinetics of lopinavir (LPV)/ritonavir (RTV) administration with irinotecan (CPT11). Eight HIV-infected, Caucasian male patients with Kaposi's sarcoma, stage IV (according to New York University classification) were administered highly active antiretroviral therapy (HAART). HAART consisted of 400 mg lopinavir/ 100 mg ritonavir (Kaletra) twice daily (b.i.d) in association with NRTIs b.i.d. for at least 1 month before the start of anticancer chemotherapy. Patients were then treated with irinotecan as a single agent (150 mg/m2) over a 90 min infusion at days 1 and 10, every 3 weeks. Concomitant LPV/RTV treatment reduced the irinotecan clearance from 21.3 +/- 6.3 to 11.3 +/- 3.5 l/h/m2 (P=0.0008) causing an 89% increase of CPT11 AUC (P=0.001) and a 20% increase in the Cmax of CPT11 (p=0.02). The LPV/RTV treatment increased the AUC of SN38 by 204% (p=0.0001) and AUC of SN38G by 94% (P=0.002). Conversely, LPV/RTV treatment caused an 81% reduction in AUC of APC (p=0.02). Overall, the authors concluded that CYP3A4 inhibitors like LPV/RTV decrease CPT11 clearance and increase SN-38 exposure, potentially leading to CPT11 toxicity if not monitored closely.(7) Strong CYP3A4 Inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	CAMPTOSAR, IRINOTECAN HCL, ONIVYDE
Eplerenone/Strong CYP3A4 Inhibitors; Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of eplerenone.(1-3) CLINICAL EFFECTS: Concurrent use of eplerenone with a strong inhibitor of CYP3A4 or a protease inhibitor may result in 5-fold increases in eplerenone concentrations and toxicity (e.g. hyperkalemia, hypotension).(1-3) PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia. PATIENT MANAGEMENT: The manufacturer of eplerenone states that the concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors are contraindicated with eplerenone.(3) The US manufacturer of itraconazole states that concurrent use of eplerenone is contraindicated during and two weeks after itraconazole treatment.(4) The starting dose of eplerenone for hypertension should be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors.(1) In all patients taking eplerenone who start taking a moderate CYP3A4 inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.(1) DISCUSSION: Ketoconazole (200 mg BID) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by 1.7-fold and 5.4-fold, respectively.(1) The concurrent use of eplerenone with less potent CYP3A4 inhibitors (erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID, and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to 1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1) Strong inhibitors of CYP3A4 and protease inhibitors linked to this monograph include: adagrasib, amprenavir, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,2)	EPLERENONE, INSPRA
Vardenafil (Greater Than 2.5 mg)/Selected Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of vardenafil by CYP3A4. CLINICAL EFFECTS: Concurrent use of vardenafil with protease inhibitors may result in increased levels of and adverse effects from vardenafil, including hypotension, visual changes, and sustained erections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: US guidelines for the use of antiretroviral agents recommends patients receiving protease inhibitors should receive no more than 2.5 mg of vardenafil every 72 hours. US labeling recommendations for concurrent use of vardenafil with protease inhibitors state: -Patients receiving any ritonavir- or cobicistat-containing regimens, including atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nirmatrelvir, paritaprevir, saquinavir, and tipranavir should receive no more than 2.5 mg of vardenafil every 72 hours. -Patients receiving unboosted atazanavir, unboosted fosamprenavir, unboosted indinavir, or nelfinavir should take no more than 2.5 mg of vardenafil every 24 hours. Canadian labeling contraindicates concurrent use of atazanavir/ritonavir, lopinavir/ritonavir, and nirmatrelvir/ritonavir with vardenafil.(6,13,17) Patients should be counseled that they are at an increased risk of vardenafil adverse effects, including hypotension, visual changes, and priapism. DISCUSSION: Concurrent use of indinavir (800 mg three times daily) with vardenafil (10 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 16-fold and 7-fold, respectively. Vardenafil half-life increased 2-fold. At 24-hours post-dose, vardenafil levels fell to approximately 4% of vardenafil Cmax. The AUC and Cmax of indinavir decreased by 30% and 40%, respectively. Concurrent use of ritonavir (600 mg twice daily)with vardenafil (5 mg) increased vardenafil AUC and Cmax by 49-fold and 13-fold, respectively. The half-life of vardenafil increased to 26 hours. The ritonavir AUC and Cmax decreased by 20%.	VARDENAFIL HCL
Alfuzosin;Silodosin;Tamsulosin/Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of alfuzosin,(1) silodosin,(2) and tamsulosin(3) by CYP3A4. CLINICAL EFFECTS: Co-administration of a protease inhibitor may result in increased alfuzosin,(1) silodosin,(2) and tamsulosin(3) levels and serious effects such as hypotension. PREDISPOSING FACTORS: In patients receiving tamsulosin, the interaction may be worse in patients who are CYP2D6 poor metabolizers because tamsulosin also undergoes metabolism by this pathway.(3) PATIENT MANAGEMENT: The US manufacturers of alfuzosin(1) and silodosin(2) state that concurrent use of strong CYP3A4 inhibitors is contraindicated. The US manufacturer of tamsulosin states that tamsulosin should not be used with strong CYP3A4 inhibitors.(3) The US manufacturers of atazanavir,(4) darunavir,(5) fosamprenavir,(6) indinavir,(7) lopinavir/ritonavir,(8) nelfinavir,(9), nirmatrelvir/ritonavir,(10 paritaprevir, (11) saquinavir,(12) and tipranavir(13) state that concurrent use of alfuzosin is contraindicated. DISCUSSION: Administration of ketoconazole (400 mg daily), another inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and 3.2-fold, respectively.(1) Administration of ketoconazole (200 mg daily) increased the Cmax and AUC of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold, respectively.(1) Administration of ketoconazole (200 mg daily for 4 days), increased the Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold, respectively.(2) Administration of ketoconazole (400 mg daily for 4 days) increased the Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold, respectively.(2) In a study in 24 healthy subjects, administration of ketoconazole (400 mg daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin (0.4 mg) by 2.2-fold and 2.8-fold, respectively.(3)	ALFUZOSIN HCL ER, DUTASTERIDE-TAMSULOSIN, JALYN, RAPAFLO, SILODOSIN, TAMSULOSIN HCL, UROXATRAL
Ivabradine/Strong CYP3A4 Inhibitors; Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of ivabradine. Increased levels of ivabradine may cause ivabradine-induced reduction in heart rate which can contribute to increased QT prolongation risk.(1,2) CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 or protease inhibitors may result in elevated levels of and toxicity from ivabradine including a reduction in heart rate which can contribute to QT prolongation or torsades de pointes.(1,2) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The manufacturer of ivabradine states that concurrent use with strong CYP3A4 inhibitors is contraindicated.(1,2) Guideline recommendations state ivabradine should not be used with protease inhibitors.(4,5) The US manufacturer of itraconazole states that concurrent use with ivabradine is contraindicated during and two weeks after itraconazole treatment.(6) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for bradycardia (heart rate less than 50 bpm), dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation (heart palpitations, chest pressure, shortness of breath). DISCUSSION: Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma exposure by 7- to 8-fold.(1) CYP3A4 inhibitors linked to this monograph include: atazanavir, boceprevir, cobicistat, darunavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.	CORLANOR, IVABRADINE HCL
Tolvaptan/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of tolvaptan.(1) Toxicity may result from an overly rapid correction of serum sodium. CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of tolvaptan.(1) Elevated levels of tolvaptan may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of tolvaptan and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent use with tolvaptan is contraindicated during and two weeks after itraconazole treatment.(2) DISCUSSION: Tolvaptan is a substrate of CYP3A4. Concurrent administration of ketoconazole (200 mg daily) increased tolvaptan exposure by 5-fold. Administration of ketoconazole at dosages of 400 mg daily would be expected to produce greater increases, as would concurrent administration with other strong CYP3A4 inhibitors.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3)	JYNARQUE, SAMSCA, TOLVAPTAN
Ranolazine/Strong CYP3A4 Inhibitors; Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of ranolazine.(1,2) CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 or protease inhibitors may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, including torsades de pointes.(1,2) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: The concurrent use of ranolazine with strong CYP3A4 inhibitors or protease inhibitors is contraindicated.(1,2,4-8) The US HIV guidelines state that ranolazine (regardless of dose) is contraindicated with atazanavir when it is boosted with ritonavir. If atazanavir is not boosted with ritonavir, ranolazine should not be coadministered.(8) The US manufacturer of itraconazole states that concurrent administration of ranolazine is contraindicated during and two weeks after itraconazole treatment.(9) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Concurrent use of ketoconazole (200 mg twice daily), a strong CYP3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice daily) by 220%.(1) Concurrent use of diltiazem, a moderate inhibitor of CYP3A4 inhibitor, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 140%, respectively.(1,2) Concurrent use of ranolazine (1000 mg twice daily) did not affect the pharmacokinetics of diltiazem (60 mg TID).(1) Concurrent use of verapamil (120 mg three times daily), a moderate inhibitor of CYP3A4 increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) Ranolazine-induced QTc prolongation is dose and concentration-related.(1,2) Strong CYP3A4 inhibitors and protease inhibitors linked to this monograph include: boceprevir; cobicistat; idelalisib; itraconazole; josamycin; ketoconazole; mibefradil; mifepristone; nefazodone; telaprevir; troleandomycin; tucatinib; ritonavir-boosted darunavir, nirmatrelvir, paritaprevir, and tipranavir; ritonavir-boosted or unboosted atazanavir or indinavir; and nelfinavir.(1,2,10,11) Ritonavir is always used with another protease inhibitor as a pharmacokinetic booster and is captured as part of the protease inhibitor regimen.	ASPRUZYO SPRINKLE, RANOLAZINE ER
Dronedarone/Strong CYP3A4 Inhibitors; Darunavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of dronedarone.(1) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The US manufacturer of dronedarone states that concurrent administration of strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of darunavir states that concurrent use of dronedarone is contraindicated.(3) The US manufacturer of itraconazole states that concurrent administration of dronedarone is contraindicated during and two weeks after itraconazole treatment.(5) If alternatives are not available and concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Concurrent use of ketoconazole and dronedarone (dosages not stated) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dronedarone by 17-fold and 9-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, cobicistat, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, telaprevir, tucatinib, ritonavir-boosted darunavir, paritaprevir, and tipranavir, ritonavir-boosted or unboosted indinavir, and nelfinavir. Ritonavir is always used with another protease inhibitor as a pharmacokinetic booster and is captured as part of the protease inhibitor regimen. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	MULTAQ
Saxagliptin (>2.5 mg)/Strong CYP3A4 Inhibitors; Atazanavir; Darunavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1) DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)	SAXAGLIPTIN HCL, SAXAGLIPTIN-METFORMIN ER
Sildenafil (for PAH)/HIV Protease Inhibitors; Cobicistat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The metabolism of sildenafil by CYP3A4 may be inhibited by the protease inhibitors and cobicistat. CLINICAL EFFECTS: The concurrent administration of sildenafil with a protease inhibitor or cobicistat may result in elevated levels of sildenafil, which may result in increased adverse effects such as hypotension, syncope, visual changes, and priapism. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturers of atazanavir,(1) darunavir,(2) fosamprenavir,(3) indinavir,(4) lopinavir/ritonavir,(5) nelfinavir,(6) nirmatrelvir/ritonavir,(7) saquinavir,(9) tipranavir,(10) cobicistat(11), and ombitasvir-paritaprevir-ritonavir-dasabuvir(15) state that the concurrent use of sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) is contraindicated. The US manufacturer of Revatio states that concurrent use is not recommended.(12) DISCUSSION: In a study in 16 subjects, administration of darunavir/ritonavir (400/100 mg twice daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of sildenafil (25 mg) by 38% and 3%, respectively, when compared to the administration of a 100 mg single dose of sildenafil given without darunavir.(3) In a study in 6 HIV-infected males, indinavir (800 mg every 8 hours) increased the AUC and Cmax of indinavir by 11% and 48%, respectively. Sildenafil AUC increased by 340%.(4) The concurrent administration of ritonavir (400 mg twice daily) at steady state with sildenafil (100 mg single dose) resulted in increases in the sildenafil Cmax and AUC by 300% (4-fold) and 1000% (11-fold), respectively.(7,12-14) After 24 hours, plasma levels of sildenafil were still approximately 200 ng/ml (normally 5 ng/ml 24 hours post-dose).(14) In a study in 27 healthy volunteers, the concurrent use of saquinavir (1200 mg 3 times daily for 8 days) increased the AUC and Cmax of a single dose of sildenafil (100 mg) by 210% and 140%, respectively.(9) Because a safe and effective dosage regimen for the use of sildenafil for PAH with concurrent protease inhibitor therapy has not been determined, the US manufacturer of the protease inhibitors state that concurrent use is contraindicated.(1-10,15)	REVATIO, SILDENAFIL CITRATE
Lurasidone/Protease Inhibitors; Cobicistat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Lurasidone is a sensitive substrate for CYP3A4.(1) Sensitive substrates will have at least a 5-fold increase in area-under-curve (AUC) when given with a strong inhibitor of the enzyme.(2) Protease inhibitors and cobicistat are strong and moderate inhibitors of CYP3A4 and may inhibit the metabolism of lurasidone.(1,3-5) CLINICAL EFFECTS: Concomitant use of lurasidone with inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism, confusion, postural instability or other lurasidone toxicities.(1) PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1) PATIENT MANAGEMENT: The US manufacturer of lurasidone states that concurrent use of a strong CYP3A4 inhibitor is contraindicated.(1) The US Department of Health and Human Services HIV guidelines state that all protease inhibitors boosted with ritonavir or cobicistat are contraindicated.(5) If a patient maintained on lurasidone requires a protease inhibitor for treatment of HIV or hepatitis C, then the patient should be converted to another antipsychotic prior to initiation of protease inhibitor therapy. If a patient is currently on lurasidone and addition of unboosted atazanavir is necessary, the dose of lurasidone should be decreased by 50% of the original dose.(5) If a patient is currently on unboosted atazanavir and lurasidone is added to therapy, the recommended starting dose of lurasidone is 20 mg per day, and the maximum dose is 80 mg daily.(5) DISCUSSION: Pretreatment with ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (10 mg) by 6.9-fold, and 9.0-fold, respectively.(1) Pretreatment with diltiazem (240 mg daily for 5 days), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1) Agents linked to this monograph are atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir, telaprevir, and tipranavir.	LATUDA, LURASIDONE HCL
Ticagrelor/Strong CYP3A4 Inhibitors; Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of ticagrelor.(1,2) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in a substantial increase in exposure to and effects from ticagrelor, including increased risk of bleeding.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The UK manufacturer of ticagrelor states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of ticagrelor states that concurrent use of strong CYP3A4 inhibitors should be avoided.(2) The US manufacturer of itraconazole states that concurrent use of ticagrelor is contraindicated during and two weeks after itraconazole treatment.(3) DISCUSSION: Concurrent ketoconazole increased ticagrelor maximum concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active ticagrelor metabolite decreased by 89% and 56%, respectively.(1) Strong CYP3A4 inhibitors linked include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir/ritonavir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(4,5)	BRILINTA, TICAGRELOR
Slt High Strength Antimuscarinics/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4,5) CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from darifenacin,(1) fesoterodine,(2) and solifenacin.(3,4,5) PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6) PATIENT MANAGEMENT: The US manufacturer of darifenacin states that the daily dose of darifenacin should not exceed 7.5 mg in patients receiving potent CYP3A4 inhibitors.(1) The US manufacturer of fesoterodine states that the daily dose of fesoterodine should not exceed 4 mg in adult patients receiving potent CYP3A4 inhibitors. In pediatric patients, the daily dose of fesoterodine in patients taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients weighing greater than 35 kilograms. Use of fesoterodine in pediatric patients weighing greater than 25 kilograms and up to 35 kilograms is not recommended.(2) The US and Swedish manufacturers of solifenacin state the daily dose should be limited to 5 mg in adults and should not exceed the starting dose in children and adolescents when administered with strong CYP3A4 inhibitors. The starting dose of solifenacin is 2 mg for patients weighing up to 15 kg, 3 mg for patients over 15 kg to 45 kg, 4 mg for patients over 45 kg to 60 kg, and 5 mg for patients over 60 kg.(3,4) The Swedish manufacturer of the combination product of tamsulosin-solifenacin states that the daily dose of solifenacin should not exceed 6 mg in patients receiving potent CYP3A4 inhibitors.(5) The US manufacturer of itraconazole states that concurrent use with fesoterodine or solifenacin is contraindicated in patients with severe renal or hepatic impairment during and two weeks after itraconazole treatment.(7) DISCUSSION: In a study in 10 extensive CYP2D6 metabolizers and 1 poor CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the poor metabolizer, compared to historical controls. The concurrent administration of ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor metabolizer, compared to historical controls.(1) Concurrent administration of darifenacin (30 mg daily) and erythromycin, a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and 95%, respectively. Administration of darifenacin (30 mg daily) and fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 84% and 88%, respectively. No dosage adjustment is recommended during concurrent therapy with moderate inhibitors of CYP3A4.(1) In a study, co-administration of ketoconazole (200 mg twice a day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and 2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6 poor metabolizers, respectively. Fesoterodine Cmax and AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) In another study, ketoconazole (200 mg daily) increased the Cmax and AUC of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers, respectively.(1,2) Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) Concurrent use of ketoconazole (400 mg daily for 21 days) increased the Cmax and AUC of solifenacin (10 mg) by 1.5-fold and 2.7-fold,respectively.(3) Based on a controlled randomized study in 28 healthy adults, oral fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily) was generally well tolerated in patients. A slightly non-clinically significant rise in plasma fesoterodine levels did occur. No clinically significant side effects were reported. The most common side effects reported by patients include: dizziness, blurred vision and abdominal distension when fluconazole was taken with fesoterodine.(8) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(9)	DARIFENACIN ER, FESOTERODINE FUMARATE ER, SOLIFENACIN SUCCINATE, TOVIAZ, VESICARE, VESICARE LS
Flibanserin/Strong or Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4, though CYP2C19 also plays a role in metabolism.(1) CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from flibanserin, including severe hypotension or syncope.(1) PREDISPOSING FACTORS: Patients with any degree of hepatic impairment, who are poor CYP2C19 metabolizers, or who also receive concomitant therapy with strong CYP2C19 inhibitors are expected to have increased systemic concentrations of flibanserin, adding to the risk for hypotension or syncopal episodes.(1) Hypotensive or syncopal episodes are more common when flibanserin is taken during waking hours.(1) PATIENT MANAGEMENT: The concomitant use of flibanserin with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations which may lead to hypotension and syncope. The manufacturer of flibanserin states moderate or strong CYP3A4 inhibitors are contraindicated.(1) If the benefit of initiating a CYP3A4 inhibitor within 2 days of stopping flibanserin clearly outweighs the risk flibanserin-associated hypotension or syncope, monitor and counsel the patient regarding symptoms of hypotension or syncope. Discontinue moderate or strong CYP3A4 inhibitors for 2 weeks before initiating or restarting flibanserin therapy.(1) DISCUSSION: In a drug interaction study with 15 healthy subjects, the combination of flibanserin (100 mg on day 6) and fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5 days) resulted in an increased flibanserin exposure of 7-fold. Hypotension or syncope requiring supine placement with leg elevation occurred in 3 subjects (20%). One patient became unresponsive with a blood pressure of 64/41 mm Hg and required emergency room treatment where she required intravenous saline.(1) Though the combination has not been studied, a similar result is plausible with voriconazole, a strong CYP3A4 inhibitor and moderate CYP2C19 inhibitor.(1) In a drug interaction study with flibanserin 50 mg (one-half of the recommended dose) and ketoconazole 400 mg, flibanserin exposure increased 4.5-fold. One of 24 patients(4%) developed syncope.(1) A study of 12 healthy men and women on itraconazole (400 mg once then 200 mg daily for 4 days) with flibanserin 50 mg given 2 hours after itraconazole found that flibanserin exposure was increased 2.6-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)	ADDYI, FLIBANSERIN
Dapoxetine; Levomilnacipran (Greater Than 80 mg); Vilazodone (Greater Than 20 mg)/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of dapoxetine(1,2) levomilnacipran(3) and vilazodone.(4) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine(1,2) levomilnacipran(3) and vilazodone.(4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of dapoxetine at any dose is contraindicated in patients taking strong inhibitors of CYP3A4.(1,2) The dose of levomilnacipran should not exceed 80 mg daily in patients taking strong inhibitors of CYP3A4.(2) The dose of vilazodone should be reduced to 20 mg daily when coadministered with strong inhibitors of CYP3A4.(3) Monitor patients receiving concurrent therapy for agitation, hallucinations, muscle twitching/stiffness/tightness, rapid heartbeat, high or low blood pressure, sweating or fever, nausea or vomiting, diarrhea, abnormal bleeding or bruising, difficulty urinating or the inability to urinate, seizures or convulsions, signs of mania (greatly increased energy, trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual). DISCUSSION: Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1) Pretreatment with ketoconazole, a strong inhibitor of CYP3A4, increased the Cmax and AUC of levomilnacipran between 1.25 and 1.50-fold and between 1.50 and 1.75-fold, respectively.(3) Ketoconazole increased vilazodone concentrations by 50%.(4) Strong inhibitors of CYP3A4 include: atazanavir, boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-6)	FETZIMA, VIIBRYD, VILAZODONE HCL
Avanafil/Strong CYP3A4 Inhibitors; Atazanavir; Darunavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1-2) CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of avanafil states that the concurrent use of strong inhibitors of CYP3A4 is contraindicated.(1) The US Department of Health and Human Services HIV guidelines state that boosted atazanavir or darunavir should not be coadministered with avanafil. Unboosted atazanavir may be coadministered with avanafil doses not exceeding 50 mg every 24 hours.(2) The US manufacturer of itraconazole states that concurrent use of avanafil is contraindicated during and two weeks after itraconazole treatment.(3) DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of CYP2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2.4-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, elvitegravir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4-5)	AVANAFIL, STENDRA
Naloxegol/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1) PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1) PATIENT MANAGEMENT: The concurrent use of naloxegol and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent administration with naloxegol is contraindicated during and two weeks after itraconazole treatment.(5) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1) DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)	MOVANTIK
Panobinostat (Greater Than 10 mg)/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of panobinostat. CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in elevated levels of and toxicity from panobinostat,(1) including increased risk of bleeding and prolongation of the QT interval which may result in life-threatening arrhythmia and death. PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Reduce the dose of panobinostat to 10 mg when coadministered with strong CYP3A4 inhibitors. Limit the starting dose of panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1) If concurrent therapy is warranted, continue standard monitoring of complete blood counts, ECG, and serum electrolytes. Instruct patients to report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or diarrhea; unusual tiredness, shortness of breath, paleness; unusual or unexplained bleeding or bruising; signs of infection such as fever, cough, or flu-like symptoms. If panobinostat toxicity occurs, panobinostat or the CYP3A4 inhibitor may need to be discontinued.(1) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In 14 patients with advanced cancer, ketoconazole (a strong CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and 73%, respectively.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(1,3-4)	FARYDAK
Elbasvir-Grazoprevir/OATP1B1-3 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of OATP1B1/3 may decrease the hepatocyte uptake and increase the plasma concentrations of elbasvir and grazoprevir.(1-3) CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1/3 may result in elevated levels of grazoprevir and an increased risk of ALT elevations.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of elbasvir-grazoprevir and OATP1B1/3 inhibitors is contraindicated.(1-2,4) If concurrent use is deemed medically necessary, monitor the patient for toxicity and elevated AST levels. DISCUSSION: In a study in 10 subjects, atazanavir/ritonavir (300/100 mg daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of elbasvir (50 mg daily) by 4.15-fold, 4.76-fold, and 6.45-fold, respectively. There were no clinically significant effects on atazanavir levels.(1,2) In a study in 12 subjects, atazanavir/ritonavir (300/100 mg daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 6.24-fold, 10.58-fold, and 11.64-fold, respectively. There were no clinically significant effects on atazanavir levels.(1,2) In a study in 14 subjects, cyclosporine (400 mg single dose) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.95-fold, 1.98-fold, and 2.21-fold, respectively. The Cmax, AUC, and Cmin of grazoprevir (200 mg daily) increased by 17-fold, 15.21-fold, and 3.39-fold, respectively. There were no clinically significant effects on cyclosporine levels.(1,2) In a study in 10 subjects, darunavir/ritonavir (600/100 mg twice daily) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 1.67-fold, 1.66-fold, and 1.82-fold, respectively. There were no clinically significant effects on darunavir levels.(1,2) In a study in 13 subjects, darunavir/ritonavir (600/100 mg twice daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 5.27-fold, 7.50-fold, and 8.05-fold, respectively. There were no clinically significant effects on darunavir levels.(1,2) In a study in 10 subjects, lopinavir/ritonavir (400/100 mg twice daily) increased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 2.87-fold, 3.71-fold, and 4.58-fold, respectively. There were no clinically significant effects on lopinavir levels.(1,2) In a study in 13 subjects, lopinavir/ritonavir (400/100 mg twice daily) increased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 7.31-fold, 12.86-fold, and 21.70-fold, respectively. There were no clinically significant effects on lopinavir levels.(1,2) In single dose studies, rifampin increased levels of both elbasvir and grazoprevir. In a study in 14 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 41%, 22%, and 31%, respectively. In a study in 14 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 29%, 17%, and 21%, respectively. In a study in 12 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and 1.77-fold, respectively. In a study in 12 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1) OATP1B1/3 inhibitors include asciminib, atazanavir, belumosudil, cyclosporine, darunavir, fostemsavir, leniolisib, letermovir, lopinavir, nirmatrelvir/ritonavir, paritaprevir, resmetirom, roxadustat, saquinavir, tipranavir, vadadustat, and voclosporin.(1-3)	ZEPATIER
Lomitapide/Strong or Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Lomitapide is primarily metabolized via CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from lomitapide.(1) PREDISPOSING FACTORS: The interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: Given the magnitude of this interaction and the potential toxicity of lomitapide, moderate and strong CYP3A4 inhibitors are contraindicated.(1) When possible use an alternative to the CYP3A4 inhibitor. If a moderate or strong CYP3A4 inhibitor is required, discontinue lomitapide. Due to its long half-life, it will take 1 to 2 weeks for remaining lomitapide to be eliminated; thus lomitapide adverse effects could occur after discontinuation. The US manufacturer of itraconazole states that concurrent use with lomitapide is contraindicated during and two weeks after itraconazole treatment.(4) DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased lomitapide area-under-curve (AUC) by 27-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-3,5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, lefamulin, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, treosulfan, and verapamil.(1-3)	JUXTAPID
Valbenazine (Greater Than 40 mg)/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of valbenazine.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for valbenazine toxicities such as QT prolongation.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Concurrent use of strong CYP2D6 inhibitors may further increase levels of valbenazine.(1) PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.(1) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a drug interaction study in healthy subjects, coadministration of ketoconazole with valbenazine increased valbenazine maximum concentration (Cmax) and area-under-the-curve (AUC) by 2 and 1.5-fold, respectively. Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 2 and 1.6-fold, respectively. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)	INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE
Cilostazol (Greater than 50 mg BID)/Selected Strong & Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of cilostazol.(1) CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP3A4.(1) DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(3)	CILOSTAZOL
Ubrogepant/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of ubrogepant with strong CYP3A4 inhibitors may result in a significant increase in exposure of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ubrogepant states coadministration with strong CYP3A4 inhibitors is contraindicated.(1) DISCUSSION: Coadministration of ubrogepant with ketoconazole, a strong CYP3A4 inhibitor, resulted in a 9.7-fold and 5.3-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)	UBRELVY
Lumateperone (>10.5 mg)/Strong CYP3A4 Inhib; Protease Inhib SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of lumateperone.(1,2) CLINICAL EFFECTS: Concurrent use of lumateperone with strong CYP3A4 inhibitors or protease inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 10.5 mg once daily in patients receiving strong CYP3A4 inhibitors.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors should not be coadministered with lumateperone.(2) DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, amprenavir, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, fosamprenavir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)	CAPLYTA
Lonafarnib/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of lonafarnib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors with lonafarnib may increase the risk of adverse reactions including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes, nausea and vomiting, increased liver enzymes, myelosuppression, and hypertension.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The use of lonafarnib with strong CYP3A4 inhibitors is contraindicated.(1) Lonafarnib dose modification recommendation: if the QTc interval is greater than or equal to 500 msec, withhold lonafarnib until the QTc interval is less than 470 msec, then resume lonafarnib at the same dosage.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the area-under-curve (AUC) and maximum concentration (Cmax) were increased by 425% and 270%, respectively.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)	ZOKINVY
Cabotegravir-Rilpivirine/Strong CYP3A4 & UGT1A1 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may induce the metabolism of cabotegravir-rilpivirine by CYP3A4 and uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may result in decreased levels and effectiveness of cabotegravir-rilpivirine, as well as the development of resistance.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of cabotegravir-rilpivirine states that concurrent use of CYP3A4 inducers and/or UGT1A1 inducers is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1) DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) In a study in 15 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of cabotegravir by 6%, 59%, and 50%, respectively.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2)	CABENUVA
Cabotegravir/UGT1A1 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir may induce the metabolism of cabotegravir by uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1) CLINICAL EFFECTS: Concurrent or recent use of carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, or ritonavir may result in decreased levels and effectiveness of cabotegravir, as well as the development of resistance.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of cabotegravir states that concurrent use of UGT1A1 inducers such as carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1) DISCUSSION: In a study in 15 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of cabotegravir by 6%, 59%, and 50%, respectively.(1) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2)	APRETUDE, CABOTEGRAVIR ER (CABENUVA), VOCABRIA
Voclosporin/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of voclosporin.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from voclosporin, including infection, neurotoxicity, nephrotoxicity, hypertension, or hyperkalemia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The prescribing information for voclosporin states the use of strong CYP3A4 inhibitors in patients undergoing therapy with voclosporin is contraindicated.(1) Consider alternatives with no or minimal enzyme inhibition. DISCUSSION: Concurrent use of voclosporin and ketoconazole 400 mg daily (strong CYP3A4 inhibitor)for 9 days increased the concentration maximum (Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold, respectively.(1) Concurrent use of voclosporin and verapamil 80 mg three times a day for 10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and AUC by 2.08-fold and 2.71-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)	LUPKYNIS
Finerenone/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of finerenone.(1) CLINICAL EFFECTS: Concurrent use of finerenone with a strong inhibitor of CYP3A4 increases finerenone concentrations and may increase the risk of toxicity (e.g. hyperkalemia, hypotension).(1) PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia. PATIENT MANAGEMENT: The manufacturer of finerenone states that the concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) In all patients taking finerenone with a moderate or weak CYP3A4 inhibitor, monitor serum potassium during drug initiation or dosage adjustment of either finerenone or the moderate or weak CYP3A4 inhibitor. Dose adjustment may be necessary.(1) DISCUSSION: Concurrent use of finerenone with itraconazole, a strong CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by greater than 400%.(1) Concurrent use of finerenone with erythromycin, a moderate CYP3A4 inhibitor, increased finerenone mean AUC by 248% and concentration maximum (Cmax) by 88%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)	KERENDIA
Conivaptan/Selected Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of conivaptan.(1) Toxicity may result from an overly rapid correction of serum sodium. Conivaptan may also increase levels of levoketoconazole.(4) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of conivaptan.(1) Elevated levels of these agents may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of conivaptan and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent use with conivaptan is contraindicated during and two weeks after itraconazole treatment.(2) DISCUSSION: Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan (10mg) and ketoconazole (a strong CYP3A4 inhibitor, 200 mg) resulted in a 4-fold increase in the AUC and an 11-fold increase in the Cmax of conivaptan.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3)	CONIVAPTAN-D5W, VAPRISOL-5% DEXTROSE
Daridorexant/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Canadian and UK manufacturers of daridorexant state that concurrent use of strong CYP3A4 inhibitors is contraindicated.(2-3) The US manufacturer of daridorexant states that concurrent use of strong CYP3A4 inhibitors with daridorexant should be avoided.(1) DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with itraconazole, a strong CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) by 400%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4)	QUVIVIQ
Pacritinib/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of pacritinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of pacritinib.(1) Elevated levels of pacritinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include bleeding, diarrhea, thrombocytopenia, major adverse cardiovascular events, thrombosis, and infection.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The use of strong CYP3A4 inhibitors is contraindicated in patients undergoing therapy with pacritinib.(1) Consider alternatives with no or minimal enzyme inhibition. If coadministration with a strong CYP3A4 inhibitor is unavoidable, monitor for prolongation of the QTc interval.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose according to labeling.(1) DISCUSSION: Clarithromycin (500 mg twice daily for 5 days) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of pacritinib (400 mg) by 30% and 80%, respectively.(1) In a 24 week clinical study, patients treated with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(3,4)	VONJO
Slt Immunosuppressants;Temsirolimus/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus by CYP3A4.(1-7) CLINICAL EFFECTS: Concurrent use of nirmatrelvir-ritonavir may result in increased levels of and risk of toxicity from cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus.(1-7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The American Society of Transplantation (AST) Statement on Oral Antiviral Therapy for COVID-19 for Organ Transplant Recipients states use of nirmatrelvir-ritonavir will be challenging in transplant patients due to significant drug interactions and difficulty with therapeutic drug monitoring in outpatients with active Covid-19 infections. Alternatives such as early use of either an appropriate monoclonal antibody or outpatient intravenous remdesivir may be preferred as first line therapy in transplant patients to prevent progression.(8) The US manufacturer of nirmatrelvir-ritonavir states concurrent use with immunosuppressants should not be used if close monitoring is not feasible.(6) Specific immunosuppressant recommendations: -Cyclosporine: For therapy with nirmatrelvir-ritonavir in patients on cyclosporine, some experts recommend lowering the cyclosporine dose by 80%. -Tacrolimus: For therapy with nirmatrelvir-ritonavir in patients on tacrolimus, experts recommend holding tacrolimus for the 5-day duration of nirmatrelvir-ritonavir therapy. Tacrolimus level is recommended on day 3 to assess the need for a one-time dose of tacrolimus during nirmatrelvir-ritonavir therapy. -As soon as possible after nirmatrelvir-ritonavir therapy, cyclosporine or tacrolimus levels should be checked, and every 2-4 days thereafter until stable, to determine when to increase cyclosporine doses or resume tacrolimus.(7) -Everolimus: For therapy with nirmatrelvir-ritonavir in patients on everolimus, AST states CYP3A4 inhibitors, such as clarithromycin, ketoconazole, voriconazole, and HIV protease inhibitors, are contraindicated with everolimus. The US manufacturer of everolimus states concurrent use should be avoided with strong CYP3A4 inhibitors. -Sirolimus: The US manufacturer of nirmatrelvir-ritonavir(6) and sirolimus protein-bound injection (Fyarro)(9) state concurrent use should be avoided. -Temsirolimus: The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as nirmatrelvir-ritonavir be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If nirmatrelvir-ritonavir is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2) For patients concurrently taking cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus with nirmatrelvir, therapeutic concentration monitoring of the immunosuppressant is recommended. DISCUSSION: A retrospective study evaluated the interaction between cyclosporine or tacrolimus and nirmatrelvir/ritonavir in 25 solid-organ transplant recipients. Upon nirmatrelvir/ritonavir initiation, cyclosporine doses were decreased by 80% and tacrolimus was held for the duration of nirmatrelvir/ritonavir therapy. No patients had acute rejection in the 30 days following nirmatrelvir/ritonavir. In 21 patients on tacrolimus, the median tacrolimus trough concentration before and after nirmatrelvir/ritonavir therapy was 7.4 ng/mL (IQR, 6.6-8.6) and 5.2 ng/mL (IQR, 3.6-8.7), respectively. Four patients had supratherapeutic tacrolimus troughs after restarting tacrolimus. In these patients, tacrolimus was resumed at either reduced dose or at pre-nirmatrelvir/ritonavir dose 2-5 days after completion of nirmatrelvir/ritonavir therapy.(5) Concurrent use of nirmatrelvir/ritonavir with tacrolimus resulted in elevated tacrolimus levels, treatment interruption, and acute kidney injury.(11) In a case series, 12 bilateral lung transplant recipients with COVID-19 were started on nirmatrelvir/ritonavir. All patients were on immediate-release tacrolimus and prednisone, and all except one were also on mycophenolate. Patients stopped tacrolimus 10-14 hours before starting nirmatrelvir-ritonavir and had tacrolimus levels checked between days 3-5 of therapy. One patient required a supplemental 0.5 mg dose of tacrolimus during nirmatrelvir-ritonavir therapy. Six patients had trough levels within goal, and 3 patients had troughs below goal but at adequate immunosuppression level based on the clinicians' judgement. Ten of the patients resumed tacrolimus at 25% of their baseline dose at day 8, and 9 of them resumed full dose tacrolimus by day 10. One patient was hospitalized for worsening COVID-19. No patients experienced tacrolimus side effects or acute rejection.(12) In a case series of 3 renal transplant recipients, tacrolimus was held 1 day before patients started nirmatrelvir-ritonavir therapy. Two patients resumed previous doses of tacrolimus one day after finishing nirmatrelvir/ritonavir; one had stable tacrolimus levels and the other was supratherapeutic. The 3rd patient received a supplemental dose of tacrolimus on day 4 of therapy and resumed his previous dose starting on day 5, and was supratherapeutic on day 6. No patients experienced adverse effects or graft rejection. The authors state that nirmatrelvir/ritonavir is not contraindicated and tacrolimus levels can be closely monitored for patients on tacrolimus.(13) In a case report of a 67-year old patient on chronic tacrolimus therapy, after 4 days of nirmatrelvir-ritonavir she presented to the emergency department with slowed speech, fatigue, weakness, and loss of appetite. The patient's tacrolimus level was 176.4 ng/mL (normal range is 5-20 ng/mL).(14) In a case series of 4 renal transplant recipients, tacrolimus was paused during nirmatrelvir-ritonavir therapy, which resulted in stable therapeutic levels. In one patient, tacrolimus was resumed immediately and resulted in a toxic tacrolimus level. In three patients, tacrolimus was resumed at a reduced dose 24 hours after nirmatrelvir-ritonavir was stopped and resulted in therapeutic to supratherapeutic tacrolimus levels.(15) In a case report of a 39-year-old female, the patient developed a sudden increase in tacrolimus levels after starting nirmatrelvir-ritonavir.(16) In a PKPB model, tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with tacrolimus alone.(17) The selected immunosuppressants linked to this monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.	AFINITOR, AFINITOR DISPERZ, ASTAGRAF XL, CYCLOSPORINE, CYCLOSPORINE MODIFIED, ENVARSUS XR, EVEROLIMUS, FYARRO, GENGRAF, NEORAL, PROGRAF, SANDIMMUNE, SIROLIMUS, TACROLIMUS, TACROLIMUS XL, TEMSIROLIMUS, TORISEL, TORPENZ, ZORTRESS
Nirmatrelvir-Ritonavir/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of nirmatrelvir.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of nirmatrelvir.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong CYP3A4 inducers with nirmatrelvir is contraindicated.(1) DISCUSSION: In a study of 12 healthy volunteers, carbamazepine was titrated to 300 mg every 12 hours and then coadministered with nirmatrelvir/ritonavir 300 mg/100 mg on day 15 of carbamazepine. Carbamazepine decreased nirmatrelvir AUC and Cmax by 55% and 43%, respectively, and decreased ritonavir AUC and Cmax both by about 74%.(2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(8,9)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI
Pimavanserin (Greater Than 10 mg)/Strong CYP3A4 Inhibitors; Protease Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of pimavanserin.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors or HIV protease inhibitors may increase systemic exposure and the risk for pimavanserin toxicities such as peripheral edema, confusion, or QT prolongation.(1,2) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) PATIENT MANAGEMENT: When concomitant use of pimavanserin and a strong CYP3A4 inhibitor or HIV protease inhibitor is needed, the pimavanserin dose should be reduced to 10 mg once daily.(1,2) With unboosted atazanavir, consider using alternative antipsychotic agents.(2) During concomitant therapy with a strong CYP3A4 inhibitor or HIV protease inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a drug interaction study, ketoconazole increased pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC) 3-fold. A thorough QTc study performed in 252 subjects found a mean maximum change from baseline of 13.5 msec (upper bound of the 90% confidence interval was 16.6 msec) at twice the therapeutic dose.(1) Thus, coadministration of pimavanserin and a QT prolonging agent, even at a reduced dose, may increase the risk for significant QT prolongation. CYP3A4 inhibitors linked to this monograph include: atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(4)	NUPLAZID
Rivaroxaban/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5) CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban,(1-3) including an increased risk of bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The US manufacturer of nirmatrelvir-ritonavir states concurrent use with rivaroxaban should be avoided.(4) The Canadian manufacturer of nirmatrelvir-ritonavir states use with rivaroxaban should not be used concomitantly.(5) The Journal of American College of Cardiology states use of nirmatrelvir-ritonavir with rivaroxaban should be avoided. Use of rivaroxaban cannot be safely adjusted or interrupted. If nirmatrelvir-ritonavir is deemed necessary, withhold rivaroxaban for 24-36 hours before starting nirmatrelvir-ritonavir. Use of an alternative anticoagulant is recommended for a total of 8 days. Rivaroxaban may be restarted on day 9.(6) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Concurrent use of rivaroxaban with ketoconazole (400 mg daily) increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively. There were also significant increases in pharmacodynamic effects.(1-3) Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban by 40% and 50%, respectively and is not expected to affect bleeding risk.(2) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(2) in patients with normal renal function.(3)	RIVAROXABAN, XARELTO
Colchicine (for Cardioprotection)/Strong CYP3A4 Inhibitors;Atazanavir;Darunavir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal or hepatic impairment.(1,2) PATIENT MANAGEMENT: The manufacturer of colchicine used for cardiovascular risk reduction states that concurrent use of colchicine with strong CYP3A4 inhibitors is contraindicated.(1) DISCUSSION: There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2% (range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%), respectively.(1) In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to 419.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,10)	LODOCO
Suzetrigine/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Suzetrigine and M6-SUZ (active metabolite of suzetrigine) are CYP3A4 substrates. Strong CYP3A4 inhibitors increase suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse reactions.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from suzetrigine including pruritis, muscle spasms, increased blood creatine phosphokinase, and rash.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of suzetrigine and strong CYP3A4 inhibitors is contraindicated.(1) DISCUSSION: Concomitant administration of itraconazole (a strong CYP3A4 inhibitor) with a single dose of suzetrigine increased the area-under-curve (AUC) of suzetrigine and active metabolite M6-SUZ by 4.8-fold and 4.4-fold, respectively, while the maximum concentration (Cmax) of suzetrigine increased by 1.5-fold and Cmax of M6-SUZ decreased by 32%.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)	JOURNAVX

Drug contraindication overview.

*History of clinically significant hypersensitivity reactions (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to nirmatrelvir, ritonavir, or any other ingredient in the preparation. *Concomitant use of drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; these drugs include, but are not limited to, alfuzosin, ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, colchicine (in patients with renal and/or hepatic impairment), lurasidone, pimozide, silodosin, eplerenone, ivabradine, dihydroergotamine, ergotamine, methylergonovine, lovastatin, simvastatin, voclosporin, lomitapide, eletriptan, ubrogepant, finerenone, naloxegol, sildenafil (Revatio(R)) for treatment of pulmonary arterial hypertension, triazolam, oral midazolam, flibanserin, and tolvaptan. *Concomitant use of potent CYP3A inducers that can significantly reduce nirmatrelvir or ritonavir plasma concentrations and result in potential loss of virologic response and possible resistance; these drugs include, but are not limited to, apalutamide, carbamazepine, phenobarbital, primidone, phenytoin, lumacaftor/ivacaftor, rifampin, rifapentine, and St.

John's wort (Hypericum perforatum). Do not start ritonavir-boosted nirmatrelvir immediately after discontinuation of any of these drugs due to the delayed offset of the recently discontinued CYP3A inducer.

Adverse reaction overview.

Adverse effects reported in >=1% of patients receiving ritonavir-boosted nirmatrelvir for the treatment of COVID-19 and more frequently than placebo include dysgeusia and diarrhea.

The FDA EUA permits use of ritonavir-boosted nirmatrelvir for the treatment of COVID-19 in certain pediatric patients >=12 years of age weighing at least 40 kg. Use of ritonavir-boosted nirmatrelvir is not authorized for pediatric patients <12 years of age or those weighing less than 40 kg. Safety and efficacy of ritonavir-boosted nirmatrelvir have not been established in pediatric patients.

The pharmacokinetics of ritonavir-boosted nirmatrelvir have not been evaluated in pediatric patients <18 years of age. The EUA-recommended dosage of ritonavir-boosted nirmatrelvir is expected to result in plasma concentrations of the drugs in patients >=12 years of age weighing at least 40 kg that are comparable to those observed in adults since adults with similar body weight were included in the EPIC-HR trial evaluating ritonavir-boosted nirmatrelvir for the treatment of COVID-19.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None