Voydeya

Dosing information for VOYDEYA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
VOYDEYA 100 MG TABLET	Maintenance	Adults take 2 tablets (200 mg) by oral route 3 times per day
VOYDEYA 150 MG DOSE TABLET	Maintenance	Adults take by oral route 3 times per day as directed per package instructions

The following drug interaction information is available for VOYDEYA (danicopan):

Contraindicated
Severe
Moderate

There are 2 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
Colchicine (for Cardioprotection)/P-glycoprotein (P-gp) 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: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2) CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; 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 P-gp inhibitors is contraindicated.(1) DISCUSSION: There are several reports of colchicine toxicity(3-5) and death(6,7) 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.(8) 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) There is one case report of colchicine toxicity with concurrent erythromycin.(9) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), 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) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, verapamil, vimseltinib, and voclosporin.(1,10,11)	LODOCO
Rosuvastatin (> 10 mg)/Danicopan 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: Danicopan is an inhibitor of the BCRP transporter and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of danicopan may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) 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. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of danicopan states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with danicopan.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, danicopan (at steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET

Drug Interaction

Drug Names

Colchicine (for Cardioprotection)/P-glycoprotein (P-gp) 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: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; 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 P-gp inhibitors is contraindicated.(1)

DISCUSSION: There are several reports of colchicine toxicity(3-5) and death(6,7) 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.(8) 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) There is one case report of colchicine toxicity with concurrent erythromycin.(9)

In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1)

In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), 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) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, verapamil, vimseltinib, and voclosporin.(1,10,11)

LODOCO

Rosuvastatin (> 10 mg)/Danicopan

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: Danicopan is an inhibitor of the BCRP transporter and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3)

CLINICAL EFFECTS: Concurrent use of danicopan may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3)

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. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The US manufacturer of danicopan states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with danicopan.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2)

DISCUSSION: In a study, danicopan (at steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)

CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET

There are 14 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Dabigatran/Selected P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3) CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding. PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-4) PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors (e.g., glecaprevir-pibrentasvir) is contraindicated. When dabigatran is used for the prevention of venous thromboembolism (VTE) after total hip or knee replacement concurrently with amiodarone, quinidine, or verapamil, the dose of dabigatran should be reduced from 110 mg twice daily to 150 mg once daily. For patients with CrCl less than 50 ml/min on verapamil, a further dabigatran dose reduction to 75 mg once daily should be considered. Verapamil should be given at least 2 hours after dabigatran to minimize the interaction.(2) The UK manufacturer of dabigatran also states the use of dabigatran with strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or itraconazole) is contraindicated. Concurrent use of ritonavir is not recommended. When dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with verapamil, the UK manufacturer recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg twice daily, taken simultaneously with verapamil. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil, consider further lowering the dabigatran dose to 75 mg daily.(3) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(5) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(6) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(7) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(9) P-gp inhibitors include amiodarone, asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan, daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir, propafenone, quinidine, ranolazine, ritonavir, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, voclosporin, and voxilaprevir.(1-9)	DABIGATRAN ETEXILATE, PRADAXA
Topotecan/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of P-glycoprotein may increase the absorption of topotecan.(1) CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of P-glycoprotein may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and P-glycoprotein inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1) DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg) increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and total topotecan to 2-fold to 3-fold of the control group, respectively.(1) P-gp inhibitors linked to this monograph include: adagrasib, amiodarone, asciminib, asunaprevir, azithromycin, belumosudil, bosutinib, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, hydroquinidine, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir/glecaprevir, pirtobrutinib, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sotorasib, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, and voclosporin.(2,3)	HYCAMTIN
Aliskiren/Selected P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Aliskiren is a substrate for the P-glycoprotein (P-gp) system. Inhibitors of P-gp may increase the absorption of aliskiren.(1-3) CLINICAL EFFECTS: The concurrent use of aliskiren and P-gp inhibitors may result in elevated levels of aliskiren. This may result in increased effect and toxicity of aliskiren including hypotension.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of aliskiren states that concurrent use of itraconazole should be avoided.(1) The UK manufacturer of aliskiren states that the concurrent use of P-gp inhibitors such as itraconazole is contraindicated.(2) The US manufacturer of itraconazole states that concurrent administration of aliskiren is not recommended during and two weeks after itraconazole treatment.(4) DISCUSSION: In a study in healthy subjects, concurrent itraconazole (100 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of aliskiren (150 mg) by 5.8-fold and 6.5-fold, respectively.(2,3) Selected P-gp inhibitors linked to this monograph include: azithromycin, belumosudil, clarithromycin, danicopan, daridorexant, fostamatinib, indinavir, itraconazole, lopinavir/ritonavir, mavorixafor, nirmatrelvir/ritonavir, pirtobrutinib, rifampin and vimseltinib.(4,5)	ALISKIREN, TEKTURNA
Pazopanib/Selected Inhibitors of P-gp or BCRP SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of pazopanib.(1) CLINICAL EFFECTS: The concurrent administration of pazopanib with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of pazopanib and signs of toxicity.(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 pazopanib states concurrent use of P-gp inhibitors or BCRP inhibitors should be avoided.(1) Monitor patients for increased side effects from pazopanib. 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: Pazopanib is a substrate of P-gp and BCRP. Inhibitors of these transporters are expected to increase pazopanib levels.(1) BCRP inhibitors linked to this monograph include: asciminib, belumosudil, clopidogrel, cyclosporine, darolutamide, eltrombopag, gefitinib, grazoprevir, lazertinib, leflunomide, leniolisib, momelotinib, oteseconazole, rolapitant, roxadustat, tafamidis, teriflunomide, and vadadustat.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)	PAZOPANIB HCL, VOTRIENT
Colchicine (for Gout & FMF)/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2) CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; 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 and/or hepatic impairment(1,2) and in patients who receive concurrent therapy. PATIENT MANAGEMENT: The concurrent use of colchicine with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken a P-gp inhibitor in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-12) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea/significant diarrhea, vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands. 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) There is one case report of colchicine toxicity with concurrent erythromycin.(10) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), 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) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, verapamil, vimseltinib, and voclosporin.(1,11,12)	COLCHICINE, COLCRYS, GLOPERBA, MITIGARE, PROBENECID-COLCHICINE
Venetoclax/Selected P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Venetoclax is a substrate for the P-glycoprotein (P-gp) system. P-gp inhibitors may lead to increased levels of venetoclax.(1) CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1) PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1) PATIENT MANAGEMENT: Avoid P-gp inhibitors and consider alternative treatments when possible. If a P-gp inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) If the P-gp inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the P-gp inhibitor.(1) DISCUSSION: In 11 healthy subjects, a single dose of rifampin (a P-gp inhibitor) increased venetoclax maximum concentration (Cmax) and area-under-curve (AUC) by 106% and 78%, respectively.(1) In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the Cmax and AUC of venetoclax 2.3-fold and 6.4-fold respectively.(1) In 12 healthy subjects, coadministration of azithromycin (500 mg Day 1, 250 mg for Days 2-5) decreased venetoclax Cmax and AUC by 25% and 35%. No dosage adjustment is needed when venetoclax is coadministered with azithromycin.(1) P-gp inhibitors include: amiodarone, asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, ivacaftor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tezacaftor, tepotinib, valbenazine, vemurafenib, vimseltinib, and voclosporin.(2)	VENCLEXTA, VENCLEXTA STARTING PACK
Cladribine/Selected Inhibitors of BCRP SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of BCRP may increase the absorption of cladribine.(1-2) CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of BCRP may result in elevated levels of cladribine and signs of toxicity.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of BCRP inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the BCRP inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored. DISCUSSION: Cladribine is a substrate of BCRP. Inhibitors of this transporter are expected to increase cladribine levels.(1-2) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, cobicistat, curcumin, danicopan, darolutamide, eltrombopag, elvitegravir, grazoprevir, lazertinib, oteseconazole, pacritinib, ritonavir, roxadustat, tafamidis, ticagrelor, turmeric, and vadadustat.(1-4)	CLADRIBINE, MAVENCLAD
Oral Lefamulin/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of P-gp inhibitors that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib).(1-3) CLINICAL EFFECTS: The concurrent administration of lefamulin with an inhibitor of P-gp may result in elevated levels of lefamulin and signs of toxicity, such as QT prolongation. Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib) may result in elevated levels and toxicities of the sensitive CYP3A4 substrate. 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.(4) 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).(4) PATIENT MANAGEMENT: The US manufacturer of lefamulin states that oral lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1) If concomitant therapy with a P-gp inhibitor is necessary, 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. Concomitant use of asunaprevir, felodipine, ivacaftor, or neratinib requires close monitoring for adverse effects of these drugs.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take lefamulin at least 6 hours before venetoclax.(5) DISCUSSION: Coadministration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) P-gp inhibitors include: asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, ledipasvir, neratinib, pirtobrutinib, propafenone, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, venetoclax, vimseltinib, and voclosporin.(1-3)	XENLETA
Relugolix/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1) CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, verapamil, vimseltinib, and voclosporin.(2,3)	MYFEMBREE, ORGOVYX
Rimegepant/P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rimegepant is a calcitonin gene-related peptide receptor antagonist. Rimegepant is a substrate of the P-glycoprotein (P-gp) transporter. P-gp inhibitors may significantly increase the absorption of rimegepant.(1) CLINICAL EFFECTS: The concurrent administration of rimegepant with an inhibitor of P-glycoprotein may result in elevated levels of rimegepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rimegepant recommends avoiding a second dose of rimegepant within 48 hours of a first dose when used concomitantly with P-gp inhibitors.(1) DISCUSSION: Rimegepant is a substrate of P-gp. Use of P-gp inhibitors may increase the exposure of rimegepant. In a study, cyclosporine (a potent P-gp and BCRP inhibitor) increased rimegepant area-under curve (AUC) and maximum concentration (Cmax) by 1.6- and 1.4-fold, respectively. Quinidine (a potent P-gp inhibitor) similarly increased rimegepant AUC and Cmax by 1.6- and 1.7-fold, respectively. Therefore, the effect of these drug interactions were concluded to be due entirely to P-gp and not BCRP.(1) P-glycoprotein inhibitors linked to this monograph include: amiodarone, azithromycin, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, glecaprevir/pibrentasvir, lapatinib, mavorixafor, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, vemurafenib, vimseltinib, and verapamil.(1-3)	NURTEC ODT
Doxorubicin/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase doxorubicin cellular concentration, as well as decrease biliary or renal elimination.(1) CLINICAL EFFECTS: Increased cellular or systemic levels of doxorubicin may result in doxorubicin toxicity, including cardiomyopathy, myelosuppression, or hepatic impairment.(1) PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with impaired renal or hepatic function. PATIENT MANAGEMENT: Avoid the concurrent use of P-gp inhibitors in patients undergoing therapy with doxorubicin.(1) Consider alternatives with no or minimal inhibition. If concurrent therapy is warranted, monitor the patient closely for signs and symptoms of doxorubicin toxicity. DISCUSSION: Doxorubicin is a substrate of P-gp.(1) Clinical studies have identified and evaluated the concurrent use of doxorubicin and P-gp inhibitors as a target to overcome P-gp mediated multidrug resistance.(2,3) P-gp inhibitors linked to this monograph include: amiodarone, asciminib, asunaprevir, azithromycin, belumosudil, capmatinib, cimetidine, cyclosporine, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, tezacaftor, valbenazine, vemurafenib, verapamil, vimseltinib, and voclosporin.(4,5)	ADRIAMYCIN, CAELYX, DOXIL, DOXORUBICIN HCL, DOXORUBICIN HCL LIPOSOME
Pralsetinib/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of pralsetinib.(1) CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from pralsetinib, including hemorrhagic events, pneumonitis, hepatotoxicity, hypertension, and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3) 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.(4) 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).(4) PATIENT MANAGEMENT: Coadministration of pralsetinib with a P-gp inhibitor should be avoided.(1) If coadministration with a P-gp inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take pralsetinib at least 6 hours before venetoclax.(5) 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 the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3) DISCUSSION: Coadministration of a single dose of cyclosporine 600 mg (a P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib concentration maximum (Cmax) by 48% and area-under-curve (AUC) by 81%.(1) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, carvedilol, cyclosporine, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tezacaftor, tepotinib, valbenazine, venetoclax, vimseltinib, and voclosporin.(6,7)	GAVRETO
Vincristine/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of vincristine.(1) CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from vincristine including myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or bowel obstruction.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of P-gp inhibitors in patients undergoing therapy with vincristine.(1) Consider alternatives with no or minimal P-gp inhibition. The manufacturer of vincristine states that concomitant use of P-gp inhibitors should be avoided.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vincristine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2) DISCUSSION: Vincristine is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of vincristine.(1) There are several case reports of neurotoxicity with concurrent administration of vincristine and itraconazole.(3-5) There is a case report of neurotoxicity with concurrent administration of lopinavir-ritonavir with vincristine.(6) In a prospective study in 22 children receiving various chemotherapy with prophylactic itraconazole oral solution (0.5 ml/kg per day), two children receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one child developed syndrome of inappropriate anti-diuretic hormone secretion (SIADH).(7) Strong inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, elagolix, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, isavuconazonium, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, pirtobrutinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, Schisandra chinensis, selpercatinib, sofosbuvir, sotorasib, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, verapamil, vilazodone, vimseltinib, and voclosporin.(8,9)	VINCASAR PFS, VINCRISTINE SULFATE
Ensartinib/Selected P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1) CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vilazodone, vimseltinib, and voclosporin.(2,3)	ENSACOVE

There are 9 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Etoposide/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase etoposide cellular concentration, decrease biliary or renal elimination, and increase systemic absorption of oral etoposide.(1-4) CLINICAL EFFECTS: Increased cellular or systemic levels of etoposide may result in etoposide toxicity. PREDISPOSING FACTORS: The interaction magnitude may be greater in patients receiving oral etoposide, or with impaired renal or hepatic function. PATIENT MANAGEMENT: Anticipate and monitor for increased hematologic and gastrointestinal toxicities. Adjust or hold etoposide dose when needed. In patients receiving high-dose cyclosporine therapy, etoposide dosages should be reduced by 50%.(1) Monitor for signs of etoposide toxicity. Dosages may need further adjustment. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to etoposide.(5) DISCUSSION: In a study in 16 patients, the administration of etoposide plus cyclosporine increased etoposide area-under-curve (AUC) by 59% and half-life by 73%. Etoposide renal clearance was decreased by 38% and nonrenal clearance was decreased by 52%. White blood cell count nadir was significantly lower during concurrent therapy with cyclosporine and etoposide (1200 mm3) when compared to etoposide alone (2500 mm3). There was also a trend for higher dosages of cyclosporine to exert increased effects on etoposide, although this difference did not reach statistical significance.(1) P-gp inhibitors linked to this monograph are asciminib, asunaprevir, azithromycin, belumosudil, cimetidine, clarithromycin, cyclosporine, daridorexant, danicopan, diosmin, flibanserin, fostamatinib, glecaprevir/pibrentasvir, itraconazole, ivacaftor, josamycin, ketoconazole, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, tucatinib, valbenazine, vemurafenib, verapamil, vimseltinib, and voclosporin.	ETOPOPHOS, ETOPOSIDE
Loperamide/CYP3A4; CYP2C8; P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1) CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2) DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5)	LOPERAMIDE
Everolimus/Moderate CYP3A4; P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 and/or p-glycoprotein (P-gp) may inhibit the metabolism of everolimus.(1) CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 and/or P-gp may result in elevated levels of and toxicity from everolimus.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If concurrent therapy with everolimus and moderate inhibitors of CYP3A4 and/or P-gp is warranted, reduce the dosage of everolimus.(1) In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal angiomyolipoma with TSC, decrease the dose of everolimus to 2.5 mg daily. An increase to 5 mg daily may be considered based on patient tolerance. If the inhibitor is discontinued, allow an elimination period of 2-3 days before increasing the dose to that used prior to the inhibitor.(1) In patients with subependymal giant cell astrocytoma with TSC, reduce the dosage of everolimus by 50% to maintain trough concentrations of 5 ng/ml to 15 ng/ml. If the patient is already receiving 2.5 mg daily, consider a dose of 2.5 mg every other day. Assess everolimus levels 2 weeks after the addition of the inhibitor. Resume the everolimus dose used prior to initiation of the inhibitor after the inhibitor has been discontinued for 3 days, and assess everolimus trough levels 2 weeks later.(1) Guidelines from the American Society of Transplantation state that protease inhibitors are contraindicated, and recommend avoiding the use of erythromycin with everolimus. If the combination must be used, lower the dose of everolimus by up to 50% upon initiation of the antibiotic and monitor levels daily.(3) DISCUSSION: In a study in healthy subjects, concurrent use of erythromycin, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1) In a study in healthy subjects, concurrent use of ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and 15.0-fold, respectively.(1) In a study in healthy subjects, concurrent use of verapamil, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.3-fold and 3.5-fold, respectively.(1) In a study in 16 healthy subjects, concurrent use of verapamil increased everolimus Cmax and AUC by 130% and 250%, respectively.(4) Moderate CYP3A4 and/or P-gp inhibitors include: abrocitinib, amiodarone, amprenavir, aprepitant, asciminib, asunaprevir, atazanavir, avacopan, azithromycin, belumosudil, cimetidine, clofazimine, conivaptan, crizotinib, danicopan, daridorexant, delavirdine, diltiazem, diosmin, dronedarone, duvelisib, erythromycin, fedratinib, flibanserin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, fostamatinib, imatinib, isavuconazonium, ivacaftor, ledipasvir, lenacapavir, letermovir, mavorixafor, netupitant, nilotinib, nirogacestat, pirtobrutinib, propafenone, schisandra, tepotinib, tezacaftor, tofisopam, treosulfan, vemurafenib, verapamil, vimseltinib, and voclosporin.(5-7)	AFINITOR, AFINITOR DISPERZ, EVEROLIMUS, TORPENZ, ZORTRESS
Afatinib/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of afatinib.(1) CLINICAL EFFECTS: The concurrent administration of afatinib with an inhibitor of P-glycoprotein may result in elevated levels of afatinib and signs of toxicity. These signs may include but are not limited to worsening diarrhea, stomatitis, skin rash/exfoliation/bullae or paronychia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of afatinib states the afatinib dose should be reduced by 10 mg if the addition of a P-glycoprotein inhibitor is not tolerated.(1) If afatinib dose was reduced due to addition of a P-gp inhibitor, resume the previous dose after the P-gp inhibitor is discontinued.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to afatinib.(2) DISCUSSION: A drug interaction study evaluated the effects of ritonavir 200 mg twice daily on afatinib exposure. Administration of ritonavir 1 hour before afatinib administration increased systemic exposure by 48%. Afatinib exposure was not changed when ritonavir was administered simultaneously with or 6 hours after afatinib dose.(1) P-glycoprotein inhibitors linked to this monograph are: amiodarone, asunaprevir, azithromycin, belumosudil, carvedilol, cimetidine, clarithromycin, cobicistat, cyclosporine, danicopan, daridorexant, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, propafenone, quinidine, ranolazine, ritonavir, saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tepotinib, tezacaftor, tucatinib, valbenazine, vemurafenib, verapamil, vimseltinib and voclosporin.(1-3)	GILOTRIF
Edoxaban (Greater Than 30 mg)/Select P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. 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: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or 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. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, oral itraconazole, indinavir, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, and voclosporin.(8)	SAVAYSA
Edoxaban (Less Than or Equal To 30 mg)/Select P-gp Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2) CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. 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: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or 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. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, verapamil vimseltinib, and voclosporin.(8)	SAVAYSA
Ubrogepant/P-gp or BCRP Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1) CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, gefitinib, grazoprevir, leniolisib, momelotinib, oteseconazole, rolapitant, roxadustat, safinamide, tafamidis, oral tedizolid, and vadadustat.(2-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, carvedilol, danicopan, daridorexant, neratinib, osimertinib, propafenone, quinidine, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, valbenazine, vimseltinib, and voclosporin.(2-5)	UBRELVY
Rosuvastatin (<= 10 mg)/Danicopan SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Danicopan is an inhibitor of the BCRP transporter and may increase the absorption and/or decrease the elimination of rosuvastatin.(1-3) CLINICAL EFFECTS: Concurrent use of danicopan may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1-3) 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. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of danicopan states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with danicopan.(1) Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study, danicopan (as steady state) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose rosuvastatin 20 mg by 2.2-fold and 3.3-fold, respectively.(1)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET
Mavorixafor/P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Mavorixafor is a substrate of the P-glycoprotein (P-gp) transporter. P-gp inhibitors may significantly increase the absorption of mavorixafor.(1) CLINICAL EFFECTS: Concurrent administration of mavorixafor with an inhibitor of P-glycoprotein may result in elevated levels of and effects from mavorixafor, including potentially life-threatening cardiac arrhythmias, torsades de pointes, and sudden death.(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, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: When used concomitantly with P-gp inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to mavorixafor.(4) 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. DISCUSSION: In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(1) P-glycoprotein inhibitors linked to this monograph include: abrocitinib, Asian ginseng, asunaprevir, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diosmin, elagolix, flibanserin, fostamatinib, ginkgo biloba, glecaprevir/pibrentasvir, ivacaftor, milk thistle, neratinib, pirtobrutinib, quercetin, rolapitant, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, velpatasvir, vilazodone, vimseltinib, and voclosporin.(1,4-6)	XOLREMDI

Paroxysmal nocturnal hemoglobinuria
D59.5	Paroxysmal nocturnal hemoglobinuria [marchiafava-micheli]

Contraindication List
Lactation
Meningococcal meningitis
Meningococcemia

Moderate List
Disease of liver
Hyperlipidemia