Vafseo (vadadustat)

Individualize vadadustat dosing and use the lowest dosage of vadadustat sufficient to reduce the need for RBC transfusions. Do not target a hemoglobin level >11 g/dL.

Vadadustat is available as tablets containing 150 mg, 300 mg, or 450 mg of the drug.

Administer vadadustat tablets orally once daily, with or without food. Swallow tablets whole; do not cut, crush, or chew.

Administer vadadustat >=1 hour before oral iron supplements, products containing iron, or iron-containing phosphate binders. Administer vadadustat >=1 hour before or 2 hours after non-iron-containing phosphate binders.

Vadadustat tablets may be administered without regard to the type or timing of dialysis treatment.

If a dose of vadadustat is missed, take the missed dose as soon as possible, unless it is on the same day as the next dose. If on the same day as the next dose, skip the missed dose and resume dosing at the normal time. Do not administer double doses to make up for a missed dose.

Store vadadustat tablets at 20--25degreesC; excursions permitted to 15--30degreesC.

No dosing information is available for this tab.

Vadadustat is primarily metabolized via glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) enzymes.

In vitro, vadadustat is not an inhibitor of major cytochrome P-450 (CYP) isoenzymes and UGT isoforms, and is not an inducer of CYP isoenzymes 1A2, 2B6, or 3A4.

In vitro, vadadustat is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, organic anion transporter (OAT) 1, and OAT3.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Bcrp Inhibitors/Topotecan

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 the BCRP transporter may increase the intestinal absorption and hepatic uptake of topotecan.(1)

CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of BCRP 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 BCRP 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), a BCRP and P-gp inhibitor, increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, dasabuvir, elbasvir, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, pibrentasvir, pirtobrutinib, regorafenib, resmetirom, ritonavir, roxadustat, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, velpatasvir, voxilaprevir, and zongertinib.(2,3)

Oat3 Inhibitors/Ketorolac

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 organic anion transporter 3 (OAT3) may inhibit the renal clearance of ketorolac.

CLINICAL EFFECTS: Enhanced ketorolac toxicity including gastrointestinal and renal toxicity as well as 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: Concomitant administration of ketorolac and organic anion transporter 3 (OAT3) inhibitors are contraindicated by the manufacturer. 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: Probenecid has been reported to increase serum concentrations and toxicity of nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ketoprofen, naproxen).(1-3) Based upon material from the manufacturer of ketorolac, concurrent administration of probenecid and ketorolac also increases serum concentrations of the NSAID ketorolac and produces a 2-fold increase in the half-life of ketorolac and a 3-fold increase in the area under the plasma concentration-time curve.(4) Ketorolac is a potent NSAID analgesic and increasing the serum concentrations may increase the risk of occurrence of serious renal, GI and hematologic side effects. OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)

Oat3 Inhibitors/Sodium Phenylbutyrate-Taurursodiol

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 organic anion transporter 3 (OAT3) may inhibit the renal elimination of conjugated sodium phenylbutyrate and sodium phenylbutyrate metabolites.(1,2)

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of sodium phenylbutyrate.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) states that concurrent use with organic anion transporter 3 (OAT3) inhibitors should be avoided.(1) The Canadian manufacturer of sodium phenylbutyrate-taurursodiol states that OAT3 inhibitors should not be used with sodium phenylbutyrate-taurursodiol.(2)

DISCUSSION: Probenecid may inhibit the renal elimination of conjugated sodium phenylbutyrate and sodium phenylbutyrate metabolites.(1,2) OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(3)

Oatp1b1-3 Inhibitors/Atrasentan

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: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of atrasentan.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atrasentan, including fluid retention and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of OATP1B1 or 1B3 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study, atrasentan maximum concentration (Cmax) was 4.3 times higher and area-under-curve (AUC) was 3.8 times higher following coadministration of a single dose of 0.75 mg atrasentan with cyclosporine (OATP1B1 and 1B3 inhibitor) compared to atrasentan alone. OATP1B1 and OATP1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cobicistat, cyclosporine, eltrombopag, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, leflunomide, leniolisib, letermovir, lopinavir, nirmatrelvir, ombitasvir-paritaprevir, resmetirom, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, voclosporin, and voxilaprevir.(1,2)

Oatp1b1-3 Inhibitors/Elbasvir-Grazoprevir

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: atazanavir, belumosudil, cyclosporine, darunavir, fostemsavir, leniolisib, letermovir, lopinavir, nirmatrelvir/ritonavir, paritaprevir, resmetirom, roxadustat, saquinavir, tipranavir, vadadustat, and voclosporin.(1-3)

P-Gp Or Bcrp Inhibitors/Ubrogepant (> 50 Mg)

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 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) For patients on concurrent therapy with vimseltinib and ubrogepant: 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) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

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, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5)

Select Bcrp Inhibitors/Aumolertinib

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: Aumolertinib is a substrate for BCRP. Inhibitors of the BCRP transporter may increase the intestinal absorption and decrease hepatic elimination of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use with selected BCRP inhibitors may result in higher systemic concentrations of aumolertinib, which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade de pointes (TdP).(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) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for 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 rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states concomitant administration of aumolertinib should be avoided with BCRP inhibitors.(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. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Based on in vitro data, aumolertinib is a substrate of BCRP.(1) BCRP inhibitors linked to this monograph include: asciminib, clopidogrel, darolutamide, elbasvir/grazoprevir, eltrombopag, enasidenib, febuxostat, fostemsavir, lazertinib, leniolisib, momelotinib, oteseconazole, regorafenib, rolapitant, roxadustat, tafamidis, ticagrelor, vadadustat, and zongertinib.(3,4)

Selected Inhibitors Of P-Gp Or Bcrp/Pazopanib

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 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. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5) 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, curcumin, darolutamide, eltrombopag, enasidenib, febuxostat, fostemsavir, grazoprevir, lazertinib, leflunomide, leniolisib, momelotinib, oteseconazole, pirtobrutinib, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, and zongertinib.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)

Strong Oatp1b1 Inhibitors/Elagolix

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 OATP1B1 may decrease the hepatic uptake of elagolix.(1,2)

CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1 may result in elevated levels of and side effects from elagolix, including an increased risk of ALT elevations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of elagolix and strong OATP1B1 inhibitors is contraindicated.(1)

DISCUSSION: Strong OATP1B1 inhibitors linked to this monograph include: belumosudil, cyclosporine, encorafenib, gemfibrozil, letermovir, paritaprevir, resmetirom, roxadustat, and vadadustat.(1,2)

Vadadustat/Rosuvastatin (> 5 Mg)

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: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1-4)

CLINICAL EFFECTS: Concurrent use of vadadustat with rosuvastatin may result in increased levels and side effects from rosuvastatin, including myopathy and rhabdomyolysis.(1-4)

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: Labelling recommendations vary between countries. The US manufacturer of vadadustat recommends a maximum daily dose of 5 mg of rosuvastatin in patients receiving concurrent therapy.(4) The UK and Australian manufacturers of vadadustat recommend a maximum daily dose of 10 mg of rosuvastatin in patients receiving concurrent therapy.(2,3) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 2- to 3-fold.(2-4)

Vadadustat/Simvastatin (>20 Mg)

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: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1-4)

CLINICAL EFFECTS: Concurrent vadadustat may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1-4)

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 exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with vadadustat.(1-4) The US manufacturer of vadadustat recommends a starting dose of simvastatin 5 mg daily when receiving concurrent therapy.(4) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) of simvastatin by approximately 2-fold.(2-4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Daprodustat; Roxadustat; Vadadustat/Lenalidomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of daprodustat, roxadustat, or vadadustat with lenalidomide may increase the risk of thrombosis.(1-5)

PREDISPOSING FACTORS: Predisposing factors include a history of thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia, hypertension, heart failure, diabetes mellitus, chronic kidney disease, COPD, obesity, tobacco smoking, major surgery with prolonged post-operative immobilization, and being bed-ridden.

PATIENT MANAGEMENT: The US manufacturer of lenalidomide states the risk of venous thromboembolism (VTE) may be increased when patients are taking concomitant therapy with erythropoietin stimulating agents. Use caution with concomitant use after a patient-specific risk-benefit assessment has been completed. Observe patients for signs and symptoms of VTE and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.(1) The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietic stimulating agents as a high risk factor for venous thromboembolism (VTE). Other risk factors include: active cancer, advanced stage cancer, certain cancer types, regional bulky lymphadenopathy, familial and/or acquired hypercoagulability, medical comorbidities, poor performance status, older age, major surgery, central venous catheter, chemotherapy including lenalidomide plus high-dose dexamethasone, hormone replacement therapy, contraceptives, tamoxifen/raloxifene, diethylstilbestrol, smoking, obesity, or activity level/exercise.(6) The NCCN Guidelines utilize a Risk Assessment Model to determine chemoprophylaxis. In patients with 0-1 risk factors, consider VTE chemoprophylaxis with aspirin 81-325 mg once daily. In patients with >/= 2 risk factors, consider VTE chemoprophylaxis with low-molecular weight heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose to maintain a target international normalized ratio (INR) 2-3.(6)

DISCUSSION: Daprodustat, roxadustat, and vadadustat increase endogenous erythropoietin by increasing transcription of the HIF-responsive genes.(2-5) The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietin as an individual risk factor for venous thromboembolism (VTE). Patients should be assessed for total risk based on NCCN guidelines and recommended for the appropriate VTE chemoprophylaxis agent based on risk category.(6) A pooled analysis of two placebo-controlled trials in multiple myeloma noted an incidence rate for VTE of 23% in patients receiving lenalidomide, dexamethasone and erythropoietic therapy versus 5% in patients without erythropoietic therapy. A multivariate analysis indicated an independent correlation between thrombosis and patients with concomitant erythropoietin therapy.(7) A pooled analysis of 125 patients from 3 trials with multiple myeloma on lenalidomide therapy noted a 17% incidence of VTE in patients on lenalidomide with concurrent erythropoietin therapy.(8) Several studies have evaluated the optimal VTE prophylaxis agent with lenalidomide-treated patients. Patients receiving lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of 11-75%, 26% with the use of aspirin, 17% with the use of aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH.(9)

Oat1 And Oat3 Inhibitors/Selected Carbapenem Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) may inhibit the renal excretion of doripenem(1), meropenem(2), and tebipenem(3) by competing with them for active tubular secretion.

CLINICAL EFFECTS: Concurrent use of OAT1 and OAT3 inhibitors may result in elevated levels of and toxicity from doripenem(1), meropenem(2) or tebipenem.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of doripenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(1) The US manufacturer of meropenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(2) The US manufacturer of tebipenem states concurrent use of tebipenem and OAT1 and OAT3 inhibitors is generally not recommended. If concurrent use with tebipenem is necessary, monitor more frequently for adverse reactions associated with tebipenem, such as diarrhea and headache.(3)

DISCUSSION: Probenecid has been shown to increase doripenem half-life (T1/2) and area-under-curve (AUC) by 53% and 75%, respectively.(1) In a study in six subjects, concurrent probenecid increased meropenem T1/2 by 33%.(4) Other studies have shown probenecid to increase the T1/2 of meropenem by 38% and the extent of meropenem systemic exposure by 58%.(2) In a study, coadministration of a single oral dose of 250 mg of tebipenem pivoxil with probenecid (OAT1 and OAT3 inhibitor) increased tebipenem maximum concentration (Cmax) by approximately 1.5-fold and plasma area-under-curve (AUC) by approximately 2.9-fold.(3) OAT1 inhibitors linked to this monograph include: cabotegravir and probenecid. OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)

Oat3 Inhibitors/Baricitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of baricitinib.(1,2)

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of baricitinib.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concurrent therapy with a strong organic anion transporter 3 (OAT3) inhibitor is warranted, and the recommended dosage is 4 mg once daily, reduce to 2 mg once daily. If the recommended dosage is 2 mg once daily, reduce dose to 1 mg once daily. If the recommended dosage is 1 mg once daily, consider discontinuing probenecid.(2) OAT3 inhibitors with less inhibitor potency are not expected to cause a clinically significant change in baricitinib levels.(1,2)

DISCUSSION: In a clinical pharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential) resulted in approximately a 2-fold increase in area-under-curve (AUC) with no change in time maximum (Tmax) or concentration maximum (Cmax) of baricitinib.(1,2) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(1-3)

Oat3 Inhibitors/Methotrexate(Oncology-Inj)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of methotrexate.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions.

DISCUSSION: Concomitant administration of methotrexate and probenecid has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone.(2-5) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(7)

Oat3 Inhibitors/Pemetrexed

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of pemetrexed.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of pemetrexed, including myelosuppression, neutropenia, renal toxicity, and gastrointestinal toxicity.

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with mild to moderate renal function insufficiency (creatinine clearance (CrCl) of 45 ml/min to 79 ml/min).

PATIENT MANAGEMENT: Avoid concomitant administration of OAT3 inhibitors before and after administration of pemetrexed when possible. If concomitant administration cannot be avoided, monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity.

DISCUSSION: In patients with normal renal function, ibuprofen (400 mg 4 times daily) decreased the clearance of pemetrexed by 20% and increased its area-under-curve (AUC) by 20%.(1) In two randomized, controlled cross-over trials, 27 cancer patients with a creatinine clearance (CrCl) less than or equal to 60 ml/min received pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days before pemetrexed administration. Ibuprofen decreased the clearance of pemetrexed by 16%, increased its maximum concentration (Cmax) by 15%, and increased the AUC by 20%.(2) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid, and vadadustat.(3)

Oatp1b1 Inhibitors/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: OATP1B1 inhibitors may decrease the hepatic uptake of eluxadoline.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 inhibitors may result in elevated levels of and side effects from eluxadoline, including constipation, nausea, abdominal pain, and impaired mental and physical abilities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent OATP1B1 inhibitors should receive a dose of eluxadoline of 75 mg twice daily. Monitor patients for impaired mental or physical abilities, abdominal pain, nausea, and constipation.(1)

DISCUSSION: Concurrent administration of a single dose (600 mg) of cyclosporine, an OATP1B1 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eluxadoline (100 mg) by 4.4-fold and 6.2-fold, respectively.(1) OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir, cyclosporine, darunavir, encorafenib, eltrombopag, erythromycin, gemfibrozil, leflunomide, leniolisib, letermovir, lopinavir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, and voclosporin.(1,2)

Oatp1b1-3 Inhibitors/Brincidofovir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of brincidofovir.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from brincidofovir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of brincidofovir states that alternative medications that are not OATP1B1 or 1B3 inhibitors should be considered. If concurrent use is necessary, instruct the patient to take the OATP1B1 or 1B3 inhibitor at least 3 hours after brincidofovir and increase monitoring for side effects, including transaminase and bilirubin elevations and GI side effects like diarrhea.(1)

DISCUSSION: In a clinical trial, single-dose oral cyclosporine (600 mg, an OATP1B1 and 1B3 inhibitor) increased the mean brincidofovir area-under-curve (AUC) and maximum concentration (Cmax) by 374% and 269%, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cyclosporine, darunavir, eltrombopag, encorafenib, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, lopinavir, ombitasvir-paritaprevir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, sofosbuvir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)

Selected Inhibitors Of Bcrp/Cladribine Oral

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, curcumin, danicopan, darolutamide, dasabuvir, eltrombopag, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir/pibrentasvir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, and zongertinib.(1-4)

Selected Oat1-Oat3 Substrates/Nitisinone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nitisinone is an inhibitor of organic anion transporter 1 and 3 (OAT1/OAT3) which may inhibit the renal excretion of substrates of OAT1/OAT3.(1)

CLINICAL EFFECTS: Administration of nitisinone with OAT1/OAT3 substrates may result in elevated levels of and toxicity of the substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of nitisinone states concurrent use with OAT1/OAT3 substrates should be avoided.(1)

DISCUSSION: Nitisinone increased the area-under-curve (AUC) and maximum concentration (Cmax) of furosemide, an OAT1/OAT3 substrate, by 72% and 12%, respectively.(1) OAT1/OAT3 substrates linked to this monograph include: adefovir, bumetanide, furosemide, tenofovir and vadadustat.(1-2)

Selected Oatp1b1-3 Inhibitors/Voxilaprevir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: OATP1B1 and OATP1B3 inhibitors may increase exposure to voxilaprevir.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 and OATP1B3 inhibitors may result in increased levels of and toxicity from voxilaprevir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent administration of voxilaprevir with OATP1B1 and OATP1B3 inhibitors is not recommended.(1,4) If concurrent therapy is warranted, monitor patients for adverse effects. The American Society of Transplantation guidelines state that the combination of voxilaprevir and cyclosporine is contraindicated.(3)

DISCUSSION: In a study in 25 subjects, cyclosporine (600 mg single dose) increased the maximum concentration (Cmax) and area-under-curve (AUC) of voxilaprevir (100 mg single dose) by 19.02-fold and 9.39-fold, respectively. There were no significant effects on cyclosporine levels.(1) OATP inhibitors include: atazanavir, belumosudil, cyclosporine, encorafenib, fostemsavir, leniolisib, letermovir, lopinavir, paritaprevir, resmetirom, roxadustat, vadadustat, and voclosporin.(1,2,4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Oat3 Inhibitors/Methotrexate (Low Strength Inj, Oral)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of methotrexate.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: If concurrent use cannot be avoided, monitor methotrexate blood levels closely and adjust the dose accordingly.

DISCUSSION: Concomitant administration of methotrexate and probenecid has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone. OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(7)

Oatp1b1-3 Inhibitors/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atogepant is a substrate of OATP1B1 and 1B3. Inhibitors of these transporters may increase the GI absorption and/or decrease the hepatic uptake of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atogepant, including nausea, constipation and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant states that, when used concurrently with an OATP inhibitor for prevention of episodic migraine, the atogepant dose should be limited to 10 mg or 30 mg once daily. When used concurrently with an OATP inhibitor for prevention of chronic migraines, the atogepant dose should be limited to 30 mg once daily.(1)

DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin, an OATP inhibitor, increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir, teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)

Oatp1b1-3 Inhibitors/Momelotinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatic uptake of momelotinib.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from momelotinib, including myelosuppression and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of momelotinib with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per momelotinib prescribing recommendations.(1)

DISCUSSION: Concurrent administration of a single dose rifampin, an OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%, respectively. The M21 metabolite Cmax increased 6% and AUC increased 12%.(1) OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir, cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib, encorafenib, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir, paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir, telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)

P-Gp Or Bcrp Inhibitors/Ubrogepant (<= 50 Mg)

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) For patients on concurrent therapy with vimseltinib and ubrogepant: 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) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

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, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5,6) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5,6)

Select Oatp1b1-3 Inhibitors/Letermovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatocyte uptake and increase the plasma concentration of letermovir.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from letermovir, including diarrhea, nausea, abdominal pain, and peripheral edema.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of letermovir with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per prescribing recommendations.(1)

DISCUSSION: Letermovir is a substrate of OATP1B1 and 1B3. Co-administration of letermovir with drugs that are inhibitors of OATP1B1 and 1B3 transporters may result in increases in letermovir plasma concentrations.(1) OAT1B1 and 1B3 inhibitors include: belumosudil, enasidenib, glecaprevir/pibrentasvir, paritaprevir, and vadadustat.(2-6)

Selected Bcrp Inhibitors/Atorvastatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atorvastatin is a substrate of the BCRP transporter.(1) Inhibitors of this transporter may increase intestinal absorption and hepatic uptake of BCRP substrates atorvastatin.(1)

CLINICAL EFFECTS: Administration of atorvastatin with BCRP inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1)

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: Concurrent use of atorvastatin with BCRP inhibitors may result in increased risk of side effects associated with atorvastatin. Close monitoring would be prudent for statin related side effects including rhabdomyolysis. If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Atorvastatin is a BCRP substrate.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, encorafenib, fostamatinib, lazertinib, leflunomide, momelotinib, oteseconazole, pacritinib, pirtobrutinib, regorafenib, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, velpatasvir, and zongertinib.(2,3)

Vadadustat/Erythropoietin Stimulating Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat and erythropoietin stimulating agents (ESAs) both stimulate endogenous erythropoietin production, resulting in increased red blood cell production.(1-2)

CLINICAL EFFECTS: Concurrent use of vadadustat and erythropoietin stimulating agents may increase the risk of thrombosis.

PREDISPOSING FACTORS: Predisposing factors include a history of thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia, hypertension, heart failure, diabetes mellitus, chronic kidney disease, COPD, obesity, tobacco smoking, major surgery with prolonged post-operative immobilization, and being bed-ridden.

PATIENT MANAGEMENT: ESAs should be stopped before initiating vadadustat.(1) For patients receiving temporary ESA rescue treatment, vadadustat should be held until hemoglobin levels are greater than or equal to 10 g/dL. The pause in vadadustat treatment should be extended to: - 2 days after last dose of epoetin - 7 days after last dose of darbepoetin alfa - 14 days after last dose of methoxy polyethylene glycol-epoetin beta Vadadustat should be resumed at the prior dose or one dose higher, with subsequent titration according to the dose titration guidelines in the vadadustat package insert.(1-2) Monitor hemoglobin levels every two weeks until stable, then monitor at least monthly.(1-2) Observe patients for signs and symptoms of venous thromboembolism and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

DISCUSSION: Vadadustat increases endogenous erythropoietin by decreasing degradation of hypoxia-inducible factor (HIF), which increases transcription of the HIF-responsive genes including EPO. Thromboembolic events were reported as very common (13.7%) in two active-controlled clinical trials in chronic kidney disease.(1-2) Controlled clinical trials of patients showed that ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, and other thromboembolic events with a higher target hemoglobin.(3)

Vadadustat/Polyvalent Cations And Phosphate Binders

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat may form a chelate with iron supplements, phosphate binders, and other medicinal products whose primary component consists of polyvalent cations such as aluminum, calcium, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of vadadustat and polyvalent cations and phosphate binders decreases the exposure and effectiveness of vadadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vadadustat states that it should be administered at least 1 hour before or 2 hours after any medications or products whose primary component consists of iron, phosphate binders and polyvalent cations.(1)

DISCUSSION: Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders.(2)

Vadadustat/Rosuvastatin (<= 5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of rosuvastatin.(1-4)

CLINICAL EFFECTS: Concurrent use of vadadustat with rosuvastatin may result in increased levels and side effects from rosuvastatin, including myopathy and rhabdomyolysis.(1-4)

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: Labelling recommendations vary between countries. The US manufacturer of vadadustat recommends a maximum daily dose of 5 mg of rosuvastatin in patients receiving concurrent therapy.(4) The UK and Australian manufacturers of vadadustat recommend a maximum daily dose of 10 mg of rosuvastatin in patients receiving concurrent therapy.(2,3) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin by 2- to 3-fold.(2-4)

Vadadustat/Simvastatin (<=20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat inhibits the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of simvastatin.(1-4)

CLINICAL EFFECTS: Concurrent vadadustat may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1-4)

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 exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with vadadustat.(1-4) The US manufacturer of vadadustat recommends a starting dose of simvastatin 5 mg daily when receiving concurrent therapy.(4) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Concurrent use of vadadustat increased the area-under-curve (AUC) of simvastatin by approximately 2-fold.(2-4)

*Known hypersensitivity to vadadustat or any component of the drug.

*Uncontrolled hypertension.

• Lactation

• Acute myocardial infarction
• Cerebrovascular accident
• Coronary artery disease
• Deep venous thrombosis
• Disease of liver
• Hypertension
• Pulmonary thromboembolism
• Thromboembolic disorder
• Vascular access thrombosis

• Central nervous system infection
• Gastrointestinal ulcer
• Iron deficiency anemia
• Lower seizure threshold
• Seizure disorder
• Tobacco smoker

The most common adverse effects reported in >=10% of patients receiving vadadustat in clinical trials include hypertension and diarrhea.

More Frequent

• Pneumonia
• Thromboembolic disorder

Less Frequent

• Arteriovenous fistula thrombosis
• Atrial fibrillation
• Seizure disorder
• Sepsis

Rare or Very Rare

• Acute myocardial infarction
• Cerebrovascular accident
• Deep venous thrombosis
• Pulmonary thromboembolism
• Transient cerebral ischemia

More Frequent

• Diarrhea
• Hypertension
• Hypotension

Less Frequent

• Abnormal hepatic function tests
• Accidental fall
• Back pain
• Cough
• Dyspnea
• Headache disorder
• Hyperbilirubinemia
• Hyperkalemia
• Hypervolemia
• Nausea
• Pain in extremities
• Upper respiratory infection
• Urinary tract infection
• Vomiting

No enhanced messaging available.

Safety and effectiveness of vadadustat have not been established in pediatric patients.

Available data on vadadustat use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease during pregnancy is associated with maternal and fetal risks (e.g., maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight, and polyhydramnios).

Oral administration of vadadustat to pregnant rats and rabbits during organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. Vadadustat was not teratogenic in rats and rabbits.

Use vadadustat during pregnancy only if the benefits justify the potential risks to the fetus.

It is not known if vadadustat is present in human milk; however, vadadustat is present in the milk of lactating rats. When a drug is present in animal milk, it is likely to be present in human milk. The effects of vadadustat on the breast-fed infant and the effects on milk production are also not known.

Given the risk of serious adverse events seen in adults treated with vadadustat (e.g., thrombotic vascular events), advise patients to avoid breast-feeding while receiving vadadustat and for 2 days following the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Of the total number of patients treated with vadadustat in the primary efficacy studies, 23% of patients were 65-74 years of age, 10% of patients were 75-84 years of age, and 1% were >=85 years of age. No overall differences in safety or effectiveness were observed between patients >=65 years of age and younger adults.