Lefluniclo (leflunomide/diclofenac sodium)

Because of the possible role of the liver in the metabolism, elimination, and recirculation of leflunomide and because adverse hepatic effects have been reported with the drug, leflunomide is not recommended in patients with preexisting acute or chronic liver disease, including those who are seropositive for hepatitis B or C, or those with baseline serum ALT concentrations exceeding twice the upper limit of normal (ULN).

The manufacturer makes no specific recommendation for dosage adjustment in patients with renal impairment; however, caution is advised if leflunomide is used in such patients.

Leflunomide is administered orally as a single daily dose. The drug may be taken without regard to meals.

When leflunomide is used for the management of rheumatoid arthritis, the manufacturer recommends that therapy be initiated with a loading dosage given for 3 days followed by the usual daily dosage. Eliminating the loading dose regimen may decrease the risk of adverse effects; this could be important for patients at increased risk of hematologic or hepatic toxicity (e.g., those currently receiving or who have recently received methotrexate or other immunosuppressive agents). If this initial loading dosage is not used, steady-state plasma concentrations may not be attained for 2 months or longer.

Aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), and low-dose corticosteroids may be continued in adults receiving leflunomide for the management of rheumatoid arthritis. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis. The manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied.

No dosing information is available for this tab.

No dosing information is available for this tab.

Although specific drug interaction studies are not available, leflunomide has been administered concomitantly with aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), or low dosages of oral corticosteroids (e.g., prednisone 10 mg daily) in clinical studies in patients with rheumatoid arthritis, and the manufacturer states that these drugs may be continued in patients receiving leflunomide. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis, but the manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied. (See Drug Interactions: Methotrexate and also see Nonsteroidal Anti-inflammatory Agents.)

Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) to decrease to undetectable concentrations following discontinuance of the drug, the possibility exists that drug interactions could occur in patients who are no longer receiving leflunomide therapy. The risk of such drug interactions can be reduced by use of a drug elimination procedure to hasten elimination of A77 1726 after discontinuance of leflunomide therapy. (See Dosage and Administration: Drug Elimination Procedures.) A drug elimination procedure may be appropriate in patients who are discontinuing leflunomide therapy and will receive subsequent therapy with a drug having a known potential for hematologic suppression. However, it is possible that such a strategy may worsen rheumatoid arthritis symptoms in patients who had been responding to leflunomide.

The manufacturer states that specific drug interaction studies between diclofenac sodium 3% gel and other topical or oral agents have not been performed.

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

Bcrp, Oatp1b1, And Oatp1b3 Substrates/Leniolisib

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: Leniolisib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1)

CLINICAL EFFECTS: Concurrent use of leniolisib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased toxicity of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1)

DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2)

Cyp1a2 Inducers/Florquinitau F-18

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: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1)

CLINICAL EFFECTS: Concurrent or recent use of CYP1A2 inducers with florquinitau F-18 may interfere with the interpretation of imaging results using fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of florquinitau F-18 states use of CYP1A2 inducers should be avoided. Patients should stop CYP1A2 inducers at least 7 days prior to diagnostic testing with florquinitau F-18.(1)

DISCUSSION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1) CYP1A2 inducers linked include: aminoglutethimide, asciminib, carbamazepine, fosphenytoin, leflunomide, marijuana smoking, montelukast, moricizine, nelfinavir, olverembatinib, omeprazole, phenobarbital, phenytoin, primidone, rifampin, ritonavir, teriflunomide, and valproic acid.(2,3)

Immunosuppressive Cyp2c8 Inhibitors/Etrasimod

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of etrasimod. Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1) Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.

CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9, concurrent use of a strong or moderate inhibitor of CYP2C8 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays. Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)

PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP2C8.(1) Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.

PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1) In addition, concomitant use with strong to moderate CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1) CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP2C8 or CYP3A4.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Moderate inhibitors of CYP2C8 include: leflunomide, pirtobrutinib, and teriflunomide.(2,3)

Immunosuppressive Cyp2c8 Inhibitors/Tolebrutinib

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: Immunosuppressive inhibitors of CYP2C8 may inhibit the metabolism of tolebrutinib and increase the risk of additive immunosuppression.(1) Leflunomide and teriflunomide are moderate CYP2C8 inhibitors.(2)

CLINICAL EFFECTS: Concomitant use of immunosuppressive CYP2C8 inhibitors may result in elevated levels and clinical effects of tolebrutinib, including immunosuppression and hepatotoxicity.(1,3)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The manufacturer of tolebrutinib states that use of concomitant strong and moderate CYP2C8 inhibitors should be avoided. If the use of strong or moderate CYP2C8 inhibitors will be short-term, treatment with tolebrutinib should be interrupted.(1) Tolebrutinib is not recommended for patients with severe immunodeficiency or bone marrow disease. Monitor patients for signs and symptoms of infections.(1)

DISCUSSION: In a study of healthy participants, concurrent use of gemfibrozil (strong inhibitor of CYP2C8) 600 mg BID for 6 days increased tolebrutinib area-under-curve (AUC) by 8.4-fold.(3) The concurrent use of moderate CYP2C8 inhibitors with tolebrutinib has not been studied. The manufacturer of tolebrutinib recommends avoiding concomitant use of moderate CYP2C8 inhibitors. In the HERCULES trial, a phase 3 randomized, double-blinded, placebo-controlled trial of 1,131 patients with a median of 133 weeks of follow-up, patients on tolebrutinib experienced respiratory infections more than placebo patients.(4) In the GEMINI 1 and 2 trials, phase 3 randomized, double-blinded, controlled trials of 1,873 patients who were followed up for a median of 139 weeks, COVID-19 infections and nasopharyngitis occurred frequently in both the tolebrutinib and teriflunomide groups (>10%). The percentage of serious infections in each group was similar (2.3% and 1.9%, respectively).(3) Immunosuppressive CYP2C8 inhibitors linked to this monograph include: leflunomide and teriflunomide.(2,5)

Immunosuppressive; Immunomod/Cladribine Onc Inj (10 Mg/5 Ml)

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: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)

DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)

Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab

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: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).

PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.

PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)

DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)

Leflunomide; Teriflunomide/Rosuvastatin (> 10 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: Teriflunomide an inhibitor of BCRP, OATP1B1 and OATP1B3 transport in the intestine.(1) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2) Rosuvastatin is a substrate for these three transporters.(4)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with rosuvastatin may result in increased absorption and systemic concentration of rosuvastatin, which could result in myopathy or 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. 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: Due to the increased risk for myopathy/rhabdomyolysis, the dosage of rosuvastatin should not exceed 10 mg once daily in patients receiving leflunomide or teriflunomide.(1) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with leflunomide or teriflunomide.(3) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

DISCUSSION: In an interaction study, teriflunomide (repeated doses) increased rosuvastatin maximum concentration (Cmax) and area-under-curve (AUC) by 2.65-fold and 2.51-fold, respectively.(1,2) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2)

Moderate Cyp1a2 Inducers/Vorasidenib

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: Moderate CYP1A2 inducers may increase the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of vorasidenib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of vorasidenib states concurrent use with moderate CYP1A2 inducers should be avoided.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib with phenytoin or rifampin (moderate CYP1A2 inducers) is predicted to decrease vorasidenib concentration maximum (Cmax) by 30% and area-under-curve (AUC) by 40%.(1) Moderate CYP1A2 inducers linked to this monograph include: fosphenytoin, leflunomide, nelfinavir, phenytoin, rifampin, ritonavir, and teriflunomide.(2)

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)

Oatp1b3 Inhibitors/Zavegepant

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: Zavegepant is a substrate of the organic anion transporting polypeptide 1B3 (OATP1B3) transporter. Inhibitors of OATP1B3 may increase zavegepant exposure.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent administration of zavegepant with OATP1B3 inhibitors should be avoided.(1)

DISCUSSION: In a study, rifampin (an OATP1B3 and NTCP inhibitor) at steady state increased the area-under-curve (AUC) and maximum concentration (Cmax) of zavegepant by 2.3-fold and 2.2-fold. Since rifampin is also a CYP3A4 inducer and zavegepant is metabolized by CYP3A4, concurrent use of zavegepant with other OATP1B3 inhibitors that are not CYP3A4 inducers may have an even more significant effect on zavegepant exposure.(1) OATP1B3 inhibitors include: atazanavir, belumosudil, cobicistat, cyclosporine, darolutamide, enasidenib, encorafenib, fostemsavir, glecaprevir/pibrentasvir, leflunomide, leniolisib, letermovir, lopinavir/ritonavir, paritaprevir, resmetirom, rifampin, ritonavir, teriflunomide, velpatasvir, voclosporin, and voxilaprevir.(2-9)

Selected Immunosuppressants/Nadofaragene Firadenovec

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: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)

CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)

DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)

Selected Immunosuppressants/Talimogene Laherparepvec

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: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)

CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.

DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

Selected Immunosuppressive Agents/Live Vaccines; Live Bcg

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: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)

CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)

PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.

PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)

DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)

Selected Inhibitors Of Bcrp With Myelosuppression/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) Also, topotecan in combination with myelosuppressive agents may result in additive or synergistic effects on the immune system.(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, thrombocytopenia, and increased risk of serious infections.(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: cyclosporine, encorafenib, leflunomide, leniolisib, momelotinib, and teriflunomide.(2,3)

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)

Selected Photosensitizers/Tretinoin-Mequinol

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: Tretinoin, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of tretinoin in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), methotrexate, phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

Weak Cyp3a4 Inhibitors/Lemborexant (> 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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 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: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib. (3,4)

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

Immunosuppressive Cyp2c8 Inhibitors/Paclitaxel

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

MECHANISM OF ACTION: Immunosuppressive inhibitors of CYP2C8 may inhibit the metabolism of paclitaxel and increase the risk of additive immunosuppression.(1) Leflunomide and teriflunomide are moderate CYP2C8 inhibitors.(3)

CLINICAL EFFECTS: Concurrent use of immunosuppressive CYP2C8 inhibitors and paclitaxel may result in elevated levels and clinical effects of paclitaxel, including immunosuppression.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of paclitaxel recommend combination use CYP2C8 inhibitors with caution. If concomitant use is necessary, paclitaxel dose reduction may be required.(1,2)

DISCUSSION: The US manufacturer of paclitaxel recommends use with CYP2C8 inhibitors with caution.(1,2)

Immunosuppressive Oat3 Inhibitors/Baricitinib

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

MECHANISM OF ACTION: Concurrent use of baricitinib with other potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Inhibitors of organic anion transporter 3 (OAT3) such as leflunomide and teriflunomide(3) 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 and may increase the risk of serious infections.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1) 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) Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)

Immunosuppressive 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. Concurrent use of methotrexate with immunosuppressive agents may result in additive or synergistic effects on the immune system.

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.(1) Concurrent use of methotrexate with immunosuppressive agents may increase the risk of serious infections.(1)

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.(1)

DISCUSSION: Concomitant administration of methotrexate and probenecid (OAT3 inhibitor) has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone.(2-5) Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia.(1) Immunosuppressive OAT3 inhibitors linked to this monograph include: leflunomide and teriflunomide.(7)

Immunosuppressive Oat3 Inhibitors/Pemetrexed

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

MECHANISM OF ACTION: Concurrent use of pemetrexed with other potent immunosuppressants may result in additive or synergistic effects on the immune system. Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of pemetrexed.(1)

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, gastrointestinal toxicity, and may increase the risk of serious infections.

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, gastrointestinal toxicity, or infection.(1)

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) Immunosuppressive OAT3 inhibitors linked to this monograph include: leflunomide and teriflunomide.(3)

Immunosuppressives; Immunomodulators/Deuruxolitinib

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

MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.

DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)

Immunosuppressives; Immunomodulators/Filgotinib

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

MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)

Immunosuppressives; Immunomodulators/Fingolimod

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

MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)

CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)

Immunosuppressives; Immunomodulators/Inebilizumab

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

MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)

Immunosuppressives; Immunomodulators/Ozanimod

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

MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ponesimod

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

MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ritlecitinib

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

MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)

Immunosuppressives; Immunomodulators/Siponimod

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

MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Tofacitinib

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

MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)

DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)

Leflunomide; Teriflunomide/Bile Acid Sequestrants

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

MECHANISM OF ACTION: Bile acid sequestrants may interfere with the enterohepatic recycling of teriflunomide.(1-4) Leflunomide is metabolized to teriflunomide.(2-3)

CLINICAL EFFECTS: Concurrent use of bile acid sequestrants may result in decreased levels and effectiveness of leflunomide and teriflunomide, even when the administration times are separated. Coadministration may result in return of disease activity.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of bile acid sequestrants with leflunomide and teriflunomide. Teriflunomide has a prolonged half-life and staggering administration times will not prevent the drug interaction.(1-4) Teriflunomide may be coadministered with bile acid sequestrants in order to accelerate elimination for suspected drug-induced liver injury, pregnancy occurs during teriflunomide therapy, patient taking teriflunomide wants to become pregnant or father a child, or other situations requiring accelerated removal of teriflunomide.(4)

DISCUSSION: After 11 days of cholestyramine administration, plasma concentrations of teriflunomide are reduced by greater than 98%.(4) In an open-label study in 18 healthy subjects, administration of teriflunomide (days 1-5; five 14 mg tablets once daily) followed by colesevelam (days 6-16, four 625 mg tablets in morning, three 625 mg tablets in evening) decreased the teriflunomide plasma concentration an average of 96.1% after 11 days.(5) In a study in 14 healthy subjects, administration of teriflunomide (70 mg daily for 3 days; 14 mg daily for 11 days) followed by colestipol (8 g twice daily for 15 days) decreased the teriflunomide plasma concentration an average of 96.9% after 11 days.(6)

Leflunomide; Teriflunomide/Selected Immunosuppressants

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

MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)

DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)

Moderate Cyp2c8 Inhibitors/Tovorafenib

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

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of tovorafenib.(1)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase tovorafenib plasma concentrations, which may increase the risk of tovorafenib toxicity, including hepatotoxicity, bleeding, and photosensitivity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tovorafenib recommends avoiding concomitant use of tovorafenib with moderate CYP2C8 inhibitors.(1)

DISCUSSION: Moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure.(1) Moderate CYP2C8 inhibitors linked to this monograph include clopidogrel, deferasirox, leflunomide, letermovir, mifepristone (chronic therapy), and teriflunomide.(2)

Myelosuppressive Mod-Weak 3A4 Inh/Sirolimus Protein-Bound

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

MECHANISM OF ACTION: Moderate and weak immunosuppressive CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4 and increase the risk of additive immunosuppression.(1)

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus including immunosuppression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(3) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(3) Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib, fedratinib, imatinib, rilzabrutinib, and treosulfan.(3,4) Weak CYP3A4 inhibitors linked to this monograph include: asciminib, avapritinib, belumosudil, capivasertib, everolimus, lapatinib, larotrectinib, leflunomide, olaparib, palbociclib, teriflunomide, vepdegestrant, and ziftomenib.(4,5)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

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)

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 Myelosuppressive Agents/Clozapine

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

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

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

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

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

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Selected Photosensitizers/Aminolevulinic Acid

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

MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

Selected Photosensitizers/Methoxsalen

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

MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1)

DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)

Selected Photosensitizers/Porfimer

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

MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1)

PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer.

DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)

Slt Inhibitors Of Bcrp With Myelosuppression/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) Also, cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(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) Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

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) Myelosuppression risk recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(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: asciminib, belumosudil, cyclosporine, encorafenib, leflunomide, leniolisib, momelotinib, pirtobrutinib, and teriflunomide.(1,2) Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)

Weak Cyp3a4 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(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. For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, vonoprazan, and ziftomenib.(4,5)

Weak Cyp3a4 Inhibitors/Lomitapide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

Weak Cyp3a4 Inhibitors/Pimozide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of pimozide.(1,2)

CLINICAL EFFECTS: Concurrent use with weak CYP3A4 inhibitors may increase the levels and effects of pimozide including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(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.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) The UK manufacturer of pimozide contraindicates concomitant use of pimozide with CYP3A4 inhibitors and CYP2D6 inhibitors, stating that inhibition of either or both CYP3A4 and CYP2D6 may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.(2) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(5) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 or CYP2D6 inhibitors if possible. 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: Pimozide is metabolized at CYP3A.(1,5) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking pimozide in combination with itraconazole and/or other CYP3A4 inhibitors.(1,2) Weak CYP3A4 inhibitors include: amlodipine, asciminib, avapritinib, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cimetidine, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fostamatinib, ginkgo, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, marijuana, olaparib, palbociclib, peppermint, piperine, pirtobrutinib, propiverine, ranitidine, resveratrol, scutellarin, sevabertinib, simeprevir, sitaxsentan, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(7,8)

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

Immunosuppressives; Immunomodulators/Cladribine Oncology Inj

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

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)

DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)

Immunosuppressives; Immunomodulators/Covid-19 Vaccines

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

MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)

CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.

DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)

Immunosuppressives; Immunomodulators/Ustekinumab

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

MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)

Leflunomide/Rifampin

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

MECHANISM OF ACTION: Rifampin may induce the metabolism of leflunomide to its active metabolite.(1)

CLINICAL EFFECTS: Concurrent or recent use of rifampin may result in elevated levels of the active metabolite of leflunomide and toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients closely who are receiving concurrent therapy with rifampin.(1)

DISCUSSION: Multiple doses of rifampin (exact dose/duration not specified) increased the maximum concentration (Cmax) of the active metabolite of leflunomide by 40% following a single dose of leflunomide. Levels are expected to increase more with multiple dosing.(1)

Leflunomide/Warfarin

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

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of leflunomide may result in elevated levels and effects of warfarin, which may increase the 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: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing leflunomide. Patients maintained on leflunomide may require lower initial dosages of warfarin. If concurrent therapy is warranted, 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. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a case report, a 61 year-old female who had stable INRs for 4 months on warfarin dosage of 36 mg/week had an elevated INR of 7.3 approximately 2 weeks after initiating leflunomide (100 mg daily for 3 days, then 20 mg daily).(1) In another case report, a 49 year-old male who had stable INR values for 1 year developed gross hematuria two days after initiating leflunomide (100 mg daily for 3 days, then 20 mg daily).(2) Four cases of elevated INR during concurrent warfarin and leflunomide have been reported to the UK Committee on Safety of Medicines.(2,3)

Leflunomide; Teriflunomide/Methotrexate (Low Str Inj, Oral)

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

MECHANISM OF ACTION: Teriflunomide inhibits organic anion transporter 3 (OAT3). The combination may also result in additive or synergistic effects on the liver or lung tissue.

CLINICAL EFFECTS: The concurrent administration of leflunomide and methotrexate may result in increased levels and toxicity from methotrexate, including hepatotoxicity, pancytopenia, agranulocytosis, or thrombocytopenia.(1) Both agents can cause interstitial lung disease (ILD).(2) Teriflunomide is the active metabolite of leflunomide and recommended doses of both agents produce similar concentrations of teriflunomide.(3)

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions This interaction should also be considered if leflunomide(1) or teriflunomide is followed by methotrexate if no drug elimination procedure is performed.

PATIENT MANAGEMENT: In patients receiving concurrent methotrexate and leflunomide or teriflunomide, platelets, white blood cells, hemoglobin or hematocrit, and ALT (SGPT) should be performed at baseline and at monthly intervals. American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Patients should be monitored for signs and symptoms of hepatotoxicity and bone marrow suppression. If evidence of bone marrow suppression occurs, treatment with leflunomide or teriflunomide should be discontinued and cholestyramine or charcoal should be used to rapidly decrease plasma concentrations of the active metabolite of leflunomide. Pulmonary status should be evaluated in patients who have recently received methotrexate and these patients should be closely monitored during therapy. Patients should be instructed to contact their doctor if any symptoms of ILD occur. Symptoms include cough and dyspnea, with or without associated fever.(2) New or worsening pulmonary symptoms may warrant therapy discontinuation. If leflunomide or teriflunomide therapy is discontinued, consider initiating washout procedures.

DISCUSSION: The combined use of leflunomide and methotrexate has not been adequately studied.(1) In clinical trials, the administration of leflunomide alone has resulted in abnormal liver enzymes in 5% of subjects. ALT (SGPT) values were greater than 3-fold of normal in 1.5-4.4% of subjects.(1) In a small trial in 30 subjects, the concurrent administration of leflunomide and methotrexate resulted in a greater than 3-fold increase in liver enzymes in five subjects and a 2- to 3-fold increase in another five subjects. Three patients met ACR criteria for liver biopsy. There was no evidence of a pharmacokinetic interaction.(1) In a 6 month study, an increase in ALT greater than or equal to 3 times the upper limit of normal was observed in 3.8% of patients (n=133) receiving concurrent leflunomide and methotrexate. In comparison, such increases were only seen in 0.8% of patients (n=130) who received methotrexate with placebo.(1) There have been rare reports of pancytopenia, agranulocytosis, and thrombocytopenia during leflunomide therapy. In most of these reports, patients were receiving concurrent therapy with methotrexate and/or another immunosuppressive agent.(1) ILD has been rarely reported with leflunomide and has been associated with fatal outcomes.(1) Many of these reports are confounded by preexisting pulmonary disease and/or previous or concomitant use of other agents that cause ILD, including methotrexate.(2) Teriflunomide is the active metabolite of leflunomide and recommended doses of both agents produce similar concentrations of teriflunomide.(3)

Leflunomide; Teriflunomide/Rosuvastatin (<= 10 Mg)

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

MECHANISM OF ACTION: Teriflunomide an inhibitor of BCRP, OATP1B1 and OATP1B3 transport in the intestine.(1) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2) Rosuvastatin is a substrate for these three transporters.(4)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with rosuvastatin may result in increased absorption and systemic concentration of rosuvastatin, which could result in myopathy or rhabdomyolysis.(1,2)

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: Due to the increased risk for myopathy/rhabdomyolysis, the dosage of rosuvastatin should not exceed 10 mg once daily in patients receiving leflunomide or teriflunomide.(1) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with leflunomide or teriflunomide.(3) If these medications are used concurrently, counsel patient to report unexplained muscle pain, tenderness, weakness, or dark, cola-colored urine.

DISCUSSION: In an interaction study, teriflunomide (repeated doses) increased rosuvastatin maximum concentration (Cmax) and area-under-curve (AUC) by 2.65-fold and 2.51-fold, respectively.(1,2) Leflunomide is a produg and is converted to its active metabolite teriflunomide.(2)

Leflunomide; Teriflunomide/Selected Cyp2c8 Substrates

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

MECHANISM OF ACTION: Teriflunomide may inhibit the metabolism of agents metabolized by CYP2C8. Leflunomide is metabolized to teriflunomide and recommended dosages of both products produce similar levels of teriflunomide.(1)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide may result in elevated levels of and toxicity from agents metabolized by CYP2C8, such as pioglitazone, repaglinide, or rosiglitazone.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with leflunomide or teriflunomide and an agent metabolized by CYP2C8 should be closely monitored. The dosage of the CYP2C8 substrate may need to be adjusted if leflunomide or teriflunomide are initiated.(1) Because of teriflunomide's slow elimination, the effects of teriflunomide on these CYP2C8 substrates may persist for some time without the use of cholestyramine or activated charcoal to increase teriflunomide elimination.(1)

DISCUSSION: Concurrent teriflunomide increased the maximum concentration (Cmax) and area-under-curve (AUC) of repaglinide (0.25 mg single dose) by 1.7-fold and 2.4-fold, respectively.(1) Leflunomide is metabolized to teriflunomide and recommended dosages of both products produce similar levels of teriflunomide.(1) CYP2C8 substrates include pioglitazone, repaglinide, or rosiglitazone.(1,2)

Moderate Cyp2c8 Inhibitors/Daprodustat

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

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of daprodustat.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP2C8 may result in elevated levels of and clinical effects of daprodustat, including the risk for thromboembolic events and hypertension.

PREDISPOSING FACTORS: Patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the past 3 months may be at increased risk of thromboembolic events. Other risk factors for thromboembolic events include 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 manufacturer of daprodustat states that the starting dose of daprodustat should be reduced by half when initiating treatment in patients on clopidogrel or moderate CYP2C8 inhibitors except in patients who starting dose is already 1 mg.(1) Monitor hemoglobin and adjust the dose of daprodustat when initiating or stopping therapy with clopidogrel or moderate CYP2C8 inhibitors.(1)

DISCUSSION: In an interaction study, gemfibrozil 600 mg twice daily for 5 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold respectively.(1) Concomitant administration of daprodustat with clopidogrel 75 mg once daily is expected to increase daprodustat AUC and Cmax by at least 4-fold and 3-fold, respectively.(1) Moderate inhibitors of CYP2C8 include deferasirox, leflunomide, letermovir, mifepristone (chronic therapy), pirtobrutinib, selpercatinib, and teriflunomide.(2,3)

Moderate Cyp2c8 Inhibitors/Resmetirom

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

MECHANISM OF ACTION: Moderate inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant use of resmetirom with moderate CYP2C8 inhibitors is not recommended. If concurrent use is warranted, reduce the dose of resmetirom based on the patient's weight. -If <100 kg, reduce the dose of resmetirom to 60 mg once daily; -If >=100 kg, reduce the dose of resmetirom to 80 mg once daily.(1)

DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Moderate CYP2C8 inhibitors linked to this monograph include: clopidogrel, deferasirox, leflunomide, mifepristone (chronic therapy), pirtobrutinib, selpercatinib, and teriflunomide.(2)

Moderate Cyp2c8 Inhibitors/Selexipag

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

MECHANISM OF ACTION: Moderate CYP2C8 inhibitors may inhibit the metabolism of selexipag.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP2C8 inhibitor may increase levels and effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When co-administered with a moderate inhibitor of CYP2C8, reduce the dose of selexipag to once daily. If the moderate CYP2C8 inhibitor is discontinued, increase the dose of selexipag to twice daily.(1) If concurrent use is warranted, monitor patients closely for increased effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.

DISCUSSION: Clopidogrel (300 mg for 1 day then 75 mg daily, a moderate CYP2C8 inhibitor) had no effect on exposure to selexipag but increased the area-under-curve (AUC) of selexipag's active metabolite by 2.7-fold.(1) A study in healthy subjects evaluated concurrent therapy with selexipag 200 mcg twice daily with clopidogrel 300 mg single does or 75 mg daily. The AUC and the maximum concentration (Cmax) of ACT-333679, the major contributor to the drug effect, increased 2.25-fold (90% confidence interval (CI) 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg.(2) Moderate CYP2C8 inhibitors linked include: clopidogrel, deferasirox, leflunomide, letermovir, selpercatinib, and teriflunomide.(3-4)

Myelosuppressive Mod-Weak Cyp3a4 Inh/Tacrolimus

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

MECHANISM OF ACTION: Moderate and weak immunosuppressive inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus and increase the risk of additive immunosuppression.(1)

CLINICAL EFFECTS: Concurrent use of an immunosuppressive CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, immunosuppression, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3) 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: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(4) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(5) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(6) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ration 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib, fedratinib, imatinib, rilzabrutinib, and treosulfan.(6) Weak CYP3A4 inhibitors linked to this monograph include: asciminib, avapritinib, belumosudil, capivasertib, everolimus, larotrectinib, leflunomide, olaparib, palbociclib, and teriflunomide.(6)

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)

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)

Selected Cyp1a2 Inducers/Olanzapine

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

MECHANISM OF ACTION: Inducers of CYP1A2 may increase the metabolism of olanzapine.(1,2)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of olanzapine.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with olanzapine and a CYP1A2 inducer may require increased dosages of olanzapine. The dosage of olanzapine may need to be adjusted if concurrent therapy with a CYP1A2 inducer is initiated or discontinued.(1,2) If a CYP1A2 inducer is initiated in a patient maintained on olanzapine, monitor for decreased effectiveness of olanzapine. If a CYP1A2 inducer is discontinued in a patient maintained on olanzapine, monitor for olanzapine toxicity.

DISCUSSION: Concurrent use of carbamazepine, a CYP1A2 inducer, increased olanzapine clearance by 50%.(1,2)

Selected Cyp1a2 Inducers/Olanzapine-Samidorphan

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

MECHANISM OF ACTION: Inducers of CYP1A2 may increase the metabolism of olanzapine.(1,2)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased levels and effectiveness of olanzapine.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with olanzapine and a CYP1A2 inducer may require increased dosages of olanzapine. The dosage of olanzapine may need to be adjusted if concurrent therapy with a CYP1A2 inducer is initiated or discontinued.(1,2) If a CYP1A2 inducer is initiated in a patient maintained on olanzapine, monitor for decreased effectiveness of olanzapine. If a CYP1A2 inducer is discontinued in a patient maintained on olanzapine, monitor for olanzapine toxicity.

DISCUSSION: Concurrent use of carbamazepine, a CYP1A2 inducer, increased olanzapine clearance by 50%.(1,2) CYP1A2 inducers linked to this monograph include: leflunomide, nelfinavir, ritonavir and teriflunomide.(3,4)

Weak Cyp3a4 Inhibitors/Lemborexant (<= 5 Mg)

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Mavacamten

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

MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1)

CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1)

PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1)

PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(3) Weak CYP3A4 inhibitors include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, resveratrol, roxithromycin, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, and viloxazine. (4,5)

Weak Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(3,4)

Known hypersensitivity to diclofenac or any ingredient in the formulation.

In the setting of coronary artery bypass graft (CABG) surgery.

• Acute hepatitis C
• Aspirin exacerbated respiratory disease
• Cerebrovascular accident
• Chronic hepatitis C
• Disease of liver
• Drug-induced hepatitis
• Hepatic failure
• History of roux-en-Y gastric bypass
• Lactation
• Post-operative from CABG surgery
• Pregnancy
• Renal transplant
• Severe bone marrow depression
• Viral hepatitis B

• Active tuberculosis
• Acute myocardial infarction
• Alcohol use disorder
• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hemorrhage
• Hepatic porphyria
• History of kidney donation
• Hypertension
• Hypoproteinemia
• Immunosuppression
• Impaired wound healing
• Inactive tuberculosis
• Increased risk of bleeding
• Infection
• Interstitial lung disease
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Nephrectomy
• Neutropenic disorder
• Non-infective meningitis
• Pancytopenia
• Systemic mastocytosis
• Thrombocytopenic disorder
• Thrombotic disorder
• Tobacco smoker

• Anemia
• Asthma
• Dehydration
• Edema
• Hypertension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Peripheral neuropathy

There is no enhanced messaging for this drug.

More Frequent

• Bronchitis
• Hepatitis
• Hypertension
• Upper respiratory infection
• Urinary tract infection

Less Frequent

• Anemia
• Body fluid retention
• Chest pain
• Dyspnea
• Edema
• Esophageal ulcer
• Gastritis
• Gastroenteritis
• Gastrointestinal ulcer
• Increased alanine transaminase
• Palpitations
• Paresthesia
• Peptic ulcer
• Skin rash
• Synovitis
• Tachycardia
• Tenosynovitis
• Tinnitus

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Abnormal vaginal bleeding
• Acute eruptions of skin
• Acute myocardial infarction
• Acute pancreatitis
• Agranulocytosis
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anaphylaxis
• Anemia
• Angioedema
• Angioedema
• Aplastic anemia
• Bacterial sepsis
• Black tarry stools
• Bloody stools
• Bloody vomit
• Bronchospastic pulmonary disease
• Bullous dermatitis
• Cerebrovascular accident
• Colitis
• Colitis
• Cystitis
• DRESS syndrome
• DRESS syndrome
• Dyspnea
• Eosinophilia
• Eosinophilia
• Epistaxis
• Epistaxis
• Erythema multiforme
• Erythema multiforme
• Esophagitis
• Exfoliative dermatitis
• Gastric ulcer
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Heart failure
• Hematuria
• Hemolytic anemia
• Hemorrhage
• Hepatic failure
• Hepatic failure
• Hepatic necrosis
• Hepatitis
• Hyperbilirubinemia
• Hyperkalemia
• Hypertension
• Infection
• Interstitial lung disease
• Interstitial nephritis
• Interstitial pneumonitis
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Leukopenia
• Memory impairment
• Nephrotic syndrome
• Nephrotoxicity
• Neutropenic disorder
• Non-infective meningitis
• Oliguria
• Pancreatitis
• Pancytopenia
• Pancytopenia
• Peripheral neuropathy
• Pneumonia
• Proteinuria
• Pulmonary fibrosis
• Pulmonary hypertension
• Pustular psoriasis
• Reactivated tuberculosis
• Renal failure
• Renal papillary necrosis
• Respiratory depression
• Retinal detachment
• Retinal hemorrhage
• Seizure disorder
• Severe infection
• Skin ulcer
• Stevens-johnson syndrome
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Thrombotic disorder
• Toxic epidermal necrolysis
• Toxic epidermal necrolysis
• Urticaria
• Vasculitis

More Frequent

• Abdominal pain with cramps
• Acute abdominal pain
• Alopecia
• Back pain
• Constipation
• Diarrhea
• Diarrhea
• Dizziness
• Dizziness
• Drowsy
• Dyspepsia
• Dyspepsia
• Headache disorder
• Headache disorder
• Hyperhidrosis
• Insomnia
• Nausea
• Nausea
• Pruritus of skin
• Skin rash
• Vomiting
• Vomiting
• Weight loss

Less Frequent

• Acne vulgaris
• Anorexia
• Aphthous stomatitis
• Conjunctivitis
• Constipation
• Fever
• Flatulence
• Flatulence
• General weakness
• Heartburn
• Malaise
• Pharyngitis
• Pruritus of skin
• Rhinitis
• Sinusitis
• Symptoms of anxiety
• Xerostomia

Rare or Very Rare

• Abscess
• Acute cognitive impairment
• Alopecia
• Appetite changes
• Arthralgia
• Asthma
• Blurred vision
• Conjunctivitis
• Cough
• Cramps in legs
• Depression
• Dream disorder
• Drowsy
• Dry skin
• Ecchymosis
• Eructation
• Fever
• Flu-like symptoms
• Flushing
• General weakness
• Hearing loss
• Hyperglycemia
• Irritability
• Leukocytosis
• Lymphadenopathy
• Medication overuse headache
• Palpitations
• Papilledema
• Purpura
• Skin photosensitivity
• Stomatitis
• Symptoms of anxiety
• Syncope
• Tachycardia
• Thrombophlebitis
• Tremor
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and efficacy not established in children. Actinic keratoses generally are not seen in the pediatric population; diclofenac sodium 3% gel should not be used by children.

Leflunomide can cause fetal toxicity when administered to pregnant women. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. Leflunomide therapy should not be initiated in a woman of childbearing potential until pregnancy is excluded and it has been confirmed that the woman is using a reliable form of contraception.

Although there are no adequate and controlled studies to date in humans, leflunomide has been shown to increase the risk of fetal death or teratogenic effects in animals. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. The potential for increased risk of birth defects should be discussed with female patients of childbearing potential, and clinicians should advise women that they may be at increased risk of having a child with birth defects if they are pregnant, become pregnant while receiving leflunomide, or do not wait to become pregnant until they have followed a drug elimination procedure following discontinuance of leflunomide.

If leflunomide is administered inadvertently during pregnancy or if the patient becomes pregnant while receiving the drug, leflunomide should be discontinued and the patient informed of the potential hazard to the fetus. Women of childbearing potential should be advised to notify their clinician immediately if they experience a delay in menses or believe they may be pregnant so that pregnancy testing can be done. Use of a drug elimination procedure to rapidly lower plasma concentrations of A77 1726 to undetectable concentrations early in a pregnancy (i.e., at the first delay in menses) may decrease the risk to the fetus. To monitor fetal outcomes of pregnant women exposed to leflunomide, clinicians are encouraged to register such patients by calling 877-311-8972.

The manufacturer recommends that all women of childbearing potential receive an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide therapy since these concentrations are presumed to be associated with minimal risk based on animal data. Following completion of the cholestyramine regimen, plasma concentrations of A77 1726 should be determined to verify that concentrations are undetectable. This is especially important in women who wish to become pregnant after discontinuing the drug.

Although available information does not indicate that leflunomide therapy is associated with an increased risk of male-mediated fetal toxicity, animal studies to evaluate this specific risk have not been conducted. To minimize risk, men wishing to father a child should consider discontinuing leflunomide therapy and undergoing an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable levels.

Reproduction studies in rats and rabbits using leflunomide oral doses of 1 mg/kg have not revealed evidence of harm to the fetus. However, reproduction studies in rats using oral leflunomide dosages of 15 mg/kg daily during organogenesis (systemic exposure approximately 10% of the human exposure level to A77 1726 based on AUC) have shown teratogenic effects (most notably anophthalmia or microphthalmia and internal hydrocephalus). Under these exposure conditions, leflunomide also caused a decrease in maternal body weight, an increase in embryolethality, and a decrease in fetal body weight for surviving fetuses. Reproduction studies in rabbits using oral leflunomide dosages of 10 mg/kg daily during organogenesis (exposure equivalent to the maximum human exposure to A77 1726 based on AUC) resulted in fused, dysplastic sternebrae in offspring. In reproduction studies in female rats using leflunomide dosages of 1.25 mg/kg daily (systemic exposure approximately 1% of the human exposure level to A77 1726 based on AUC) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (exceeding 90%) decreases in postnatal survival.

Safety of diclofenac sodium 3% gel has not been established during pregnancy.

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice. (See Advice to Patients.)

Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy. Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios. Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis. Deaths associated with neonatal renal failure have been reported. Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis, such as diclofenac, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.

No evidence of teratogenicity was observed in reproduction studies in mice, rats, or rabbits at diclofenac doses at least 15 times the maximum recommended human dose of diclofenac sodium 3% gel. In rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weight and growth, and reduced fetal survival.

The effects of diclofenac on labor and delivery in pregnant women are unknown.

A77 1726 distributes into milk in rats. It is not known whether A77 1726 is distributed into human milk. Because of the potential for serious adverse reactions to leflunomide in nursing infants if it were distributed, a decision should be made whether to proceed with nursing or initiate therapy with leflunomide, taking into account the importance of the drug to the woman.

Discontinue nursing or the drug because of potential risk in nursing infants.

Individuals 65 years of age or older were included in clinical trials since actinic keratoses occur frequently in an older patient population. No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.