Harliku (nitisinone)

No dosing information is available for this tab.

Nitisinone is administered orally. The drug is commercially available as capsules (2, 5, 10, or 20 mg), tablets (2, 5, or 10 mg), or oral suspension (4 mg/mL) for the treatment of hereditary tyrosinemia type 1 (HT-1) in adults and pediatric patients, and as a 2-mg tablet formulation (Harliku(R)) for the treatment of alkaptonuria (AKU) in adults.

No dosing information is available for this tab.

Nitisinone is minimally metabolized by cytochrome P-450 (CYP) 3A4. The drug is a moderate inhibitor of CYP2C9 and a weak inducer of CYP2E1, but does not inhibit CYP2D6. Nitisinone is an inhibitor of organic anion transporter (OAT)1/OAT3.

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

Nitisinone/Oat1-Oat3 Substrates That Prolong Qt

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

CLINICAL EFFECTS: Administration of nitisinone with OAT1/OAT3 substrates that prolong the QT interval may result in elevated levels of and toxicity of the substrates, including QT prolongation, which may lead to life-threatening cardiac arrhythmias like torsade 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of nitisinone states that concurrent use with OAT1/OAT3 substrates should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Nitisinone increased the area-under-curve (AUC) and maximum concentration (Cmax) of furosemide, an OAT1/OAT3 substrate, by 72% and 12%, respectively.(1) OAT1/OAT3 substrates that prolong QT linked to this monograph include: ciprofloxacin.(3)

Oat3 Inhibitors/Ketorolac

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

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

CLINICAL EFFECTS: Enhanced ketorolac toxicity including gastrointestinal and renal toxicity as well as increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concomitant administration of ketorolac and organic anion transporter 3 (OAT3) inhibitors are contraindicated by the manufacturer. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

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

Oat3 Inhibitors/Sodium Phenylbutyrate-Taurursodiol

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Strong & Moderate Cyp2c9 Inhibitors/Deuruxolitinib

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 or moderate CYP2C9 inhibitors may inhibit the metabolism of deuruxolitinib.(1)

CLINICAL EFFECTS: Concurrent use of deuruxolitinib with a strong or moderate inhibitor of CYP2C9 may result in elevated levels of and toxicity from deuruxolitinib, including hematologic toxicities (neutropenia, lymphopenia, anemia), lipid abnormalities, infection, and thrombosis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of deuruxolitinib states that concomitant treatment with a strong or moderate CYP2C9 inhibitor is contraindicated.(1)

DISCUSSION: Concurrent use with strong CYP2C9 inhibitors has not been studied. Based on pharmacokinetic modelling, deuruxolitinib area-under-curve (AUC) is predicted to be increased by 200% and maximum concentration (Cmax) by 25% following concomitant use of multiple dosages of a strong CYP2C9 inhibitor with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg dose).(1) Deuruxolitinib AUC increased by 140% and Cmax by 21% following concomitant use of multiple dosages of 200 mg fluconazole (dual moderate CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg dose).(1) Strong CYP2C9 inhibitors linked to this monograph include: camizestrant and sulfaphenazole.(2-3) Moderate CY2C9 inhibitors linked to this monograph include: amiodarone, apazone, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and piperine.(2-3)

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

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)

Nitisinone/Aspartame; Phenylalanine; Tyrosine

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

MECHANISM OF ACTION: Aspartame contains phenylalanine, which is metabolized into tyrosine. Nitisinone prevents the breakdown of tyrosine.(1)

CLINICAL EFFECTS: Elevated levels of tyrosine can cause vision changes (cornea ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin problems (painful hyperkeratotic plaques on the soles and palms), and nervous system toxicity (variable degrees of mental retardation and developmental delay).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving nitisinone should following dietary restrictions concerning the consumption of aspartame, phenylalanine, and tyrosine, including medications that contain these ingredients.(1)

DISCUSSION: In most patients, eye symptoms resulting from elevated tyrosine levels were transient, lasting less than one week; however, six patients had prolonged episodes lasting up to almost 2 years.(1)

Nitisinone/Selected Oat1-Oat3 Substrates

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Oat1 And Oat3 Inhibitors/Selected Carbapenem Antibiotics

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Oat3 Inhibitors/Baricitinib

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Oat3 Inhibitors/Methotrexate(Oncology-Inj)

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

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

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

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

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

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

Oat3 Inhibitors/Pemetrexed

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

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

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

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

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

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

Strong And Moderate Cyp2c9 Inhibitors/Bosentan

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

MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP2C9 inhibitors may inhibit the CYP2C9 mediated metabolism of bosentan.(1-2)

CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP2C9 may result in elevated levels of and toxicity from bosentan.(1)

PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP2C9 inhibitor and a CYP3A4 inhibitor could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.

PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP3A4 inhibitor (e.g. aprepitant, boceprevir, ceritinib, ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosaprepitant, idelalisib, imatinib, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, netupitant, nilotinib, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, verapamil, and voriconazole). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP2C9 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like bosentan by one-half.(3)

DISCUSSION: Concurrent use with CYP2C9 inhibitors has not been studied. In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) Strong CYP2C9 inhibitors linked to this monograph include: miconazole.(4) Moderate CYP2C9 inhibitors linked to this monograph include: amiodarone, apazone, asciminib, benzbromarone, nitisinone, oxandrolone, piperine, sulfaphenazole, and phenylbutazone.(4)

Strong Cyp3a4 Or Strong & Moderate Cyp2c9 Inhib/Erdafitinib

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

MECHANISM OF ACTION: Erdafitinib is metabolized by CYP3A4 and CYP2C9. Strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 may inhibit the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 or moderate CYP2C9 inhibitors may increase the levels and effects of erdafitinib, including retinopathy and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information states that concurrent use of erdafitinib with strong CYP3A4 inhibitors or moderate CYPC9 inhibitors should be avoided. If concurrent use cannot be avoided, monitor closely for adverse reactions and consider a dose modification based on prescribing information. If the strong CYP3A4 or moderate CYP2C9 inhibitor is discontinued, consider increasing the erdafitinib dose if patient does not have any drug-related toxicity.(1) If concurrent use with nitisinone cannot be avoided, the manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like erdafitinib by one-half.(2)

DISCUSSION: In PKPB models, concurrent use of fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) resulted in erdafitinib mean ratios for concentration maximum (Cmax) and area-under-curve (AUC) of 121% and 148% , respectively, compared to erdafitinib alone.(1) In PKPB models, concurrent use of itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) resulted in erdafitinib mean ratios for Cmax and AUC of 105% and 134%, respectively, compared to erdafitinib alone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4) Strong CYP2C9 inhibitors include: camizestrant.(3,4) Moderate inhibitors of CYP2C9 include: adagrasib, amiodarone, apazone, asciminib, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and sulfaphenazole.(3,4)

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

Moderate Cyp2c9 Inhibitors/Lesinurad

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

MECHANISM OF ACTION: Moderate inhibitors of CYP2C9 may inhibit the metabolism of lesinurad.(1)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP2C9 may result in elevated levels and toxicity from lesinurad, include nephrotoxicity.(1)

PREDISPOSING FACTORS: Patients with decreased renal function (CrCl less than 60 ml/min) and patients not receiving a xanthine oxidase inhibitor may be at increased risk of nephrotoxicity.(1)

PATIENT MANAGEMENT: Approach the concurrent use of lesinurad and moderate inhibitors of CYP2C9 with caution.(1) Monitor renal function in patients receiving concurrent therapy closely. Interrupt therapy and measure serum creatinine promptly in patients who report flank pain and/or nausea/vomiting.

DISCUSSION: Fluconazole (200 mg daily), a moderate inhibitor of CYP2C9, increased lesinurad levels by 50%.(1)

Nitisinone/Selected Cyp2c9 Substrates

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

MECHANISM OF ACTION: Nitisinone is a moderate inhibitor of CYP2C9.(1,2)

CLINICAL EFFECTS: Decreased clearance may increase systemic concentrations of drugs primarily metabolized by CYP2C9, leading to toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Decrease the dosage of the CYP2C9 substrate drug by one-half. Additional dose adjustments may be necessary. Closely monitor patients stable on CYP2C9 substrates for altered therapeutic effect or toxicity when nitisinone therapy is started or adjusted.(1)

DISCUSSION: In a study, 16 healthy subjects who were pre-treated with nitisinone (80 mg daily) for 14 days and received a single dose of tolbutamide (500 mg) had an increase in tolbutamide area-under-curve (AUC) and maximum concentration (Cmax) of 131 % and 16 %, respectively, compared to tolbutamide administered alone.(1,2) Medications linked to this interaction include fluvastatin, fosphenytoin, glimepiride, glipizide, phenytoin, tolbutamide, and warfarin. These drugs have a narrow therapeutic range or are designated as CYP2C9 Sensitive Substrates(3,4) (i.e. moderate 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold).

Oat3 Inhibitors/Methotrexate (Low Strength Inj, Oral)

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

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

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

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

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

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

Selected Cyp2c9 Inhibitors/Selected Nsaids

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

MECHANISM OF ACTION: The major metabolic pathway for many non-steroidal anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include: amiodarone, asciminib, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

CLINICAL EFFECTS: Concurrent use of NSAIDs with inhibitors of CYP2C9 may result in increased levels of and adverse effects from NSAIDs, including increased risk for bleeding. NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen, ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib.

PREDISPOSING FACTORS: Higher doses of either agent would be expected to increase the risk for serious adverse effects such as gastrointestinal bleeding (GIB) or renal failure. Patients who smoke, are elderly, debilitated, dehydrated, have renal impairment, or who have a history of GIB due to NSAIDs are also at increased risk for serious adverse events.(3-7) 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: Patients on routine NSAID therapy when an inhibitor of CYP2C9 is started should be evaluated for patient-specific risk factors for NSAID toxicity. Based upon this risk assessment, consider dose reduction of the NSAID or close monitoring for adverse effects. For a patient already receiving a CYP2C9 inhibitor when an NSAID is started, consider initiating the NSAID at a lower than usual dose, particularly when predisposing risk factors for harm are present. The manufacturer of celecoxib recommends that celecoxib be introduced at the lowest recommended dose in patients receiving fluconazole therapy.(3) The manufacturer of fluconazole states that half the dose of celecoxib may be necessary when fluconazole is added.(4) It would be prudent to follow this recommendation with other CYP2C9 inhibitors and to decrease the dose of celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib therapy. The manufacturer of diclofenac-misoprostol states that the total daily dose of diclofenac should not exceed the lowest recommended dose of 50 mg twice daily in patients taking CYP2C9 inhibitors.(5) It would be prudent to use the lowest recommended dose of other diclofenac formulations in patients taking CYP2C9 inhibitors. The manufacturer of parecoxib states that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.(6) It would be prudent to follow this recommendation with other CYP2C9 inhibitors. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate by one-half.(7) 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.

DISCUSSION: The concomitant administration of celecoxib and fluconazole (200 mg daily) resulted in a 2-fold increase in celecoxib plasma concentration.(3) In vitro studies in human hepatocytes found that amiodarone inhibited diclofenac metabolism.(8) In two separate studies, single doses of diclofenac (50 mg) or ibuprofen (400 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean AUC of diclofenac by 78% and increased the AUC of the active isomer of ibuprofen by 100%.(9-11) Coadministration of diosmin increased diclofenac levels by 63%.(2) Coadministration of flurbiprofen or ibuprofen with fluconazole increased the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared with either agent alone.(4) Concurrent voriconazole increased meloxicam AUC by 47%.(12,13) The concurrent administration of fluconazole and parecoxib resulted in increases in the area-under-curve (AUC) and maximum concentration (Cmax) of valdecoxib (the active metabolite of parecoxib) by 62% and 19%, respectively.(6) In a study, single dose diclofenac (50mg) given concurrently with the last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12 hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold, respectively. (5) Inhibitors of CYP2C9 include: amiodarone, asciminib, camizestrant, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

Selected Moderate Cyp2c9 Inhibitors/Siponimod

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

MECHANISM OF ACTION: Inhibitors of CYP2C9 may inhibit the metabolism of siponimod.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C9 may result in elevated levels of and clinical effects of siponimod, including immunosuppression and increased risk of infection.(1) Concurrent use of siponimod with immunosuppressive or immune-modulating agents, such as asciminib, may result in an additive risk and increased risk of serious infections.

PREDISPOSING FACTORS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may increase the effects of the interaction.

PATIENT MANAGEMENT: Monitor for adverse reactions during concomitant use of siponimod with moderate CYP2C9 inhibitors or moderate CYP2C9 and CYP3A4 dual inhibitors.(1) Review the patient's therapy for concurrent use of strong or moderate inhibitors of CYP3A4 prior to initiating siponimod. If concurrent use is necessary, the manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like siponimod by one-half.(2)

DISCUSSION: Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%). Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1 genotype increased the area-under-curve (AUC) of siponimod (4 mg single dose) by 2-fold. Siponimod half-life increased by 50%. Fluconazole increased siponimod AUC by 2-fold to 4-fold across all CYP2C9 genotypes.(1) Selected moderate CYP2C9 inhibitors linked to this monograph include: apazone, asciminib, benzbromarone, felbamate, miconazole, milk thistle, nitisinone, oxandrolone, phenylbutazone, piperine, silibinin, and sulfaphenazole.(3)

*None.

There are no contraindication contraindications for this drug.

• Hypertyrosinemia

• Leukopenia
• Thrombocytopenic disorder

The most common adverse reactions (>1%) to nitisinone in patients with HT-1 include elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash, and alopecia.

The most common adverse reactions (>1%) to nitisinone in patients with AKU include elevated tyrosine levels, keratitis, and thrombocytopenia.

More Frequent

• Acute hepatic failure
• Corneal opacity
• Exfoliative dermatitis
• Granulocytopenic disorder
• Keratitis
• Leukopenia
• Malignant neoplasm of liver
• Thrombocytopenic disorder

Less Frequent

• Cataracts
• Porphyria

Rare or Very Rare

• Abnormal hepatic function tests
• Bacterial sepsis
• Corneal ulcer
• Dehydration
• Enanthema
• Encephalopathy
• Gastrointestinal hemorrhage
• Hepatomegaly
• Hyperkeratosis
• Hyperkinesis
• Hypertyrosinemia
• Hypoglycemic disorder
• Neoplasm of brain
• Seizure disorder

More Frequent

• Alopecia
• Blepharitis
• Conjunctivitis
• Dry skin
• Epistaxis
• Maculopapular rash
• Ocular pain
• Photophobia
• Pruritus of skin

Rare or Very Rare

• Acute abdominal pain
• Black tarry stools
• Bronchitis
• Cyanosis
• Diarrhea
• Polydipsia

No enhanced messaging available.

Safety and efficacy of nitisinone for the treatment of HT-1 have been established in patients from birth to 22 years of age (median age was 9 months).

Safety and efficacy of nitisinone for the treatment of AKU have not been established in pediatric patients.

Available data from published case reports with nitisinone use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproductive studies, skeletal malformations, decreased pup survival, and maternal toxicity were observed.

Nitisinone is distributed into milk in rats. It is not known whether nitisinone is distributed into human milk or if the drug has any effects on the breastfed infant or on milk production; consider the developmental and health benefits of breastfeeding along with the mother's clinical need for nitisinone and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Safety and efficacy of nitisinone for the treatment of HT-1 have not been established in adults 65 years of age or older.

In clinical studies for AKU, there was 1 patient who was 65 years of age or older, which is an insufficient number to determine whether geriatric patients respond differently from younger adult patients.