Deferasirox (deferasirox)

For patients currently receiving deferasirox tablets for oral suspension (e.g., Exjade(R)) for chelation therapy, when converting to film-coated tablets or granules (e.g., Jadenu(R)) the dosage should be reduced by about 30%, rounded to the nearest whole tablet or whole sachet dosage strength (Table 1).

Table 1. Conversion from Deferasirox Tablets for Oral Suspension to Deferasirox Film-Coated Tablets or Granules for Oral Use

Dosage of Deferasirox Dosage of Deferasirox Tablets for Oral Tablets or Granules for Suspension Oral Use Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg per day 14 mg/kg per day Titration Increments 5-10 mg/kg 3.5-7 mg/kg Maximum Dose 40 mg/kg per day 28 mg/kg per day Non-Transfusion-Dependen t Thalassemia Syndrome Starting Dose 10 mg/kg per day 7 mg/kg per day Titration Increments 5-10 mg/kg 3.5-7 mg/kg Maximum Dose 20 mg/kg per day 14 mg/kg per day

Deferasirox is administered orally as tablets for oral suspension (e.g., Exjade(R)), as film-coated tablets for oral use (e.g., Jadenu(R)), and as granules for oral use (e.g., Jadenu(R) Sprinkle). Dosing conversion is required when switching between deferasirox formulations. In patients currently receiving chelation therapy with deferasirox tablets for oral suspension (e.g., Exjade(R)), conversion to film-coated tablets use (e.g., Jadenu(R)) or granules for oral use (e.g., Jadenu(R) Sprinkle) requires a decrease in dosage.

Administer deferasirox tablets for oral suspension (e.g., Exjade(R)) and film-coated tablets or granules (e.g., Jadenu(R)) once daily on an empty stomach (at least 30 minutes before eating), preferably at the same time each day. Film-coated tablet and granule preparations may also be administered with a light meal (containing less than 7% fat and approximately 250 calories).

Store all deferasirox preparations between 20-25degreesC (excursions permitted between 15-30degreesC). Protect from moisture.

Deferasirox is metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and to a lesser extent by UGT1A3; cytochrome P-450 (CYP) isoenzymes appear to play a minor role (approximately 8%). Deferasirox inhibits CYP isoenzymes 3A4, 2C8, 1A2, 2A6, 2D6, and 2C19 in vitro.

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

Cyp1a2 Inhibitors/Fezolinetant

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 CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Iron Chelators/Exagamglogene Autotemcel

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: Treatment with exagamglogene autotemcel requires hematopoietic stem cell (HSC) mobilization which can suppress the immune system.

CLINICAL EFFECTS: Iron chelators should be held prior to and after infusion with exagamglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Iron chelators should be discontinued 7 days prior to initiation of mobilization or conditioning. Avoid myelosuppressive iron chelators for six months after exagamglogene autotemcel infusion. Avoid non-myelosuppressive iron chelators for three months after exagamglogene autotemcel infusion. If iron chelation is needed, consider phlebotomy in lieu of iron chelation when appropriate.(1)

DISCUSSION: In preparation for infusion of exagamglogene autotemcel, iron chelation should be discontinued 7 days prior to initiation of mobilization or conditioning.(1)

Moderate 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: Moderate inhibitors of CYP2C8 may inhibit the metabolism of tolebrutinib.(1-2)

CLINICAL EFFECTS: Concomitant use of a moderate CYP2C8 inhibitor may result in elevated levels and clinical effects of tolebrutinib, including immunosuppression and hepatotoxicity.(1-2)

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 moderate CYP2C8 inhibitors should be avoided. If the use of moderate CYP2C8 inhibitors will be short-term, treatment with tolebrutinib should be interrupted.(1)

DISCUSSION: The impact of moderate CYP2C8 inhibitors on the pharmacokinetics of tolebrutinib has not been investigated in clinical studies. Moderate CYP2C8 inhibitors are predicted to increase tolebrutinib exposure.(1-2) 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) exposure by 8.4-fold.(2) Moderate CYP2C8 inhibitors linked to this monograph include clopidogrel, deferasirox, letermovir, pirtobrutinib, and selpercatinib.(3,4)

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

Deferasirox/Aluminum Salts

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

MECHANISM OF ACTION: Decreased absorption of deferasirox possibly from complex formation with the aluminum salt.

CLINICAL EFFECTS: The therapeutic effects of deferasirox may be reduced.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of deferasirox states patients taking deferasirox should not take aluminum salts or aluminum-containing antacid products.

DISCUSSION: Simultaneous administration of deferasirox and aluminum has not been studied. Even though deferasirox has a lower affinity for aluminum than iron, it should not be taken with aluminum-containing products.

Deferasirox/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 deferasirox.(1)

CLINICAL EFFECTS: Concurrent use of bile acid sequestrants may result in decreased levels and effectiveness of deferasirox, even when the administration times are separated.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of bile acid sequestrants with deferasirox. If concurrent therapy is warranted, consider increasing the initial dose of deferasirox by 50%. Further dosage adjustments should be made based upon serum ferritin levels and clinical response. Doses above 40 mg/kg are not recommended.(1)

DISCUSSION: In a study in healthy subjects, administration of cholestyramine (12 g twice daily, 4 and 10 hours after deferasirox) decreased the area-under-curve (AUC) of a single dose of deferasirox (dosage not stated) by 45%.(1)

Deferasirox/Busulfan

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

MECHANISM OF ACTION: Deferasirox may increase the plasma concentrations of busulfan.(1-3) The exact mechanism is unknown but may involve competitive inhibition of glucuronidation enzymes.(2)

CLINICAL EFFECTS: Concurrent use of deferasirox may result in elevated levels of and toxicity from busulfan.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be closely monitored for toxicity. The dosage of busulfan may need to be adjusted.(1-3)

DISCUSSION: In a case report, co-administration of deferasirox with busulfan led to a 1.5-fold increase in area under the curve (AUC) and 37% decrease in drug clearance (CL).(2) In another case report, concomitant use of busulfan and deferasirox led to a 2-fold increase in AUC and 46% decrease in CL.(3) In both reports, the dose of busulfan when used with concomitant deferasirox was approximately half of the dose required with busulfan alone.

Deferasirox/Hormonal Contraceptives

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

MECHANISM OF ACTION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of deferasirox may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a non-hormonal method of birth control during deferasirox therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Deferasirox may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a non-hormonal method of birth control during deferasirox therapy.(1)

Deferasirox/Selected Cyp1a2 Substrates

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

MECHANISM OF ACTION: Deferasirox is a weak inhibitor of CYP1A2. The FDA defines weak inhibition as an increase in drug area-under-curve (AUC) greater than 1.25 fold, but less than 2 fold.(1-3)

CLINICAL EFFECTS: Concurrent use of deferasirox may lead to increased levels and effects of drugs primarily metabolized by CYP1A2.(1)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP1A2 inhibition. With tizanidine, 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 deferasirox recommends avoiding concomitant therapy with theophylline or CYP1A2 narrow therapeutic range substrates such as tizanidine.(1) The Australian and UK manufacturers of deferasirox state that concomitant use with theophylline or other substances predominantly metabolized by CYP1A2 and with a narrow therapeutic index (e.g., clozapine, tizanidine) is not recommended.(5,6) If concomitant use is necessary in patients already receiving CYP1A2 substrates such as clozapine, theophylline, or tizanidine, the dose of the CYP1A2 substrate may need to be reduced when deferasirox is started. Theophylline AUC and elimination half-life may double. Monitor theophylline concentrations and adjust dose accordingly.(1) Patients already receiving deferasirox when a CYP1A2 substrate is started may be more susceptible to adverse effects. A lower than usual dose of the CYP1A2 substrate may be needed. The US manufacturer of tizanidine recommends avoiding concomitant therapy with CYP1A2 inhibitors. If concurrent therapy is necessary, tizanidine should be initiated at 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(7) The US manufacturer of clozapine recommends monitoring patients closely when clozapine is coadministered with moderate or weak CYP1A2 inhibitors. Consider reducing the clozapine dosage if necessary.(8)

DISCUSSION: In a study with healthy volunteers, deferasirox dosage of 30mg/kg/day (duration not stated) and a single dose of theophylline 120 mg led to an approximate doubling of the theophylline area-under-curve (AUC) and elimination half-life.(1) Although interactions between deferasirox and clozapine or tizanidine have not been specifically studied, clozapine and tizanidine are considered CYP1A2 narrow therapeutic range substrates.

Deferasirox/Strong Ugt Inducers

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

MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase (UGT) may induce the metabolism of deferasirox.(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine, efavirenz, etravirine, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, or ritonavir may result in decreased levels and effectiveness of deferasirox.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong UGT inducers with deferasirox. If concurrent therapy is warranted, consider increasing the initial dose of deferasirox by 50%. Further dosage adjustments should be made based upon serum ferritin levels and clinical response. Doses above 40 mg/kg are not recommended.(1)

DISCUSSION: In a study in healthy subjects, administration of rifampin (600 mg/day for 9 days) decreased the area-under-curve (AUC) of a single dose of deferasirox (30 mg/kg) by 44%.(1) Other strong inducers of UGT, such as carbamazepine, efavirenz, fosphenytoin, phenobarbital, phenytoin, primidone, and ritonavir are expected to produce similar results.(1)

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)

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

Deferasirox/Repaglinide

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

MECHANISM OF ACTION: Deferasirox may inhibit the metabolism of repaglinide by CYP2C8.(1)

CLINICAL EFFECTS: Concurrent use of deferasirox may result in elevated levels of and increased effects of repaglinide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with deferasirox and repaglinide closely. Consider decreasing the dosage of repaglinide.(1)

DISCUSSION: In a study in healthy subjects, administration of deferasirox (30 mg/kg/day for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.5 mg) by 2.3-fold and 62%, respectively.(1)

Iron Chelators/Lovotibeglogene Autotemcel

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

MECHANISM OF ACTION: Treatment with lovotibeglogene autotemcel requires hematopoietic stem cell (HSC) mobilization which can suppress the immune system.

CLINICAL EFFECTS: Iron chelators should be held prior to and after infusion with lovotibeglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Iron chelators should be discontinued 7 days prior to initiation of mobilization or conditioning. Avoid myelosuppressive iron chelators for six months after lovotibeglogene autotemcel infusion. Avoid non-myelosuppressive iron chelators for three months after lovotibeglogene autotemcel infusion. If iron chelation is needed, consider phlebotomy in lieu of iron chelation when appropriate.(1)

DISCUSSION: In preparation for infusion of lovotibeglogene autotemcel, iron chelation should be discontinued 7 days prior to initiation of mobilization or conditioning.(1)

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)

Selected Strong And Moderate Cyp2c8 Inhibitors/Paclitaxel

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

MECHANISM OF ACTION: Inhibitors of CYP2C8 may inhibit paclitaxel metabolism by this pathway. Clopidogrel and gemfibrozil are strong inhibitors of CYP2C8. Deferasirox is a moderate inhibitor of CYP2C8.(1-3)

CLINICAL EFFECTS: Concurrent use of CYP2C8 inhibitors and paclitaxel may result in elevated levels and clinical effects of paclitaxel.(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)

Strong And Moderate Cyp2c8 Inhibitors/Etrasimod

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

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)

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.

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)

PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1)

DISCUSSION: 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 strong or moderate inhibitors of CYP2C8.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Strong inhibitors of CYP2C8 include: clopidogrel and gemfibrozil.(2,3) Moderate inhibitors of CYP2C8 include: deferasirox.(2,3)

*eGFR less than 40 mL/minute per 1.73 m2

*Poor performance status

*High-risk myelodysplastic syndrome

*Advanced malignancy

*Platelet counts less than 50,000/mm3

*Known hypersensitivity to deferasirox or any ingredient in the formulation

• Acute renal failure
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Lactation

• Child-pugh class B hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Dehydration
• Disease of liver
• Hyperbilirubinemia
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Malignancy
• Multiple organ failure
• Myelodysplastic syndrome
• Neutropenic disorder
• Ocular hypertension
• Pregnancy
• Thrombocytopenic disorder

• Anemia
• Cataracts
• Hearing loss
• Proteinuria

Adverse effects reported in more than 5% of patients receiving deferasirox with transfusional iron overload include diarrhea, vomiting, nausea, abdominal pain, rash, and increases in serum creatinine concentration.

Adverse effects reported in more than 5% of patients receiving deferasirox with NTDT syndromes include diarrhea, rash, and nausea.

More Frequent

• Kidney disease with reduction in glomerular filtration rate (GFr)

Less Frequent

• Urticaria

Rare or Very Rare

• Abnormal hepatic function tests
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Biliary calculus
• Cataracts
• DRESS syndrome
• Erythema multiforme
• Fanconi syndrome
• Gastritis
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hearing loss
• Hepatic failure
• Hepatitis
• Hyperbilirubinemia
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• IgA vasculitis
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial nephritis
• Maculopathy
• Neutropenic disorder
• Ocular hypertension
• Optic neuritis
• Pancreatitis
• Renal failure
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Diarrhea
• Nausea
• Pharyngitis
• Proteinuria
• Skin rash
• Vomiting

Less Frequent

• Dysmenorrhea
• Increased defecation frequency
• Insomnia
• Lymphadenopathy
• Sleep disorder
• Upper respiratory infection
• Vertigo

Rare or Very Rare

• Alopecia
• Dizziness
• Dyschromia
• Edema
• Esophagitis
• Fatigue
• Fever
• Hyperkinesis
• Symptoms of anxiety

No enhanced messaging available.

Safety and efficacy for transfusional iron overload have not been established in children younger than 2 years of age.

Use of deferasirox for transfusional iron overload is based on data from 292 pediatric patients ranging from 2 to less than 16 years of age with various congenital and acquired anemias.

Safety and efficacy for chronic iron overload in non-transfusion-dependent thalassemia (NTDT) syndromes have not been established in children younger than 10 years of age.

Use of deferasirox for chronic iron overload in NTDT is based on data from 16 pediatric patients with chronic iron overload and NTDT who were 10 to less than 16 years of age with a liver iron concentration (LIC) of at least 5 mg Fe/g dry weight and a serum ferritin concentration of more than 300 mcg/L. Additional data from well-designed pediatric and adult studies support this use.

Systemic exposure of deferasirox in children less than 6 years of age is lower than that in adults.

No data are available to inform the drug-associated risk of deferasirox use in pregnancy. Animal reproductive studies demonstrated decreases in offspring viability and increases in renal anomalies at doses less than or similar to the equivalent human dose. Use deferasirox during pregnancy only if benefits clearly outweigh the potential risks of treatment.

Deferasirox is distributed into milk in rats; it is not known whether the drug is distributed into human milk. The effects of deferasirox on milk production, and the effects on the breastfed infant are not known. Consider the benefits of breastfeeding along with the potential for adverse effects from deferasirox exposure to the breast-fed infant, along with the mother's clinical need for the drug. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

The manufacturer makes no specific dosage recommendations in geriatric patients; however, in clinical trials, geriatric patients experienced a higher frequency of adverse reactions compared to younger adult patients. Due to decreased hepatic, renal, and cardiac function, in addition to the presence of other coexisting conditions, careful selection of the dosage of deferasirox is necessary in geriatric patients, and dosing is usually initiated at the lower end of the dosing range.

Deferasirox should be used with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly. Geriatric patients receiving deferasirox should be monitored closely for early signs and/or symptoms of adverse reactions that may require dosage adjustment. Select the dose cautiously in geriatric patients.

In clinical studies of deferasirox, geriatric patients 65 years of age or older experienced a higher incidence of adverse reactions than younger adults. The majority of these geriatric patients had myelodysplastic syndrome (MDS).