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Fedratinib

Medically reviewed by Drugs.com. Last updated on Nov 5, 2018.

Pronunciation

(fed RA ti nib)

Index Terms

  • Fedratinib dihydrochloride monohydrate
  • Inrebic
  • SAR302503
  • SAR302503a
  • TG101348

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Inrebic: 100 mg

Brand Names: U.S.

  • Inrebic

Pharmacologic Category

  • Antineoplastic Agent, FLT3 Inhibitor
  • Antineoplastic Agent, Janus Associated Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Janus Associated Kinase Inhibitor

Pharmacology

Fedratinib is a kinase inhibitor with activity against both wild-type and mutated Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is selective for JAK2, with higher inhibitory activity for JAK2 (versus JAK1, JAK3, and TYK2). Abnormal JAK2 activation is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. Fedratinib reduces phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibits cell proliferation, and induces apoptosis in mutated JAK2 and FLT3 cell lines, improving WBC counts, hematocrit, splenomegaly, and fibrosis.

Distribution

Vd: 1,770 L

Metabolism

Via CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3)

Excretion

Feces (77%; 23% as unchanged drug); Urine (5%; 3% as unchanged drug); Clearance: 13 L/hour

Onset of Action

STAT3 phosphorylation inhibition (maximal): ~2 hours

Time to Peak

3 hours (range: 2 to 4 hours)

Duration of Action

STAT3 phosphorylation inhibition: 24 hours

Half-Life Elimination

Effective: 41 hours; Terminal: ~114 hours

Protein Binding

≥92% to plasma proteins

Special Populations: Renal Function Impairment

Following a single 300 mg fedratinib dose, the AUCinf increased by 1.5-fold in subjects with moderate (CrCl 30 to 59 mL/minute) impairment and 1.9-fold in subjects with severe (CrCl 15 to 29 mL/minute) impairment, compared to that in subjects with CrCl ≥90 mL/minute).

Use: Labeled Indications

Myelofibrosis: Treatment of intermediate-2 or high-risk primary or secondary (post polycythemia vera or post-essential thrombocythemia) myelofibrosis in adults.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: Evaluate baseline thiamine levels prior to treatment initiation; do not initiate fedratinib in patients with thiamine deficiency. Replete thiamine prior to fedratinib initiation and during treatment if thiamine levels are low. Consider antiemetics to prevent nausea and vomiting during fedratinib treatment. Patients transitioning from ruxolitinib to fedratinib must taper and discontinue ruxolitinib (refer to ruxolitinib monograph for ruxolitinib taper/discontinuation).

Myelofibrosis: Oral: 400 mg once daily (in patients with a baseline platelet count ≥50,000/mm3).

Dosage adjustment for concomitant strong CYP3A4 inhibitors: Consider alternative agents that do not strongly inhibit CYP3A4 activity. If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, reduce the fedratinib dose to 200 mg once daily. When the concomitant strong CYP3A4 inhibitor is discontinued, increase the fedratinib dose to 300 mg once daily for the first 2 weeks after the strong CYP3A4 inhibitor is discontinued, then increase fedratinib to 400 mg once daily thereafter as tolerated.

Missed doses: If a fedratinib dose is missed, the next scheduled dose should be administered the following day. Do not administer 2 doses to make up for the missed dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Modify fedratinib dose for adverse reactions. Discontinue fedratinib if unable to tolerate 200 mg once daily.

Hematologic toxicities: Consider dose reduction for patients who become transfusion dependent during fedratinib therapy.

Anemia: May require RBC transfusion; consider dose reduction in patients who become RBC transfusion dependent. May require permanent discontinuation.

Neutropenia (grade 4): Interrupt fedratinib until resolved to ≤ grade 2 or baseline, then resume with the dose reduced by 100 mg/day below the prior fedratinib dose.

Thrombocytopenia (grade 3 with active bleeding or grade 4): Interrupt fedratinib until resolved to ≤ grade 2 or baseline, then resume with the dose reduced by 100 mg/day below the prior fedratinib dose. May require platelet transfusion and/or permanent discontinuation of fedratinib for thrombocytopenia and bleeding requiring clinical intervention.

Nonhematologic toxicities:

GI toxicity (≥ grade 3 nausea, vomiting, or diarrhea not responding to supportive measures within 48 hours): Interrupt fedratinib until resolved to ≤ grade 1 or baseline, then resume with the dose reduced by 100 mg/day below the prior fedratinib dose.

Diarrhea: Promptly manage diarrhea with antidiarrheal medications at the first onset of symptoms.

Amylase or lipase elevations (≥ grade 3): Interrupt fedratinib until resolved to ≤ grade 1 or baseline, then resume with the dose reduced by 100 mg/day below the prior fedratinib dose.

Wernicke encephalopathy: If encephalopathy is suspected, immediately discontinue fedratinib and initiate parenteral thiamine; monitor until symptoms resolve or improve and thiamine levels normalize.

Other toxicities (≥ grade 3): Interrupt fedratinib until resolved to ≤ grade 1 or baseline, then resume with the dose reduced by 100 mg/day below the prior fedratinib dose.

Administration

Oral: May administer with or without food; administration with a high-fat meal may reduce the incidence of nausea and vomiting. Consider antiemetics to prevent nausea and vomiting during fedratinib treatment.

Storage

Store below 86°F (30°C).

Drug Interactions

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Consider therapy modification

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

Brigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Consider therapy modification

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabidiol: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cilostazol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Reduce the cilostazol dose to 50 mg twice daily in patients who are also receiving moderate inhibitors of CYP2C19. Monitor clinical response to cilostazol closely. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (eg, serotonin syndrome, QT prolongation). Consider therapy modification

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Codeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See full monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2C19 Substrates (High risk with Inhibitors): CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Tamoxifen. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Fedratinib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Fedratinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated. Consider therapy modification

CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Trabectedin; Vinorelbine. Monitor therapy

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Disopyramide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Disopyramide. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Encorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and moderate CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose prior to initiation of the CYP3A4 inhibitor. See full monograph for details. Consider therapy modification

Entrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Entrectinib. Management: Avoid moderate CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 200 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. No alternative dosing provided for others. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Estrogen Derivatives: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fluconazole: May increase the serum concentration of Fedratinib. Avoid combination

Fosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant. Avoid combination

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Management: Extreme caution, with possibly increased monitoring of ECGs, should be used if halofantrine is combined with moderate CYP3A4 inhibitors. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor. Consider therapy modification

Ivosidenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivosidenib. Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lefamulin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lefamulin. Management: Monitor for lefamulin adverse effects during coadministration of lefamulin tablets with moderate CYP3A4 inhibitors. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification

Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Monitor therapy

Meperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine. Management: Consider reducing meperidine dose if concomitant use with moderate CYP3A4 inhibitors is required. Monitor for signs and symptoms of respiratory depression and sedation when these agents are combined. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Metoprolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoprolol. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Neratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Consider therapy modification

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Pexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Pitolisant. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Silodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sirolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Consider therapy modification

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy

Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tezacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days from tezacaftor/ivacaftor. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided. Consider therapy modification

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Voriconazole: May increase the serum concentration of Fedratinib. Avoid combination

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fatigue (≤19%)

Endocrine & metabolic: Hyponatremia (26%), increased amylase (24%)

Gastrointestinal: Diarrhea (66%), nausea (62%), vomiting (39%), increased serum lipase (35%)

Hematologic & oncologic: Anemia (40% to 74%; grades ≥3: 30% to 34%), thrombocytopenia (47%; grades ≥3: 12%), neutropenia (23%; grades ≥3: 5%)

Hepatic: Increased serum alanine aminotransferase (9% to 43%), increased serum aspartate aminotransferase (5% to 40%)

Neuromuscular & skeletal: Asthenia (≤19%), muscle spasm (12%)

Renal: Increased serum creatinine (10% to 59%)

1% to 10%:

Cardiovascular: Cardiac failure (5%), hypertension (4%), cardiogenic shock (1%)

Central nervous system: Headache (9%), dizziness (8%)

Endocrine & metabolic: Weight gain (9%)

Genitourinary: Dysuria (6%), urinary tract infection (6%)

Hematologic & oncologic: Severe anemia (2%)

Neuromuscular & skeletal: Limb pain (10%), ostealgia (8%)

Frequency not defined:

Central nervous system: Encephalopathy (including Wernicke's)

Gastrointestinal: Gastrointestinal toxicity

Genitourinary: Cystitis

ALERT: U.S. Boxed Warning

Encephalopathy, including Wernicke

Serious and fatal encephalopathy, including Wernicke, has occurred in patients treated with fedratinib. Wernicke encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting fedratinib, periodically during treatment, and as clinically indicated. Do not start fedratinib in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue fedratinib and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Warnings/Precautions

Concerns related to adverse effects:

• Encephalopathy: [US Boxed Warning]: Serious and fatal encephalopathy (including Wernicke encephalopathy, a neurologic emergency) has occurred with fedratinib. Assess thiamine levels (in all patients) prior to fedratinib initiation, periodically during treatment, and as clinically indicated. Replete thiamine prior to treatment initiation; do not initiate fedratinib in patients with thiamine deficiency. If encephalopathy is suspected, immediately discontinue fedratinib and initiate parenteral thiamine; monitor until symptoms resolve or improve and thiamine levels normalize. Wernicke encephalopathy results from thiamine deficiency. Signs/symptoms of Wernicke encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (eg, nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy (including Wernicke) and prompt a full evaluation, including a neurologic examination, assessment of thiamine levels, and imaging.

• GI toxicity: GI toxicities, including diarrhea, nausea, and vomiting, commonly occur with fedratinib. Grade 3 diarrhea and vomiting have occurred. The median time to onset (for any grade) of nausea, vomiting, and diarrhea was 1 day, with most events occurring within 2 weeks of treatment. Consider prophylactic antiemetic therapy during fedratinib treatment. Promptly manage diarrhea with antidiarrheal medications at the first onset of symptoms. For grade 3 or higher nausea, vomiting, or diarrhea that is not responsive within 48 hours to supportive measures, interrupt fedratinib until resolved to grade 0 or 1 or to baseline; then reinitiate with the dose reduced. Monitor thiamine levels and replete as needed. Grade 3 or higher amylase and/or lipase elevations have developed with fedratinib. The median time to onset (for any grade) of amylase or lipase elevation was 15 days, with most cases occurring within 1 month of starting fedratinib treatment. Pancreatitis has been observed (rare) and resolved with fedratinib discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For grade 3 or higher amylase and/or lipase elevations, interrupt fedratinib until resolved to grade 0 or 1 or to baseline; then reinitiate with the dose reduced.

• Hematologic toxicity: Anemia, thrombocytopenia, and neutropenia may occur with fedratinib. New or worsening grade 3 anemia occurred in approximately one-third of patients. The median time to onset of grade 3 anemia (first event) was ~2 months, with most cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks, with partial recovery and stabilization after 16 weeks. Approximately half of patients received RBC transfusions. Fedratinib was permanently discontinued due to anemia in a small percentage of patients. Consider dose reduction in patients who become RBC transfusion dependent. New or worsening grade 3 or higher thrombocytopenia has been reported with fedratinib. The median time to onset of grade 3 thrombocytopenia (first event) was ~1 month, with most cases occurring within 4 months. A small percentage of patients received platelet transfusions and/or required permanent discontinuation due to thrombocytopenia and bleeding requiring clinical intervention. Obtain a CBC at baseline, periodically during treatment, and as clinically indicated. For grade 3 thrombocytopenia with active bleeding or grade 4 thrombocytopenia, interrupt fedratinib treatment until resolved to ≤ grade 2 or baseline; then reinitiate with the dose reduced and monitor platelets as clinically indicated.

• Hepatotoxicity: ALT and AST elevations (all grades) occurred commonly with fedratinib treatment; grade 3 events have been reported (rare). The median time to onset of transaminase elevation (any grade) was ~1 month, with most cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For grade 3 or higher ALT and/or AST elevations (>5 times ULN), interrupt fedratinib treatment until resolved to grade 0 or 1 or to baseline; then resume at a reduced dose. Discontinue fedratinib treatment for recurrence of grade 3 or higher ALT or AST elevations. Avoid fedratinib use in patient with baseline severe hepatic impairment.

Disease-related concerns:

• Renal impairment: Dose reduction recommended in patients with severe renal impairment (CrCl <30 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Assess thiamine levels (in all patients) prior to fedratinib initiation, periodically during treatment, and as clinically indicated. Monitor CBC (with platelets), hepatic function, amylase, lipase, and renal function (creatinine and BUN) at baseline, periodically during treatment, and as clinically indicated. Monitor for signs/symptoms of encephalopathy (if encephalopathy occurs, monitor until symptoms resolve or improve and thiamine levels normalize). Monitor for signs/symptoms of diarrhea, nausea/vomiting, and bleeding. Monitor adherence.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

Further information

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