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Drug Interactions between budesonide and fedratinib

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

budesonide fedratinib

Applies to: budesonide and fedratinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the systemic bioavailability of budesonide, which undergoes extensive first-pass and systemic metabolism via intestinal and hepatic CYP450 3A4. In pharmacokinetic studies, 6- to 8-fold increases in budesonide systemic exposure (AUC) have been observed during coadministration of the potent CYP450 3A4 inhibitor ketoconazole with different oral formulations of budesonide. When ketoconazole was administered 12 hours after budesonide in one study, the AUC increase was approximately half that reported during simultaneous administration. In a prospective study of a cystic fibrosis center patient population, 11 of 25 patients receiving high-dose itraconazole (400 to 600 mg/day) and budesonide oral inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency, including one who developed Cushing's syndrome, compared to none in a group of 12 patients treated with itraconazole alone. There was also no adrenal insufficiency in a group of 30 cystic fibrosis patients retrospectively included as controls, 24 of whom had been treated with high-dose inhaled budesonide for several years. Adrenal function improved, but did not normalize, in 10 of the 11 patients during a follow-up of two to ten months after discontinuation of itraconazole and institution of hydrocortisone replacement therapy. Limited pharmacokinetic data indicate that itraconazole (200 mg once daily) may increase the plasma levels of budesonide by about 4-fold following inhalation of a single 1000 mcg dose, which may be mainly due to increased bioavailability of the swallowed portion of the dose.

MANAGEMENT: The possibility of increased systemic adverse effects of budesonide should be considered during coadministration with CYP450 3A4 inhibitors. If concomitant use cannot be avoided, the dosing times between budesonide and the CYP450 3A4 inhibitor should be separated by as much as possible. In addition, the lowest effective dosage of budesonide should be prescribed, and further adjustments made as necessary according to therapeutic response and tolerance. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents.

References (16)
  1. Jonsson G, Astrom A, Andersson P (1995) "Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver." Drug Metab Dispos, 23, p. 137-42
  2. (2001) "Product Information. Entocort (budesonide)." AstraZeneca Pharma Inc
  3. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT (2002) "Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole." Clin Pharmacol Ther, 72, p. 362-369
  4. Main KM, Skov M, Sillesen IB, et al. (2002) "Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient." Acta Paediatr, 91, p. 1008-11
  5. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S (2002) "Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide." Eur Respir J, 20, p. 127-33
  6. De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J (2003) "Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide." Eur J Pediatr
  7. Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN (2004) "Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole." Ann Pharmacother, 38, p. 46-9
  8. Edsbacker S, Andersson T (2004) "Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease." Clin Pharmacokinet, 43, p. 803-21
  9. De Wachter E, Malfroot A, De Schutter I, Vanbesien J, De Schepper J (2003) "Inhaled budesonide induced Cushing's syndrome in cystic fibrosis patients, due to drug inhibition of cytochrome P450." J Calif Dent Assoc, 2, p. 72-5
  10. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  11. Cerner Multum, Inc. "Australian Product Information."
  12. Molimard M, Girodet PO, Pollet C, et al. (2008) "Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation." Drug Saf, 31, p. 769-74
  13. Daveluy A, Raignoux C, Miremont-Salame G, et al. (2009) "Drug interactions between inhaled corticosteroids and enzymatic inhibitors." Eur J Clin Pharmacol
  14. Kedem E, Shahar E, Hassoun G, Pollack S (2010) "Iatrogenic Cushing's syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient." J Asthma, 47, p. 830-1
  15. (2011) "Product Information. Victrelis (boceprevir)." Schering-Plough Corporation
  16. (2011) "Product Information. Incivek (telaprevir)." Vertex Pharmaceuticals

Drug and food interactions

Moderate

budesonide food

Applies to: budesonide

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations and systemic effects of orally administered budesonide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the manufacturer, the systemic exposure of oral budesonide approximately doubles after extensive intake of grapefruit juice.

MANAGEMENT: Patients receiving budesonide should avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma budesonide levels and systemic effects.

References (1)
  1. (2001) "Product Information. Entocort (budesonide)." AstraZeneca Pharma Inc
Moderate

fedratinib food

Applies to: fedratinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of fedratinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 300 mg oral dose of fedratinib (0.75 times the recommended dose) was coadministered with 200 mg twice daily ketoconazole, a potent CYP450 3A4 inhibitor, fedratinib total systemic exposure (AUC(inf)) increased by approximately 3-fold. Using physiologically based pharmacokinetic (PBPK) simulations, coadministration of fedratinib 400 mg once daily and ketoconazole 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold. Coadministration with the moderate CYP450 3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), is predicted to increase fedratinib AUC by approximately 1.5- to 2-fold following single-dose administration and by approximately 1.2-fold at steady state. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased fedratinib exposure may potentiate the risk of adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies.

Food does not affect the oral bioavailability of fedratinib to a clinically significant extent. Administration of a single 500 mg dose (1.25 times the recommended dose) with a low-fat, low-calorie meal (162 calories; 6% from fat, 78% from carbohydrate, 16% from protein) or a high-fat, high-calorie meal (815 calories; 52% from fat, 33% from carbohydrate, 15% from protein) increased fedratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by up to 14% and 24%, respectively.

MANAGEMENT: Fedratinib may be taken with or without food. However, administration with a high-fat meal may help reduce the incidence of nausea and vomiting. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with fedratinib.

References (3)
  1. Wu F, Krishna G, Surapaneni S (2020) "Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib." Cancer Chemother Pharmacol, 86, p. 461-73
  2. (2022) "Product Information. Inrebic (fedratinib)." Bristol-Myers Squibb
  3. (2021) "Product Information. Inrebic (fedratinib)." Bristol-Myers Squibb Pharmaceuticals Ltd

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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