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Drug Interactions between adagrasib and Dexacort Phosphate in Turbinaire

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

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Moderate

dexAMETHasone nasal adagrasib

Applies to: Dexacort Phosphate in Turbinaire (dexamethasone nasal) and adagrasib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of corticosteroids, which are primarily metabolized by the isoenzyme. The interaction has been reported with potent inhibitors such as clarithromycin, erythromycin, itraconazole, nefazodone, cobicistat, and ritonavir during concomitant use of various corticosteroids, including inhaled, nasal, and ophthalmic formulations. Systemic corticosteroid adverse effects may occur following intensive or long-term continuous ophthalmic corticosteroid therapy. Cushing's syndrome and adrenal insufficiency have been attributed to the interaction.

MANAGEMENT: The possibility of increased corticosteroid effects should be considered during coadministration with potent and moderate CYP450 3A4 inhibitors. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. If the combination is considered necessary, a lower dosage of the corticosteroid may be required. When indicated for intranasal or inhalational use, alternative corticosteroids such as beclomethasone, which is less dependent on CYP450 3A4 metabolism, should be considered, particularly if long term treatment is required. 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. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if the corticosteroid is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma).

References

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  3. Ulrich B, Frey FJ, Speck RF, Frey BM (1992) "Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction." J Pharmacol Exp Ther, 260, p. 487-90
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  5. Glynn AM, Slaughter RL, Brass C, et al. (1986) "Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion." Clin Pharmacol Ther, 39, p. 654-9
  6. Itkin IH, Menzel ML (1970) "The use of macrolide antibiotic substances in the treatment of asthma." J Allergy Clin Immunol, 45, p. 146-62
  7. LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M (1983) "Inhibition of methylprednisolone elimination in the presence of erythromycin therapy." J Allergy Clin Immunol, 72, p. 34-9
  8. Finkenbine RD, Frye MD (1998) "Case of psychosis due to prednisone-clarithromycin interaction." Gen Hosp Psychiat, 20, p. 325-6
  9. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ (1998) "Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole." Clin Pharmacol Ther, 64, p. 363-8
  10. Hillebrand-Haverkort ME, Prummel MF, ten Veen JH (1999) "Ritonavir-induced Cushing's syndrome in a patient treated with nasal fluticasone." AIDS, 13, p. 1803
  11. Varis T, Kivisto KT, Neuvonen PJ (2000) "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone." Eur J Clin Pharmacol, 56, p. 57-60
  12. Varis T, Backman JT, Kivisto KT, Neuvonen PJ (2000) "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone." Clin Pharmacol Ther, 67, p. 215-21
  13. Garey KW, Rubinstein I, Gotfried MH, Khan IJ, Varma S, Danziger LH (2000) "Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma." Chest, 118, p. 1826-7
  14. Lebrun-Vignes B, Archer VC, Diquest B, et al. (2001) "Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects." Br J Clin Pharmacol, 51, p. 443-50
  15. Couturier J, Steele M, Hussey L, Pawliuk G (2001) "Steroid-induced mania in an adolescent: risk factors and management." Can J Clin Pharmacol, 8, p. 109-12
  16. Gupta SK, Dube MP (2002) "Exogenous Cushing syndrome mimicking human immunodeficiency virus lipodystrophy." Clin Infect Dis, 35, E69-71
  17. 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
  18. 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
  19. 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
  20. Kotlyar M, Brewer ER, Golding M, Carson SW (2003) "Nefazodone inhibits methylprednisolone disposition and enhances its adrenal-suppressant effect." J Clin Psychopharmacol, 23, p. 652-6
  21. 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
  22. Edsbacker S, Andersson T (2004) "Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease." Clin Pharmacokinet, 43, p. 803-21
  23. Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA (2005) "Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in HIV-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases." J Clin Endocrinol Metab, 90, p. 4394-8
  24. Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J (2005) "Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction." Intern Med J, 35, p. 67-8
  25. Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J (2005) "Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers." J Acquir Immune Defic Syndr, 40, p. 573-80
  26. EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
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Drug and food interactions

Major

adagrasib food

Applies to: adagrasib

ADJUST DOSING INTERVAL: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Theoretically, coadministration with grapefruit juice before adagrasib has reached steady-state may significantly increase the plasma concentrations of adagrasib, which is primarily metabolized by CYP450 3A4. 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 the potent CYP450 3A4 inhibitor, itraconazole. In a clinical drug interaction study, adagrasib peak plasma concentration (Cmax) and systemic exposure (AUC) were increased by 2.4-fold and 4-fold, respectively following concomitant use of a single dose of adagrasib (200 mg) with itraconazole. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole. 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 exposure to adagrasib may increase the risk of adverse effects such as QT prolongation, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, and renal impairment.

Adagrasib pharmacokinetics were not significantly affected when administered with a high-fat meal.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit or grapefruit juice until adagrasib concentrations have reached steady state (after approximately 8 days). Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Adagrasib may be administered with or without food.

References

  1. (2022) "Product Information. Krazati (adagrasib)." Mirati Therapeutics, Inc.

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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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