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Drug Interactions between fluticasone and lonafarnib

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

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Major

fluticasone lonafarnib

Applies to: fluticasone and lonafarnib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure to fluticasone following intranasal administration or oral inhalation. Fluticasone undergoes extensive first-pass and systemic metabolism via CYP450 3A4, thus inhibition of the isoenzyme may significantly increase systemic bioavailability of the drug. However, the extent of interaction may depend on route of fluticasone administration and the specific formulation. In 18 healthy subjects, coadministration of fluticasone propionate nasal spray (200 mcg once daily) with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily) for 7 days resulted in an approximately 25-fold increase in fluticasone Cmax and 350-fold increase in AUC, accompanied by an 86% decrease in mean plasma cortisol AUC. In another study, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mcg) with ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In a study using intranasal fluticasone furoate, 6 of 20 subjects who were coadministered ketoconazole (200 mg once a day for 7 days) had measurable but low levels of fluticasone furoate compared to 1 of 20 subjects who received placebo. There was an estimated 5% reduction in 24-hour serum cortisol levels with ketoconazole relative to placebo. Similarly, when fluticasone furoate-vilanterol oral inhalation (200 mcg-25 mcg once daily for 7 days) was coadministered with ketoconazole (400 once daily for 11 days) in healthy subjects, fluticasone AUC was increased 36% relative to coadministration with placebo, and the increase was associated with a 27% reduction in 24-hour weighted mean serum cortisol. A study of 17 lung transplant patients found that mean fluticasone trough level in subjects receiving fluticasone propionate (1 mg twice daily by oral inhalation for 14 days) with itraconazole was 2.5 times that observed in subjects not receiving itraconazole. Clinically, systemic glucocorticoid adverse effects may occur in association with the interaction. Adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported during worldwide postmarketing use of orally inhaled or intranasal fluticasone, primarily in combination with ritonavir. However, there have also been a few case reports of adrenal suppression associated with concomitant use of inhaled fluticasone propionate and azole antifungal agents. Recovery of adrenal function was reportedly slow in some patients following discontinuation of fluticasone. Investigators suggest that this could be related to the highly lipophilic nature of fluticasone, which allows for prolonged seepage of drug into the circulation from fat stores.

MANAGEMENT: Concomitant use of most orally inhaled fluticasone preparations with potent CYP450 3A4 inhibitors is not recommended unless the potential benefit outweighs the risk of systemic side effects. Alternatives to fluticasone should be considered whenever possible. A less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone or flunisolide may be appropriate. The lowest effective dosage of orally inhaled corticosteroid should be used, and further adjustments made as necessary according to therapeutic response and tolerance. Intranasal fluticasone and fluticasone furoate-vilanterol oral inhalation powder may be used cautiously in combination with potent CYP450 3A4 inhibitors except ritonavir. 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 fluticasone 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). Systemic glucocorticoids may be necessary until adrenal function recovers.

References

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  2. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
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  4. Grahnen A, Eckernas SA, Brundin RM, Ling-Andersson A "An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers." Br J Clin Pharmacol 38 (1994): 521-5
  5. "Product Information. Flovent (fluticasone)." Glaxo Wellcome PROD (2001):
  6. Sastre J "Pharmacology of fluticasone propionate." J Investig Allergol Clin Immunol 7 (1997): 382-4
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  8. Lipworth BJ "Systemic adverse effects of inhaled corticosteroid therapy - A systematic review and meta-analysis." Arch Intern Med 159 (1999): 941-55
  9. Hillebrand-Haverkort ME, Prummel MF, ten Veen JH "Ritonavir-induced Cushing's syndrome in a patient treated with nasal fluticasone." AIDS 13 (1999): 1803
  10. Gupta SK, Dube MP "Exogenous Cushing syndrome mimicking human immunodeficiency virus lipodystrophy." Clin Infect Dis 35 (2002): E69-71
  11. Schmid C, Naef R, Speich R, Boehler A "Addition of inhaled fluticasone propionate to systemic immunosuppression after lung transplantation: Cushing's Syndrome in patients on itraconazole comedication." Transplantation 76 (2003): 263-4
  12. Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA "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 (2005): 4394-8
  13. Gillett MJ, Cameron PU, Nguyen HV, Hurley DM, Mallal SA "Iatrogenic Cushing's syndrome in an HIV-infected patient treated with ritonavir and inhaled fluticasone." AIDS 19 (2005): 740-1
  14. Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J "Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction." Intern Med J 35 (2005): 67-8
  15. Woods DR, Arun CS, Corris PA, Perros P "Cushing's syndrome without excess cortisol." BMJ 332 (2006): 469-70
  16. Johnson SR, Marion AA, Vrchoticky T, Emmanuel PJ, Lujan-Zilbermann J "Cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and fluticasone." J Pediatr 148 (2006): 386-388
  17. Li AM "Ritonavir and fluticasone: Beware of this potentially fatal combination." J Pediatr 148 (2006): 294-5
  18. Arrington-Sanders R, Hutton N, Siberry GK "Ritonavir-fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents." Pediatr Infect Dis J 25 (2006): 1044-1048
  19. Pessanha TM, Campos JM, Barros AC, Pone MV, Garrido JR, Pone SM "Iatrogenic Cushing's syndrome in a adolescent with AIDSs on ritonavir and inhaled fluticasone. case report and literature review." AIDS 21 (2007): 529-32
  20. Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM "Exogenous Cushing syndrome with inhaled fluticasone in a child receiving lopinavir/ritonavir." Ann Pharmacother 41 (2007): 1306-9
  21. Jinno S, Goshima C "Progression of Kaposi sarcoma associated with iatrogenic Cushing syndrome in a person with HIV/AIDS." AIDS Read 18 (2008): 100-4
  22. Molimard M, Girodet PO, Pollet C, et al. "Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation." Drug Saf 31 (2008): 769-74
  23. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE "Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature." HIV Med 9 (2008): 389-96
  24. Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, Molina JM "Iatrogenic Cushing's syndrome in HIV-infected patients receiving ritonavir and inhaled fluticasone: description of 4 new cases and review of the literature." J Int Assoc Physicians AIDS Care 8 (2009): 113-21
  25. Daveluy A, Raignoux C, Miremont-Salame G, et al. "Drug interactions between inhaled corticosteroids and enzymatic inhibitors." Eur J Clin Pharmacol (2009):
  26. Nocent C, Raherison C, Dupon M, Taytard A "Unexpected effects of inhaled fluticasone in an HIV patient with asthma." J Asthma 41 (2004): 793-5
  27. Kedem E, Shahar E, Hassoun G, Pollack S "Iatrogenic Cushing's syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient." J Asthma 47 (2010): 830-1
  28. Pearce RE, Leeder JS, Kearns GL "Biotransformation of fluticasone: in vitro characterization." Drug Metab Dispos 34 (2006): 1035-40
  29. Vassiliadi D, Tsagarakis S "Unusual causes of Cushing's syndrome." Arq Bras Endocrinol Metabol 51 (2007): 1245-52
  30. Rouanet I, Peyriere H, Mauboussin JM, Vincent D "Cushing's syndrome in a patient treated by ritonavir/lopinavir and inhaled fluticasone." HIV Med 4 (2003): 149-50
  31. Brus R "Effects of high-dose inhaled corticosteroids on plasma cortisol consentrations in healthy adults." Arch Intern Med 159 (1999): 1903-8
  32. Parmar JS, Howell T, Kelly J, Bilton D "Profound adrenal suppression secondary to treatment with low dose inhaled steroids and itraconazole in allergic bronchopulmonary aspergillosis in cystic fibrosis." Thorax 57 (2002): 749-50
  33. Todd GR, Acerini CL, Ross-Russell, Zahra S, Warner JT, McCance D "Survey of adrenal crisis associated witwh inhaled corticosteroids in the United Kingdom." Arch Dis Child 87 (2002): 457-61
  34. Fardon TC, Lee DK, Haggart K, McFarlane LC, Lipworth BJ "Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate." Am J Respir Crit Care Med 170 (2004): 960-6
  35. Naef R, Schmid C, Hofer M, Minder S, Speich R, Boehler A "Itraconazole comedication increases systemic levels of inhaled fluticasone in lung transplant recipients." Respiration 74 (2007): 418-22
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  37. Boorsma M, Andersson N, Larsson P, Ullman A "Assessment of the relative systemic potency of inihaled fluticasone and budesonide." Eur Respir J 9 (1996): 1427-32
  38. Bernecker C, West TB, Mansmann G, Scherbaum WA, Willenberg HS "Hypercortisolism caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid therapy. 2 case reports and a review of the literature." Exp Clin Endocrinol Diabetes 120 (2012): 125-7
  39. "Product Information. Breo Ellipta (fluticasone-vilanterol)." GlaxoSmithKline (2013):
  40. Kempsford R, Norris V, Siederer S "Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD." Pulm Pharmacol Ther 26 (2013): 256-64
View all 40 references

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Drug and food interactions

Major

lonafarnib food

Applies to: lonafarnib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lonafarnib. 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 50 mg oral dose of lonafarnib was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. 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 lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension.

ADJUST DOSING INTERVAL: Food does not have clinically relevant effects on the oral bioavailability of lonafarnib. When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions. When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting. However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

MANAGEMENT: Lonafarnib should be administered with the morning and evening meals and an adequate amount of water. Patients should avoid consumption of grapefruit or grapefruit juice and Seville oranges (also known as bitter or sour oranges).during treatment with lonafarnib.

References

  1. "Product Information. Zokinvy (lonafarnib)." Eiger BioPharmaceuticals (2020):

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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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