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Drug Interactions between azelastine / fluticasone nasal and dasabuvir / ombitasvir / paritaprevir / ritonavir

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

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Interactions between your drugs

Major

ritonavir fluticasone nasal

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir and azelastine / fluticasone nasal

GENERALLY AVOID: Coadministration with ritonavir may significantly increase the systemic exposure to fluticasone following intranasal administration or oral inhalation. The mechanism is ritonavir inhibition of fluticasone metabolism via hepatic and intestinal CYP450 3A4. In 18 healthy subjects, administration of fluticasone propionate nasal spray (200 mcg once daily) in combination with ritonavir (100 mg twice daily) for 7 days resulted in an approximately 25-fold increase in fluticasone peak plasma concentration (Cmax) and 350-fold increase in systemic exposure (AUC) compared to administration alone. These changes were accompanied by an 86% decrease in mean plasma cortisol AUC. Systemic glucocorticoid adverse effects such as adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported during postmarketing use of orally inhaled or intranasal fluticasone in patients receiving ritonavir-containing antiretroviral regimens. In an analysis of 25 suspected cases of the interaction reported in the medical literature, the mean dosage of orally inhaled fluticasone was 992 mcg/day (range 500 to 2000 mcg/day) in adult cases and 455 mcg/day (range 200 to 1000 mcg/day) in pediatric cases. Dosages of ritonavir used included both low, "boosting" dosages (100 to 200 mg daily) and high, "treatment" dosages (800 to 1200 mg/day). The average onset of cushingoid appearance was approximately 2.75 months (range 2 weeks to 6 months) in adult cases and 2.1 months (range 2 weeks to 3 months) in pediatric cases. For the three cases involving intranasal fluticasone, the dosage used ranged from 200 to 800 mcg/day and the onset of cushingoid appearance ranged from 5 to 18 months of concomitant use with ritonavir. 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: The use of intranasal or orally inhaled fluticasone in combination with ritonavir is not recommended unless the potential benefit outweighs the risk of systemic side effects. Alternatives to fluticasone should be considered whenever possible if ritonavir must be used. A less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone, budesonide, flunisolide or triamcinolone may be appropriate, although probably most, if not all, corticosteroids can interact with ritonavir to some extent. The lowest effective dosage of orally inhaled corticosteroid should be used, 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. It is important to distinguish between hypercorticism and the lipodystrophy syndrome caused by antiretroviral treatment, as the overlap of certain clinical features may delay the recognition and diagnosis of Cushing's syndrome. In general, the lack of peripheral atrophy and the presence of abdominal striae, easy bruising, and facial plethora would suggest iatrogenic Cushing's syndrome rather than antiretroviral-related lipodystrophy. 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 ritonavir, 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

  1. "Product Information. Flonase (fluticasone)." Glaxo Wellcome PROD (2001):
  2. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
  3. Lonnebo A, Grahnen A, Jansson B, Brundin RM, Lingandersson A, Eckernas SA "An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers." Eur J Clin Pharmacol 49 (1996): 459-63
  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
  7. Kelly HW "Comparison of inhaled corticosteroids." Ann Pharmacother 32 (1998): 220-32
  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. 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
  12. 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
  13. 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
  14. 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
  15. Li AM "Ritonavir and fluticasone: Beware of this potentially fatal combination." J Pediatr 148 (2006): 294-5
  16. 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
  17. 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
  18. 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
  19. 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
  20. Molimard M, Girodet PO, Pollet C, et al. "Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation." Drug Saf 31 (2008): 769-74
  21. 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
  22. 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
  23. Daveluy A, Raignoux C, Miremont-Salame G, et al. "Drug interactions between inhaled corticosteroids and enzymatic inhibitors." Eur J Clin Pharmacol (2009):
  24. 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
  25. 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
  26. Pearce RE, Leeder JS, Kearns GL "Biotransformation of fluticasone: in vitro characterization." Drug Metab Dispos 34 (2006): 1035-40
  27. Vassiliadi D, Tsagarakis S "Unusual causes of Cushing's syndrome." Arq Bras Endocrinol Metabol 51 (2007): 1245-52
  28. 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
  29. Brus R "Effects of high-dose inhaled corticosteroids on plasma cortisol consentrations in healthy adults." Arch Intern Med 159 (1999): 1903-8
  30. 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
  31. 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
  32. 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
  33. 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
View all 33 references

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Drug and food interactions

Moderate

ritonavir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):

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Moderate

azelastine nasal food

Applies to: azelastine / fluticasone nasal

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc. (1990):
  3. "Product Information. Fycompa (perampanel)." Eisai Inc (2012):
  4. "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc (2015):
View all 4 references

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Moderate

paritaprevir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.

References

  1. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):

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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.

See also

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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.

Further information

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