Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir and fluticasone

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.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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