Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide and Xhance

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.

Switch to consumer interaction data

MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

Switch to consumer interaction data

GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

Switch to consumer interaction data