Drug Interaction Report

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.

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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.

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ADJUST DOSE: Coadministration with the pharmacokinetic booster cobicistat may increase the plasma concentrations of tadalafil. The mechanism is cobicistat inhibition of tadalafil metabolism via CYP450 3A4. The interaction has not been studied with cobicistat, but has been reported with ritonavir, a pharmacokinetic booster with a similar metabolic profile to cobicistat. In study subjects, administration of a single 20 mg dose of tadalafil during treatment with ritonavir 500 mg or 600 mg twice daily at steady state resulted in a 30% reduction in tadalafil peak plasma concentration (Cmax) and 32% increase in systemic exposure (AUC) compared to tadalafil administered alone. Administration of the same dose of tadalafil in combination with ritonavir 200 mg twice a day was associated with a 124% increase in tadalafil AUC and no change in Cmax. The pharmacokinetics of tadalafil in the treatment of pulmonary arterial hypertension (PAH) have been studied in the presence of tipranavir/ritonavir. Tadalafil concentrations increased when coadministered with the first dose of tipranavir/ritonavir, but not with tipranavir/ritonavir at steady-state. This would suggest that the initial inhibitory effect of ritonavir on CYP450 3A4 may be mitigated by a more slowly evolving induction effect so that after about one week of ritonavir administered twice daily, the exposure to tadalafil is similar in the presence and absence of ritonavir.

MANAGEMENT: Caution is advised if tadalafil is administered in combination with cobicistat. For the treatment of erectile dysfunction, the dosage of tadalafil should not exceed 10 mg once every 72 hours when used on an as-needed basis. When given for once-daily use in the treatment of erectile dysfunction or benign prostatic hyperplasia, the maximum recommended dose is 2.5 mg. According to some authorities, concomitant use of tadalafil and cobicistat for the treatment of pulmonary arterial hypertension (PAH) is not recommended. If coadministration is required, for the treatment of PAH, tadalafil should be started at 20 mg once daily in patients who have been receiving cobicistat for at least one week. The dosage may be increased to 40 mg once daily based upon individual tolerability. The use of tadalafil for PAH should be avoided during the initiation of cobicistat-containing antiretroviral therapy. The manufacturers recommend that tadalafil be discontinued at least 24 hours prior to initiating the cobicistat regimen. After at least one week, tadalafil may be resumed at 20 mg once daily, and the dosage increased to 40 mg once daily based upon individual tolerability. All patients treated with tadalafil should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

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GENERALLY AVOID: Additive hypotensive effects may occur when phosphodiesterase-5 (PDE5) inhibitors such as tadalafil are used with alcohol, as both are mild systemic vasodilators. In clinical pharmacology studies, more subjects administered alcohol at a dose of 0.7 g/kg (equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male; consumed within 10 minutes in study subjects, providing blood alcohol levels of 0.08%) in combination with tadalafil 10 or 20 mg single doses had clinically significant decreases in blood pressure than with alcohol alone. There were reports of postural dizziness, and orthostatic hypotension was observed in some. When tadalafil 20 mg was administered with alcohol at a lower dose of 0.6 g/kg (equivalent to approximately 4 ounces of 80-proof vodka in an 80-kg male), orthostatic hypotension was not observed, dizziness occurred with similar frequency relative to alcohol alone, and the hypotensive effects of alcohol were not potentiated. Neither tadalafil nor alcohol affected the plasma concentrations of the other.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of tadalafil, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients taking tadalafil should avoid consuming large amounts of alcohol (for example, 5 units or more), which may increase the potential for orthostatic signs and symptoms including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. It may also be appropriate to avoid consuming large amounts of grapefruit juice.

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ADJUST DOSING INTERVAL: Food enhances the oral bioavailabilities of both elvitegravir and tenofovir. When a single dose of cobicistat/elvitegravir/emtricitabine/tenofovir (trade name Stribild) was given with a light meal (approximately 373 kcal; 20% fat), mean elvitegravir and tenofovir systemic exposures (AUCs) increased by 34% and 24%, respectively, relative to fasting conditions. When administered with a high-fat meal (approximately 800 kcal; 50% fat), the mean AUC of elvitegravir and tenofovir increased by 87% and 23%, respectively, relative to fasting conditions. The alterations in mean AUCs of cobicistat and emtricitabine were not clinically significant with either the light or high-fat meal.

MANAGEMENT: Cobicistat/elvitegravir/emtricitabine/tenofovir as a fixed-dose preparation should be administered once daily with food. Elvitegravir as a single-ingredient preparation should also be administered once daily with food.

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Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.

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