Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir disoproxil and sildenafil

CONTRAINDICATED: Coadministration with protease inhibitors (PIs) may significantly increase the plasma concentrations and effects of sildenafil. The mechanism is PI inhibition of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of sildenafil. This interaction also extends to cobicistat, a potent and selective mechanism-based CYP450 3A4 inhibitor. Pharmacokinetic models predict that this interaction may be more significant for oral rather than intravenous formulations of sildenafil, due at least partly to effects from first pass metabolism. In healthy adult volunteers (n=14), administration of a single dose of sildenafil (100 mg) during treatment with ritonavir (500 mg twice a day for 7 days) increased the mean sildenafil peak plasma concentration (Cmax) and systemic exposure (AUC) by 300% and 1000%, respectively, compared to administration alone. At 24 hours, sildenafil plasma levels were approximately 200 ng/mL as opposed to about 5 ng/mL with sildenafil alone. No change in safety or tolerability of sildenafil was observed. In HIV-infected patients (n=6) stabilized on triple antiretroviral therapy containing indinavir (800 mg three times a day), the AUC of a single dose of sildenafil (25 mg) was 4.4 times higher than dose-normalized data from historical controls. These patients experienced headache, flushing, dyspepsia and rhinitis, as well as a mean maximal decrease in blood pressure of 14/10 mmHg. This interaction was also suspected in the death of a 47-year-old man who used sildenafil (25 mg) during treatment with both ritonavir and saquinavir. However, there are a few case studies available in the literature which describe the successful use of sildenafil in combination with ritonavir and 1 case study of use in combination with cobicistat in HIV-infected patients being treated for pulmonary arterial hypertension (PAH). These cases report the use of therapeutic drug monitoring for sildenafil. Data regarding this interaction in pediatric patients has not been reported by the manufacturers of sildenafil.

MANAGEMENT: A safe and effective dosage of sildenafil has not been established for the treatment of pulmonary arterial hypertension (PAH) when used in the presence of protease inhibitors (PIs) or cobicistat. Some professional guidelines and product labeling consider its use with PIs and/or cobicistat in this setting to be contraindicated. Some authorities advise monitoring and a reduction of sildenafil dosing to 20 mg oral (10 mg intravenous) once daily in adult patients receiving potent CYP450 3A4 inhibitors like clarithromycin, telithromycin, or nefazodone. Although generally considered contraindicated, there are some case reports available in the literature which describe initiating sildenafil at reduced doses (10 mg orally every 8 hours for example) in combination with therapeutic drug monitoring for PAH in HIV-infected patients receiving ritonavir or cobicistat-boosted antiretroviral regimens. When used for erectile dysfunction, a lower starting dose of 25 mg is generally recommended with a warning that the maximum dosage of sildenafil should not exceed 25 mg in 48-hours. Regardless of indication, the product labeling for both medications involved should be consulted to ensure the most up to date dosing recommendations are being followed. Additionally, all patients should be monitored closely for adverse effects and advised to promptly notify their doctor if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, hypotension, sudden decrease or loss of hearing, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

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.

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.