Drug Interactions between itraconazole and sildenafil

GENERALLY AVOID: Coadministration with the highly potent CYP450 3A4 inhibitors itraconazole, levoketoconazole, ketoconazole, and/or ritonavir may significantly increase the plasma concentrations and effects of sildenafil, which is primarily metabolized by the isoenzyme. 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. In a parallel study of healthy adult volunteers (n=14), un-boosted saquinavir (soft gelatin capsule 1200 mg three times a day for 7 days) increased single-dose sildenafil's (100 mg) Cmax and AUC by 140% and 210%, respectively. No change in safety or tolerability of sildenafil was observed with either CYP450 3A4 inhibitor. However, other studies of sildenafil in combination with potent inhibitors have observed increases in AUC and adverse effects (headache, flushing, dyspepsia, rhinitis, hypotension). Potent CYP450 3A4 inhibitors like clarithromycin, telithromycin, and nefazodone are generally assumed to increase sildenafil's exposure by 7-fold, an effect in between that of ritonavir and saquinavir. Despite the potential risks, 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 drug interaction in pediatric patients has not been reported by the manufacturers of sildenafil.

MANAGEMENT: Concurrent use of the highly potent CYP450 3A4 inhibitors ketoconazole, itraconazole, and/or ritonavir in combination with sildenafil indicated for pulmonary arterial hypertension (PAH) should generally be avoided and is considered contraindicated by some authorities. The product labeling for both sildenafil and the potent CYP450 3A4 inhibitor should be consulted for more detailed guidance. For example, some authorities recommend avoiding sildenafil for PAH during and for 2 weeks after treatment with itraconazole. Although the manufacturer considers the combination to be contraindicated, consultation with available clinical guidelines and literature may be considered as some data are available which describe the use of therapeutic drug monitoring of sildenafil in HIV-infected PAH patients who are also on ritonavir. When indicated for erectile dysfunction, the initial dose of sildenafil should not exceed 25 mg, and in some cases should be limited to 25 mg in a 48-hour time frame. Additionally, if concomitant use is clinically necessary, 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).