Drug Interactions between Liqrev and telithromycin

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 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: Coadministration with potent CYP450 3A4 inhibitors should generally be avoided when sildenafil is indicated for pulmonary arterial hypertension (PAH). When indicated for erectile dysfunction, the initial dose of sildenafil should not exceed 25 mg, and in some situations should be limited to 25 mg in a 48-hour time frame, if coadministration is required. Recommendations vary according to the indication of sildenafil, the patient's age, the presence of renal and/or hepatic impairment, and the specific potency of the CYP450 3A4 inhibitor(s) in question. For example, when indicated for PAH, some authorities consider the administration of inhibitors similar in potency to itraconazole, ketoconazole, or ritonavir to be contraindicated with sildenafil. If coadministration with inhibitors considered slightly less potent (e.g., clarithromycin, telithromycin, or nefazodone) is required in adult patients with PAH, they suggest reducing sildenafil's dose to 20 mg orally (10 mg IV) once daily. Consult the product labeling for both sildenafil and the potent CYP450 3A4 inhibitor for more detailed guidance and recommendations. Clinical literature regarding therapeutic drug monitoring of sildenafil may also be helpful if the combination is clinically necessary. In addition, if concomitant use is in the best interests of the patient, all patients, regardless of indication, 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).