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Effects of other medicinal products on Sildenafil: Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce Sildenafil clearance and inducers of these isoenzymes may increase Sildenafil clearance.
The efficacy and safety of Sildenafil co-administered with other treatments for pulmonary arterial hypertension (e.g. Ambrisentan, Iloprost) has not been studied. Therefore, caution is recommended in case of co-administration.
The efficacy and safety of Sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients.
Reduction in Sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of Sildenafil in pulmonary arterial hypertension patients, which was confirmed with a CYP3A4 inducer Bosentan.
Efficacy of Sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as Carbamazepine, Phenytoin, Phenobarbital, St. John's wort and Rifampicin.
Co-administration of the HIV protease inhibitor Ritonavir, which is highly potent P450 inhibitor, at steady state with Sildenafil resulted in a 4-fold increase in Sildenafil Cmax and an 11-fold increase in Sildenafil plasma AUC. Based on these pharmacokinetic results co-administration of Sildenafil with Ritonavir is contraindicated in pulmonary arterial hypertension patients. Saquinavir, CYP3A4 inhibitor, at steady state with Sildenafil resulted in 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on Saquinavir pharmacokinetics.
Erythromycin, moderate CYP3A4 inhibitor at steady state, there was a 182% increase in Sildenafil systemic exposure (AUC).
No dose adjustment is required for Azithromycin and Cimetidine.
The most potent of the CYP3A4 inhibitors such as Ketoconazole and Itraconazole would be expected to have effects similar to Ritonavir. CYP3A4 inhibitors like Clarithromycin, Telithromycin and Nefazodone are expected to have an effect between that of Ritonavir and CYP3A4 inhibitors like Saquinavir or Erythromycin. Therefore, dose adjustments are recommended when using CYP3A4 inhibitors.
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with Sildenafil.
Effects of Sildenafil on other medicinal products: Sildenafil when co-administered with Amlodipine in hypertensive patients had an additional reduction on supine systolic blood pressure.
When Sildenafil and Doxazosin were administered simultaneously to patients stabilized on Doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of Sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals.
Consistent with its known effects on the nitric oxide/cGMP pathway, Sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with Nitric oxide donors or nitrates in any form is therefore contraindicated.
Pediatric population: Interaction studies have only been performed in adults.
