Cedafil Drug Interactions

Effects of other substances on tadalafil: Cytochrome P450 inhibitors: Tadalafil is principally metabolized by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole, increased tadalafil exposure (AUC) and Cmax relative to the AUC and Cmax values for tadalafil alone. Ritonavir, a protease inhibitor, which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil AUC 2-fold with no change in Cmax. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would be expected to increase plasma concentrations of tadalafil. Consequently, the incidence of the adverse reactions might be increased.
Transporters: The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known. Therefore, there is the potential of drug interactions mediated by inhibition of transporters.
Cytochrome P450 inducers: A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone. This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other drug products: Nitrates: In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. In a patient prescribed any dose of tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Antihypertensives (including calcium channel blockers): The coadministration of doxazosin and tadalafil increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended. In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted. In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil had no clinically significant interaction with any of these classes. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha blockers) is, in general, minor and not likely to be clinically relevant.
Riociguat: Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated.
5-alpha reductase inhibitors: In a clinical trial that compared tadalafil 5 mg co-administered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.
CYP1A2 substrates (e.g. theophylline): When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.
Ethinylestradiol and terbutaline: Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Alcohol: Alcohol concentrations were not affected by coadministration with tadalafil. In addition, no changes in tadalafil concentrations were seen 3 hours after coadministration with alcohol. Alcohol was administered in a manner to maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil did not augment the mean blood pressure decrease produced by alcohol but in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol, hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil.
Cytochrome P450 metabolized medicinal products: Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolized by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19. CYP2C9 substrates (e.g. R-warfarin) Tadalafil had no clinically significant effect on exposure (AUC) to S-warfarin or R- warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Aspirin: Tadalafil did not potentiate the increase in bleeding time caused by acetyl salicylic acid.