|Interaction studies were conducted with 10mg and/or 20mg tadalafil, as indicated below. With regard to those interaction studies where only the 10mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.|
Effects of Other Substances on Tadalafil
Cytochrome P450 inhibitorsTadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) exposure (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 (see section 4.4). Consequently, the incidence of the adverse reactions listed in section 4.8 might be increased.
TransportersThe 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 inducersA CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10mg). 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 Medicinal Products
NitratesIn clinical studies, tadalafil (5mg, 10mg and 20mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects received daily doses of tadalafil 20mg for 7 days and 0.4mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5mg - 20mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.
Anti-hypertensives (including calcium channel blockers)The co-administration of doxazosin (4 and 8mg daily) and tadalafil (5mg daily dose and 20mg as a single dose) 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 (see section 4.4).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 (10mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater, although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20mg may induce a blood pressure decrease, which (with the exception of alpha-blockers - see above) is, in general, minor and not likely to be clinically relevant. Analysis of Phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.
5- alpha reductase inhibitorsIn a clinical trial that compared tadalafil 5 mg coadministered 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 10mg 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 terbutalineTadalafil 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.
AlcoholAlcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10mg or 20mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180ml of 40% alcohol [vodka] in an 80 kg male) but, in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6g/kg), 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 (10mg).
Cytochrome P450 metabolised medicinal productsTadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised 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 (10mg and 20mg) 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.
AspirinTadalafil (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Antidiabetic medicinal productsSpecific interaction studies with antidiabetic medicinal products were not conducted.