Tadalafil (Generic) Complete Drug-Drug Interaction Profile

Which drugs can never be taken with tadalafil?

The two interaction categories that are contraindicated are organic nitrates and guanylate cyclase stimulators such as riociguat [1][2].

Organic nitrates. Nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and organic nitrites such as amyl nitrite are contraindicated with Cialis, whether used regularly or intermittently, because tadalafil potentiates their blood-pressure-lowering effect [1]. The Adcirca label carries the same contraindication and says not to use nitrates within 48 hours of the last dose [2].

The Cialis label's only timing statement is an emergency rule: in a life-threatening situation where a nitrate is medically necessary, at least 48 hours should have elapsed after the last Cialis dose, and the nitrate should be given only under close medical supervision with hemodynamic monitoring [1]. That is not permission to space the two drugs out for routine use. The Cialis label also says patients who have anginal chest pain after taking Cialis should seek immediate medical attention [1].

The time course comes from a crossover study of 150 men who took tadalafil 20 mg or placebo daily for seven days, then received sublingual nitroglycerin 0.4 mg [3]. Standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours after the dose, with no difference between groups at 48, 72 and 96 hours [3].

Riociguat. Cialis and Adcirca are both contraindicated with guanylate cyclase stimulators such as riociguat, because PDE5 inhibitors may potentiate the hypotensive effect of the stimulator [1][2].

Why tadalafil's interaction window lasts longer

The mean terminal half-life of Cialis is 17.5 hours in healthy subjects [1], against about 4 hours for sildenafil [3]. Once-daily dosing reaches steady state within 5 days, with exposure about 1.6-fold that of a single dose, so daily tadalafil gives continuous blood levels; the label flags this when weighing interactions with nitrates, alpha-blockers, antihypertensives and potent CYP3A4 inhibitors [1]. The Adcirca label reports a 15-hour half-life in healthy subjects and 35 hours in patients with pulmonary hypertension who are not taking bosentan [2].

Strong CYP3A4 inhibitors: the labeled dose caps

Tadalafil is a substrate of and is predominantly metabolized by CYP3A4 [1]. Ketoconazole 400 mg daily raised single-dose tadalafil 20 mg exposure (AUC) by 312% and peak concentration (Cmax) by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% [1]. Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in Cmax, while ritonavir 500 or 600 mg twice daily raised AUC by 32% and lowered Cmax by 30% [1]. Erythromycin, itraconazole and grapefruit juice were not studied, but the label states they would likely increase tadalafil exposure [1].

The Cialis label's response is a ceiling, not avoidance: for use as needed, a maximum of 10 mg, not more often than once every 72 hours; for once-daily use, a dose not above 2.5 mg [1].

Adcirca takes a different route and says to avoid use in patients taking potent CYP3A inhibitors such as ketoconazole and itraconazole [2]. For a patient who has been on ritonavir for at least a week, the Adcirca label says to start at 20 mg once daily, and to stop Adcirca at least 24 hours before starting ritonavir [2].

CYP3A4 inducers: lower exposure, weaker effect

Rifampin 600 mg daily reduced tadalafil 10 mg AUC by 88% and Cmax by 46% [1]. Carbamazepine, phenytoin and phenobarbital would likely lower tadalafil exposure but were not studied [1]. The Cialis label calls for no dose adjustment, but notes that reduced exposure can be anticipated to decrease the efficacy of once-daily Cialis, with the size of that decrease unknown [1]. The Adcirca label says to avoid use in patients chronically taking potent inducers such as rifampin [2].

Alpha-blockers: additive blood pressure lowering

Tadalafil and alpha-blockers are both vasodilators, so the effect on blood pressure is additive and symptomatic hypotension such as fainting can occur [1]. The numbers differ sharply by alpha-blocker. Doxazosin 8 mg daily with tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (3.6 mm Hg supine), and in a second doxazosin study 16 of 24 subjects had a systolic reading below 85 mm Hg or a fall over 30 mm Hg after 8 a.m. tadalafil, against 6 on placebo [1]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg alongside tadalafil 10 mg and 2.3 mm Hg alongside 20 mg, and tadalafil 5 mg daily plus tamsulosin produced no outliers [1]. Alfuzosin 10 mg with tadalafil 20 mg gave a 4.4 mm Hg standing fall [1].

The label's rule depends on the indication. For erectile dysfunction, the Cialis label says patients should be stable on alpha-blocker therapy before Cialis is started, and that Cialis should be started at the lowest recommended dose [1]. For BPH, the label does not recommend Cialis in combination with alpha-blockers, because efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering; it also says a patient taking an alpha-blocker for BPH should stop it at least one day before starting once-daily Cialis for BPH [1].

Antihypertensives and alcohol

Clinical pharmacology studies of tadalafil with amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril and metoprolol found small reductions in blood pressure compared with placebo [1]. On its own in healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo [1].

Alcohol and tadalafil are both mild vasodilators, and substantial alcohol (5 units or more) with Cialis can increase orthostatic signs and symptoms: higher heart rate, lower standing blood pressure, dizziness and headache [1]. Tadalafil did not change alcohol plasma concentrations, and alcohol did not change tadalafil concentrations [1].

Drugs with no significant interaction

Warfarin: tadalafil had no significant effect on exposure to S-warfarin or R-warfarin, and did not affect the prothrombin time changes induced by warfarin [1]. Aspirin: tadalafil did not potentiate the increase in bleeding time caused by aspirin [1]. Midazolam and lovastatin: no significant effect on exposure to either [1]. Digoxin: tadalafil 40 mg daily for 10 days did not significantly alter digoxin 0.25 mg daily at steady state [1]. Theophylline: no significant effect on pharmacokinetics, with a small 3 beats per minute addition to theophylline's heart-rate rise [1]. Antacids (magnesium hydroxide/aluminum hydroxide) reduced the apparent rate of tadalafil absorption without altering AUC, and nizatidine had no significant effect on pharmacokinetics [1].

Tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1, so it is not expected to change the clearance of drugs handled by those enzymes [1].

Other PDE5 inhibitors and other tadalafil products

The Cialis label states that combinations with other PDE5 inhibitors or other erectile dysfunction treatments have not been studied [1]. The Adcirca label says patients should not take other PDE5 inhibitors, including Cialis, and that the safety and efficacy of that combination has not been studied [2]. Opsynvi is a single tablet combining macitentan 10 mg with tadalafil 40 mg for chronic PAH [4].

For product information, see tadalafil.