Cialis (Tadalafil) Complete Drug-Drug Interaction Profile

What is actually contraindicated with Cialis?

Two interaction classes, plus serious hypersensitivity to tadalafil [1].

Organic nitrates. The Cialis label contraindicates any form of organic nitrate, whether used regularly or intermittently, because tadalafil 5 to 20 mg was shown to potentiate the hypotensive effect of nitrates [1]. The contraindication is not limited to a single product, and it covers nitroglycerin, isosorbide and organic nitrites [1].

The clearest data come from a 150-man crossover study in which men took tadalafil 20 mg or placebo daily for 7 days, then received sublingual nitroglycerin 0.4 mg. Standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours (P<0.05), with no difference between groups at 48, 72 and 96 hours [2].

Riociguat and other guanylate cyclase stimulators. These are contraindicated because PDE5 inhibitors, including Cialis, may potentiate their blood-pressure-lowering effect [1].

Other ED treatments. The Cialis label says not to combine Cialis with other PDE5 inhibitors or other ED treatments, and those combinations have not been studied [1].

The 48-hour nitrate rule, precisely

The label gives one emergency provision. In a life-threatening situation where a nitrate is medically necessary, at least 48 hours should elapse after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with appropriate hemodynamic monitoring [1]. That is an emergency instruction, not a schedule for routine use, and the nitroglycerin interaction was still significant at 24 hours in the crossover study [2].

Alpha-blockers

Tadalafil and alpha-adrenergic blockers are both vasodilators with blood-pressure-lowering effects, and the combination is additive; symptomatic hypotension such as fainting can occur [1]. The label's clinical pharmacology studies tested three of them:

• Doxazosin 8 mg daily. Tadalafil 20 mg produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (supine 3.6 mm Hg). In a second doxazosin study, 16 of 24 subjects had a systolic reading below 85 mm Hg or a fall greater than 30 mm Hg after 8 a.m. tadalafil, versus 6 on placebo [1].
• Tamsulosin 0.4 mg. Standing systolic falls were 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with 20 mg; tadalafil 5 mg daily plus tamsulosin produced no outliers [1].
• Alfuzosin 10 mg. A 4.4 mm Hg standing systolic fall with tadalafil 20 mg [1].

The label's rule depends on why tadalafil is being taken. For ED, the Cialis label says to be stable on the alpha-blocker first and to start Cialis at the lowest dose [1]. For BPH, the Cialis label does not recommend combining Cialis with an alpha-blocker. Its dosing instructions specify stopping the alpha-blocker at least one day before starting once-daily Cialis for BPH [1].

CYP3A4 inhibitors: which drugs raise tadalafil levels

Tadalafil is metabolized mainly by CYP3A4 [1]. The measured effects in the label:

• Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and Cmax by 22%. Ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% and Cmax by 15% [1].
• Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in Cmax. Ritonavir 500 or 600 mg twice daily raised AUC by 32% and lowered Cmax by 30% [1].

For potent CYP3A4 inhibitors such as ketoconazole or ritonavir, the Cialis label limits as-needed dosing to 10 mg every 72 hours and once-daily dosing to 2.5 mg [1]. It says erythromycin, itraconazole and grapefruit juice would likely increase tadalafil exposure, but those combinations were not studied [1].

CYP3A4 inducers: which drugs lower tadalafil levels

Rifampin 600 mg daily reduced tadalafil 10 mg AUC by 88% and Cmax by 46% [1]. Carbamazepine, phenytoin and phenobarbital were not studied, but the label says they would likely decrease tadalafil exposure [1].

The Cialis label calls for no dose adjustment with inducers, but notes that the reduced exposure can be anticipated to decrease the efficacy of once-daily Cialis, and that the size of that decrease is unknown [1].

Blood pressure medicines

The label reports clinical pharmacology studies with amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril and metoprolol. Small reductions in blood pressure occurred when tadalafil was given with these agents compared with placebo [1]. For scale, tadalafil 20 mg alone lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo in healthy volunteers [1].

Alcohol

Substantial alcohol, meaning 5 units or more, taken with Cialis can increase orthostatic signs and symptoms: higher heart rate, lower standing blood pressure, dizziness and headache [1]. The label notes that both alcohol and tadalafil are mild vasodilators [1]. The two do not change each other's plasma levels — tadalafil did not affect alcohol concentrations and alcohol did not affect tadalafil concentrations [1].

What tadalafil does not meaningfully affect

Tadalafil did not change warfarin exposure or prothrombin time, did not potentiate the increase in bleeding time caused by aspirin, did not change midazolam or lovastatin exposure, and did not alter digoxin 0.25 mg daily at steady state after tadalafil 40 mg daily for 10 days [1]. With theophylline it added a small heart-rate rise of about 3 beats per minute [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].

An antacid containing magnesium hydroxide and aluminum hydroxide slowed the rate of tadalafil absorption without altering total exposure (AUC), and nizatidine had no significant effect on tadalafil pharmacokinetics [1].

Bosentan and the pulmonary arterial hypertension setting

Bosentan induces CYP3A4 and CYP2C9. In an open-label crossover study of 15 healthy men, 10 days of bosentan 125 mg twice daily reduced tadalafil 40 mg AUC by 41.5% (ratio 0.59), with a smaller fall in Cmax, while bosentan exposure rose by less than 20% [3].

Tadalafil for PAH is a different product from Cialis: Adcirca is a separate tadalafil product available as a 20 mg tablet [4]. In a pulmonary arterial hypertension trial, tadalafil was studied at 40 mg once daily [5]. In the 500-patient AMBITION trial of treatment-naive PAH, initial ambrisentan 10 mg plus tadalafil 40 mg reduced clinical failure to 18% versus 31% with pooled monotherapy (hazard ratio 0.50, 95% CI 0.35 to 0.72) [6].

Kidney and liver limits

The Cialis label's limits:

• As-needed use, creatinine clearance 30 to 50 mL/min: start at 5 mg, maximum 10 mg not more often than every 48 hours [1].
• Creatinine clearance below 30 mL/min or hemodialysis: maximum 5 mg not more often than every 72 hours, and once-daily use is not recommended [1].
• BPH or ED with BPH, creatinine clearance 30 to 50 mL/min: start at 2.5 mg, with 5 mg considered based on response [1].
• Mild or moderate liver impairment (Child-Pugh A or B): as-needed dose not above 10 mg, and once-daily use has not been extensively evaluated [1].
• Severe liver impairment (Child-Pugh C): Cialis is not recommended [1].