Tadalafil (Generic) and Anesthesia: Perioperative Interaction Guide

What the labels say that matters before an operation

The Cialis label opens its cardiovascular warning with a point that matters going into any surgery: erectile dysfunction treatments, including Cialis, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status [1].

The same section names groups that were left out of the clinical trials and for whom Cialis is therefore not recommended: myocardial infarction within the last 90 days, unstable angina or angina during intercourse, NYHA Class 2 or greater heart failure within the last 6 months, uncontrolled arrhythmias, hypotension below 90/50 mm Hg or uncontrolled hypertension, and stroke within the last 6 months [1].

The vasodilator effect on its own is small in healthy people. In a clinical pharmacology study, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg relative to placebo [1]. The label adds that people with left ventricular outflow obstruction, such as aortic stenosis, can be sensitive to vasodilators including PDE5 inhibitors, and that those with severely impaired autonomic control of blood pressure may be particularly sensitive [1]. The Adcirca label carries the same caution for pre-existing hypotension, autonomic dysfunction and left ventricular outflow obstruction [2].

Which tadalafil product is involved matters too. Cialis is an oral tadalafil tablet for erectile dysfunction (ED) and benign prostatic hyperplasia (BPH), sold as 5, 10 and 20 mg tablets, with the 2.5 mg tablet listed as discontinued in Drugs@FDA [1][5]. Adcirca is a separate tadalafil tablet product for pulmonary arterial hypertension (PAH), taken as 40 mg once daily [2][6]. Generic tadalafil tablets labeled for ED or BPH follow the Cialis indications, while tadalafil 20 mg tablets labeled for PAH, such as brand Adcirca and the branded generic Alyq, follow the Adcirca label, which tells patients not to take Cialis or another PDE5 inhibitor with it [5][2][6][7]. The Tadliq oral suspension is also a PAH product, dosed at 40 mg (10 mL) once daily [8].

The nitrate rule is the core perioperative issue

Cialis and Adcirca are both contraindicated with any form of organic nitrate, taken regularly or intermittently, because tadalafil potentiates the hypotensive effect of nitrates [1][2]. Both labels also contraindicate guanylate cyclase stimulators such as riociguat, which can add to the same blood pressure fall [1][2].

How long the nitrate effect lasts has been measured. In a crossover study, 150 men took tadalafil 20 mg or placebo daily for 7 days, then received sublingual nitroglycerin 0.4 mg [4]. When nitroglycerin was given 4, 8 or 24 hours after the last tadalafil dose, standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil than on placebo (P<0.05), and there was no difference at 48, 72 or 96 hours [4]. Mean maximal standing systolic pressure falls were also greater at 8 and 24 hours (P<0.02) and not significantly different at 48 hours or later [4]. The authors concluded that the interaction lasted 24 hours and was not seen at 48 hours [4].

The labels' 48-hour figure is an emergency provision, not a way to space the two drugs apart. The Cialis label says that where nitrate administration is deemed medically necessary for a life-threatening situation, 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]. The Adcirca label puts it more briefly: do not use nitrates within 48 hours of the last Adcirca dose [2].

General anesthesia and spinal blocks: what is documented

A case report described three adolescents with severe PAH who were taking tadalafil, ambrisentan and subcutaneous treprostinil and had an implantable pump placed under general anesthesia [3]. One patient, in functional class IV, had postoperative hemodynamic instability and a small pneumothorax; a second was discharged four days after surgery and a third developed a hematoma at the pump site [3]. The report does not establish whether tadalafil changes blood pressure during general anesthesia [3].

Spinal anesthesia causes hypotension on its own. In a prospective study of 952 patients having spinal anesthesia, systolic blood pressure fell below 90 mm Hg in 314 of them, or 33% [9]. Factors that raised the odds of hypotension included a peak block height at or above T5 (odds ratio 3.8), age 40 or older (odds ratio 2.5), a baseline systolic pressure below 120 mm Hg (odds ratio 2.4), combined spinal and general anesthesia (odds ratio 1.9), puncture at or above the L2-L3 interspace (odds ratio 1.8) and phenylephrine added to the local anesthetic (odds ratio 1.6) [9]. That study was published in 1992, before tadalafil's 2003 approval, so it says nothing about tadalafil [5][9].

Other drugs that add to the same blood pressure effect

Cialis and alpha-blockers are both vasodilators, the effect on blood pressure is additive, and symptomatic hypotension such as fainting can occur [1]. For ED, the label says a patient should be stable on the alpha-blocker first and tadalafil started at the lowest dose; for BPH, the label does not recommend the combination because efficacy has not been adequately studied and because of the blood pressure risk [1].

Selected antihypertensives (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril and metoprolol) produced small additional blood pressure reductions compared with placebo when given with tadalafil [1]. Substantial alcohol, 5 units or more, with Cialis can increase orthostatic signs and symptoms, including a rise in heart rate, a fall in standing blood pressure, dizziness and headache; tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

If tadalafil is for pulmonary arterial hypertension

Adcirca is tadalafil 20 mg tablets taken as 40 mg once daily for PAH [2]. Its label contraindicates organic nitrates, and it tells patients not to take other PDE5 inhibitors, including Cialis, with it [2]. It is not recommended in pulmonary veno-occlusive disease because pulmonary vasodilators may worsen that condition [2]. Neither Cialis nor Adcirca has a boxed warning [1][2].

Drug levels and what to record

Cialis reaches peak concentration between 30 minutes and 6 hours after a dose and has a mean terminal half-life of 17.5 hours in healthy subjects [1]. Once-daily dosing reaches steady state within 5 days at about 1.6 times the exposure of a single dose, and the label notes that once-daily use provides continuous plasma tadalafil levels [1]. In PAH patients not taking bosentan, the Adcirca label reports a terminal half-life of 35 hours after a 40 mg dose [2].

Four facts cover the useful history: the drug name (tadalafil, Cialis, Adcirca, Alyq or Tadliq), the dose, whether it is taken daily or as needed, and the date and time of the last dose.