Tadalafil (Generic) Withdrawal and Discontinuation Syndrome: What Patients and Clinicians Need to Know

Does tadalafil cause withdrawal?

The Cialis and Adcirca labels describe no withdrawal, dependence or rebound reaction [1][2]. Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor. During sexual stimulation, nitric oxide raises cyclic GMP in penile smooth muscle, and tadalafil slows the enzyme that breaks that messenger down; the Cialis label says it has no effect without sexual stimulation [1]. PDE5 is also present in pulmonary vascular smooth muscle, and the label says how tadalafil reduces BPH symptoms has not been established [1].

The Cialis label sets doses by response, with no stopping schedule: as-needed use starts at 10 mg and can go up to 20 mg or down to 5 mg based on efficacy and tolerability, and once-daily use for ED starts at 2.5 mg and can go to 5 mg [1]. For BPH alone, and for ED with BPH, the dose is 5 mg once daily [1].

How long tadalafil stays in the body

Tadalafil reaches peak blood levels between 30 minutes and 6 hours after a dose (median 2 hours), food does not change absorption, and the mean terminal half-life is 17.5 hours in healthy volunteers [1].

With once-daily tadalafil, blood levels reach steady state within 5 days and exposure is about 1.6 times that of a single dose [1]. Exposure is 25% higher in healthy men aged 65 or older, and about doubled in mild or moderate renal impairment after single 5 to 10 mg doses [1][2].

For Adcirca in PAH the numbers differ: after a 40 mg dose the terminal half-life is 15 hours in healthy subjects and 35 hours in patients with pulmonary hypertension who are not taking bosentan [2].

What the trials measured

For erectile dysfunction, the as-needed Cialis regimen improves erectile function compared with placebo for up to 36 hours after a dose, and once-daily dosing keeps a continuous level without regard to the timing of sexual activity [1]. That is a duration of effect, not a continuous erection; sexual stimulation is still required [1]. In an integrated analysis of five 12-week trials in 1,112 men, tadalafil 20 mg as needed improved the erectile function domain of the International Index of Erectile Function by a mean 7.9 points, 75% of intercourse attempts were completed successfully, and 81% of men reported improved erections versus 35% on placebo [3].

For BPH, tadalafil 5 mg once daily lowered the International Prostate Symptom Score by 5.6 points versus 3.6 on placebo (P=0.004) in a 12-week trial of 325 men (161 on tadalafil, 164 on placebo), with improvement apparent after 1 week and significant by week 4 [4]. Peak urine flow and post-void residual volume did not improve significantly [4].

For PAH, Adcirca is tadalafil 20 mg tablets taken as 40 mg (two tablets) once daily, to improve exercise ability in WHO Group 1 disease [2]. In the 16-week PHIRST trial only the 40 mg dose met the prespecified significance level, with a placebo-corrected six-minute walk gain of 33 m (95% CI 15 to 50) and a delay in clinical worsening (P=0.041) [5]. Neither the Cialis nor the Adcirca label carries a boxed warning [1][2].

Generic tadalafil tablets labeled for ED or BPH follow the Cialis indications, and tadalafil tablets labeled for PAH follow the Adcirca indication [1][6][2][7].

The nitrate interaction outlasts the last tablet

Cialis is contraindicated with any form of organic nitrate. The label gives a rule for emergencies only: if a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [1].

That timing rests on a 150-man crossover study in which tadalafil 20 mg daily for 7 days was followed by sublingual nitroglycerin 0.4 mg at set times. Standing systolic pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [9]. The Cialis label adds that at 48 hours, by most hemodynamic measures, the interaction was not seen, although a few more tadalafil subjects still had greater blood pressure falls than placebo subjects [1]. The Adcirca label says not to use nitrates within 48 hours of the last dose [2].

So the interaction was still present 24 hours after the last dose in that study. The 48-hour figure is an emergency rule, not permission to combine the two drugs and not a safe-timing guide for routine use [1].