Cialis (Tadalafil): History and Development

When was tadalafil first approved, and for what?

The original Cialis approval carries an action date of 11/21/2003 and is classified in Drugs@FDA as a Type 1 submission, a new molecular entity, reviewed under standard priority [1]. The application number is NDA 021368 and the company listed is Lilly [1].

The product line has changed since. Drugs@FDA now lists the Cialis 5, 10 and 20 mg tablets as prescription products and the 2.5 mg tablet as discontinued, with a Federal Register note that the product was not discontinued or withdrawn for safety or effectiveness reasons [1]. The label in force, effective June 3, 2026, covers three indications: erectile dysfunction, the signs and symptoms of BPH, and ED together with BPH [3]. When Cialis is used with finasteride to start BPH treatment, the label recommends use for up to 26 weeks, because the added benefit over finasteride falls from week 4 to week 26 and beyond 26 weeks is unknown [3].

What the chemistry record shows about how tadalafil was designed

The published discovery account is a 2003 Journal of Medicinal Chemistry paper by Daugan and colleagues [4]. The team started from ethyl beta-carboline-3-carboxylate, described as a modest PDE5 inhibitor, and built a series of tetrahydro-beta-carboline derivatives [4]. Optimising the hydantoin side chain and the aromatic ring at position 5 produced compound 6e, a potent and selective PDE5 inhibitor with greater selectivity for PDE5 over PDE1 to PDE4 than sildenafil [4]. In that paper the lead compound lowered blood pressure durably in hypertensive rats after intravenous dosing but showed only moderate efficacy when given orally [4], which places it well before a marketable tablet.

Selectivity is the property that survived into the label. In vitro, tadalafil is about 700-fold more potent for PDE5 than for PDE6, the retinal enzyme, and 14-fold (PDE11A1) and 40-fold (PDE11A4) more potent for PDE5 than for PDE11 [3]. The label states that PDE11 inhibition has no defined clinical consequence in humans [3].

How tadalafil works, and why the half-life mattered

During sexual stimulation, nitric oxide raises cyclic GMP in penile smooth muscle, relaxing it and increasing blood flow; tadalafil blocks PDE5, the enzyme that breaks cGMP down, so it has no effect without sexual stimulation [3]. PDE5 also sits in prostate, bladder and pulmonary vascular smooth muscle, though the label says the mechanism by which tadalafil reduces BPH symptoms has not been established [3].

Tadalafil's pharmacokinetic profile includes a mean terminal half-life of 17.5 hours, an oral clearance of 2.5 L/h, a peak concentration between 30 minutes and 6 hours (median 2 hours), and steady state within 5 days of once-daily dosing at about 1.6 times the exposure of a single dose [3]. The Cialis label contrasts this with sildenafil, whose half-life is about 4 hours, and it includes both as-needed dosing, with benefit up to 36 hours, and once-daily dosing [3].

On duration, the label says that Cialis for use as needed improves erectile function compared with placebo for up to 36 hours after a dose, and sexual stimulation is still required [3]. Carson and colleagues pooled 11 randomised, double-blind, placebo-controlled 12-week trials covering 2,102 men and reported efficacy up to 36 hours after dosing, with the most frequent adverse events being headache, dyspepsia, back pain and myalgia [5].

Once-daily use was tested before it reached the label. Porst and colleagues ran a 12-week trial of 268 men given placebo, tadalafil 5 mg daily or tadalafil 10 mg daily; the erectile function domain of the IIEF rose by 9.7 and 9.4 points against 0.9 on placebo, and 3.4% of participants discontinued for adverse events [6]. Drugs@FDA records a supplement approved on 01/07/2008 filed as an efficacy change for a new dosing regimen [1]; the once-daily doses in the current label are 2.5 mg for ED and 5 mg for BPH or ED with BPH [3].

Which trials built the label

The often-cited 2002 Journal of Urology paper by Brock and colleagues was not a single study. It was an integrated analysis of five 12-week randomised, double-blind, placebo-controlled trials that together enrolled 1,112 men with a mean age of 59 (range 22 to 82) and mild to severe ED of various causes, randomised to placebo or tadalafil 2.5, 5, 10 or 20 mg as needed [7]. At 20 mg, the IIEF erectile function domain improved by a mean 7.9 points, 75% of intercourse attempts were successful on the Sexual Encounter Profile question 3, and 81% reported improved erections against 35% on placebo, all P<0.001 [7]. Headache and dyspepsia were the most common adverse events [7].

For BPH, the 2011 European Urology trial by Porst and colleagues randomised 161 men to tadalafil 5 mg once daily and 164 to placebo for 12 weeks; total IPSS fell 5.6 points against 3.6 (P=0.004), with a difference apparent at week 1 and significant by week 4 [8]. Peak urine flow and post-void residual volume did not improve significantly, and the most common adverse events were headache (3.7%) and back pain (3.1%) [8]. The BPH indication appears in Drugs@FDA as supplements approved on 10/06/2011 and classified as an efficacy change for a new indication [1].

Co-initiation with finasteride had its own trial. Casabé and colleagues randomised 695 men to tadalafil 5 mg plus finasteride 5 mg (n=345) or placebo plus finasteride (n=350); IPSS fell 4.0, 5.2 and 5.5 points at weeks 4, 12 and 26 against 2.3, 3.8 and 4.5 on placebo plus finasteride (P 0.022 or lower at every visit), while the gap between arms shrank from 1.7 points at week 4 to 1.0 point at week 26 [9]. That narrowing is the reason the label limits co-initiation to 26 weeks [3][9].

The nitrate interaction study

One study examined the time course of the nitrate interaction. Kloner and colleagues gave 150 men tadalafil 20 mg or placebo daily for seven days, then sublingual nitroglycerin 0.4 mg at set intervals, with a crossover after a 10- to 21-day washout [10]. 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 significant difference at 48, 72 and 96 hours [10].

Organic nitrates in any form remain contraindicated with Cialis [3]. The label says that in a life-threatening situation where a nitrate is medically necessary, at least 48 hours should have passed since the last Cialis dose before a nitrate is considered, and then only under close medical supervision with haemodynamic monitoring [3]. That is an emergency provision, not a spacing schedule.

Where the pulmonary arterial hypertension product came from

Adcirca was approved as a separate 20 mg tadalafil tablet on May 22, 2009, under NDA 022332 [2]. Cialis and Adcirca are separate tadalafil products with different indications, and both come as 20 mg tablets [1][2].

The supporting trial was PHIRST, a 16-week double-blind study of 405 patients with PAH who were treatment-naive or on background bosentan, randomised to placebo or tadalafil 2.5, 10, 20 or 40 mg once daily [11]. Only the 40 mg dose met the prespecified significance level for six-minute walk distance (the overall mean placebo-corrected effect across the study was 33 m, 95% CI 15 to 50 m), and tadalafil 40 mg delayed clinical worsening (P=0.041) [11]. Generic 20 mg tadalafil tablets labelled for PAH, such as Alyq, appear in the same therapeutic-equivalence listing as Adcirca [2]. The Cialis label says combinations with other PDE5 inhibitors or other ED treatments have not been studied [3].

Generic tadalafil

Generic tadalafil 20 mg tablets from makers including Cipla, Hetero and Chartwell are listed in Drugs@FDA in the same therapeutic-equivalence table as Adcirca [2]. Cialis is indicated for ED, BPH, and ED with BPH [3]. Drugs@FDA lists Cialis tablets as prescription products [1]. HealthRX.com offers tadalafil by prescription.