Cialis FDA Approval History: Every Indication, Label Change, and Safety Update

The original approval: November 21, 2003

Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor. During sexual stimulation, nitric oxide raises cyclic GMP in penile smooth muscle, relaxing it and increasing blood flow; tadalafil blocks the enzyme that breaks cGMP down, so it has no effect without sexual stimulation [2].

Drugs@FDA lists NDA 021368, held by Lilly, with an original approval of 11/21/2003, action type ORIG-1, classified Type 1 - New Molecular Entity, review priority STANDARD [1]. The Orange Book shows the Cialis 5 mg, 10 mg and 20 mg tablets with the same November 21, 2003 approval date [4]. The 2.5 mg tablet has a later approval date, January 7, 2008, and is now listed as Discontinued, with a Federal Register determination that it was not discontinued or withdrawn for safety or effectiveness reasons [4][1].

The current label covers three indications: erectile dysfunction, the signs and symptoms of BPH, and ED with BPH; when Cialis is used with finasteride to start BPH treatment, use is recommended for up to 26 weeks [2]. The label is effective June 3, 2026, and Cialis has no boxed warning [2].

The trial package behind the ED approval

The integrated analysis by Brock et al. (J Urol 2002) pooled five 12-week double-blind, placebo-controlled trials: 1,112 men, mean age 59, randomized to placebo or tadalafil 2.5, 5, 10 or 20 mg as needed. With 20 mg, the erectile function domain of the IIEF improved by a mean 7.9 points, 75% of intercourse attempts were successful, and 81% reported improved erections versus 35% on placebo (P<0.001 for each) [5].

The label describes duration this way: improved erectile function compared with placebo for up to 36 hours after a dose. That is a window of responsiveness, not a continuous erection; sexual stimulation is still required, and an erection lasting over 4 hours is a reason to seek emergency care [2].

Once-daily dosing: January 7, 2008

The NDA 021368 supplement list shows an action on 01/07/2008 (SUPPL-11) categorized as an efficacy new dosing regimen, and the Orange Book dates the 2.5 mg tablet to the same day [1][4]. That matches the regimen the label now describes: 2.5 mg once daily at about the same time every day, without regard to timing of sexual activity, increased to 5 mg based on efficacy and tolerability [2].

Once-daily dosing gives continuous blood levels: steady state is reached within 5 days, with exposure about 1.6-fold that of a single dose [2]. The mean terminal half-life is 17.5 hours in healthy subjects, which is why one as-needed dose can help for up to 36 hours and why interactions last longer than with a shorter-acting PDE5 inhibitor such as sildenafil, whose half-life is about 4 hours [2][10].

BPH and ED/BPH: October 6, 2011

Drugs@FDA lists two supplements dated 10/06/2011, SUPPL-20 and SUPPL-21, both categorized as efficacy new indications [1]. The current label covers BPH signs and symptoms at 5 mg once daily, and ED with BPH at 5 mg once daily [2].

The BPH trial behind the label is Porst et al. (Eur Urol 2011): a 12-week randomized, double-blind, placebo-controlled trial in men 45 or older with an IPSS of 13 or higher, tadalafil 5 mg once daily (n=161) versus placebo (n=164). Total IPSS fell 5.6 points with tadalafil and 3.6 with placebo (P=0.004); the improvement was apparent at week 1 and significant by week 4. Peak urine flow and post-void residual volume did not improve significantly. Headache (3.7%) and back pain (3.1%) were the most common adverse events [6].

Why combined use with finasteride is capped at 26 weeks

Casabé et al. (J Urol 2014) randomized 695 men who had not taken a 5-alpha-reductase inhibitor to tadalafil 5 mg plus finasteride 5 mg (n=345) or placebo plus finasteride (n=350) for 26 weeks. IPSS fell 4.0, 5.2 and 5.5 points at weeks 4, 12 and 26 with tadalafil, versus 2.3, 3.8 and 4.5 with placebo (P 0.022 or lower at all visits). The gap between arms narrowed from 1.7 points at week 4 to 1.0 point at week 26, and the label states that the benefit of Cialis beyond 26 weeks is unknown [7][2].

PAH and Adcirca: May 22, 2009

Adcirca is a separate FDA application: NDA 022332, tadalafil 20 mg tablets, Lilly, original approval 05/22/2009, submitted as Type 6 - New Indication (no longer used) with standard review [3]. Its approved use is pulmonary arterial hypertension [3]. PAH is not a Cialis indication.

PHIRST (Circulation 2009) randomized 405 patients with PAH, treatment-naive or on bosentan, to placebo or tadalafil 2.5, 10, 20 or 40 mg once daily for 16 weeks. Only 40 mg met the prespecified significance level; the mean placebo-corrected change in 6-minute walk distance was 33 m (95% CI 15 to 50), 44 m in bosentan-naive patients and 23 m (95% CI -2 to 48) on background bosentan. The 40 mg dose delayed clinical worsening (P=0.041) [8].

AMBITION (N Engl J Med 2015) tested initial combination therapy in 500 treatment-naive patients with WHO functional class II or III symptoms, randomized 2:1:1 to ambrisentan plus tadalafil, ambrisentan alone or tadalafil alone. Clinical failure occurred in 18% on combination versus 34% on ambrisentan, 28% on tadalafil and 31% on pooled monotherapy (hazard ratio 0.50, 95% CI 0.35 to 0.72, P<0.001) [9].

Generic tadalafil

Generic tadalafil tablets are approved under many ANDAs. For example, Drugs@FDA lists Alyq (Teva) and generic tadalafil 20 mg tablets from several other manufacturers as rated AB2 to Adcirca [3]. Generic tadalafil labeled for PAH follows the Adcirca label and dose, while generic 2.5, 5, 10 and 20 mg tablets follow the Cialis indications (ED and BPH). HealthRX.com offers tadalafil by prescription.

Dated labeling actions on NDA 021368

Beyond the dosing and indication supplements above, Drugs@FDA lists these actions without describing what each changed: labeling actions on 03/07/2006 (SUPPL-8), 10/23/2006 (SUPPL-9 and 10), 10/18/2007 (SUPPL-12) and 08/07/2008 (SUPPL-13); labeling-package insert actions on 02/01/2010, 04/29/2014, 09/16/2015, 04/22/2016 and 05/05/2017; and efficacy-labeling changes with clinical data on 10/10/2013 and 02/15/2018 [1].

What the current label warns about

Nitrates. Any form of organic nitrate, taken regularly or intermittently, is contraindicated [2]. The label allows one exception: in a life-threatening situation where a nitrate is medically necessary, at least 48 hours should elapse after the last Cialis dose before one is considered, and then only under close medical supervision with hemodynamic monitoring. That is an emergency rule, not a way to space the two medicines in routine use [2]. The 150-man crossover study behind it gave tadalafil 20 mg or placebo daily for 7 days, then sublingual nitroglycerin 0.4 mg: 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 or 96 hours [10].

Alpha-blockers. Both lower blood pressure and the effect is additive. The label does not recommend combining Cialis with an alpha-blocker for BPH; for ED, a man who is stable on an alpha-blocker can start Cialis at the lowest dose [2].

CYP3A4. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312%; ritonavir 200 mg twice daily raised it by 124%. With such inhibitors, the label caps as-needed Cialis at 10 mg every 72 hours and once-daily Cialis at 2.5 mg [2]. Rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46%; the label calls for no dose adjustment but notes that once-daily efficacy may fall by an unknown amount [2].

Vision and hearing. NAION has been reported rarely after marketing with all PDE5 inhibitors; the label says to stop Cialis and seek medical attention for sudden vision loss in one or both eyes. Two observational case-crossover studies suggested about a 2-fold risk (2.15, 95% CI 1.06 to 4.34; and 2.27, 95% CI 0.99 to 5.20), and the label states that neither the reports nor those studies substantiate a causal relationship [2]. Sudden hearing decrease or loss, sometimes with tinnitus and dizziness, has also been reported, and the label says it cannot be determined whether it is directly related [2].

Prolonged erection. An erection lasting more than 4 hours, painful or not, needs emergency care; painful erections over 6 hours are priapism and can cause irreversible damage to erectile tissue [2].

Cardiovascular limits. ED drugs should not be used by men for whom sexual activity is inadvisable because of cardiovascular status. The label lists groups not studied and therefore not recommended: myocardial infarction within 90 days, unstable angina or angina during intercourse, NYHA class 2 or greater heart failure within 6 months, uncontrolled arrhythmia, blood pressure below 90/50 mm Hg or uncontrolled hypertension, and stroke within 6 months [2]. In healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo [2].