Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Eli Lilly Nederland B.V., Orteliuslaan 1000, 3528 BD Utrecht, The Netherlands
Pharmacotherapeutic group: Urologicals, drugs used in erectile dysfunction
ATC code: G04BE08
Tadalafil is a potent and selective inhibitor of PDE5, the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations within the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of the pulmonary vascular smooth muscle cell and vasodilation of the pulmonary vascular bed.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10 000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10 000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10 000-fold more potent for PDE5 than for PDE7 through PDE10.
A randomised, double-blind, placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension. Allowed background therapy included bosentan (stable maintenance dose up to 125 mg twice daily) and chronic anticoagulation, digoxin, diuretics and oxygen. More than half (53.3%) of the patients in the study were receiving concomitant bosentan therapy.
Patients were randomised to one of five treatment groups (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or placebo). Patients were at least 12 years of age and had a diagnosis of PAH that was idiopathic, related to collagen disease, related to anorexigen use, related to human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of at least 1 year in duration of a congenital systemic-to-pulmonary shunt (for example, ventricular septal defect, patent ductus arteriosus). The mean age of all patients was 54 years (range 14 to 90 years) with the majority of patients being Caucasian (80.5%) and female (78.3%). Pulmonary arterial hypertension (PAH) aetiologies were predominantly idiopathic PAH (61.0%) and related to collagen vascular disease (23.5%). The majority of patients had a World Health Organization (WHO) Functional Class III (65.2%) or II (32.1%). The mean baseline 6-minute-walk-distance (6MWD) was 343.6 meters.
The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance (6MWD). Only tadalafil 40 mg achieved the protocol defined level of significance with a placebo- adjusted median increase in 6MWD of 26 metres (p=0.0004; 95% CI: 9.5, 44.0; Pre-specified Hodges-Lehman method) (mean 33 metres, 95% CI: 15.2, 50.3). The improvement in walk distance was apparent from 8 weeks of treatment. Significant improvement (p < 0.01) in the 6MWD was demonstrated at week 12 when the patients were asked to delay taking study medicinal product in order to reflect trough active substance concentration. Results were generally consistent in subgroups according to age, gender, PAH aetiology and baseline WHO functional class and 6MWD. The placebo-adjusted median increase in 6MWD was 17 metres (p=0.09; 95% CI: : -7.1, 43.0; Pre-specified Hodges-Lehman method) (mean 23 metres, 95% CI; -2.4, 47.8) in those patients who received tadalafil 40 mg in addition to their concomitant bosentan (n=39), and was 39 metres (p<0.01, 95% CI:13.0, 66.0; Pre-specified Hodges-Lehman method) (mean 44 metres, 95% CI: 19.7, 69.0) in those patients who received tadalafil 40 mg alone (n=37).
The proportion of patients with improvement in WHO functional class by week 16 was similar in the tadalafil 40 mg and placebo groups (23% vs. 21%). The incidence of clinical worsening by week 16 in patients treated with tadalafil 40 mg (5%; 4 of 79 patients) was less than placebo (16%; 13 of 82 patients). Changes in the Borg dyspnoea score were small and non-significant with both placebo and tadalafil 40 mg.
Additionally, improvements compared to placebo were observed with tadalafil 40 mg in the physical functioning, role-physical, bodily pain, general health, vitality and social functioning domains of the SF 36. No improvements were observed in the role emotional and mental health domains of the SF-36. Improvements compared to placebo were observed with tadalafil 40 mg in the EuroQol (EQ 5D) US and UK index scores comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression components, and in the visual analogue scale (VAS).
Cardiopulmonary haemodynamics was performed in 93 patients. Tadalafil 40 mg increased cardiac output (0.6 L/min) and reduced pulmonary artery pressures (-4.3 mmHg) and pulmonary vascular resistance (-209 dyn.s/cm 5) compared to baseline (p<0.05). However, post hoc analyses demonstrated that changes from baseline in cardiopulmonary haemodynamic parameters for the tadalafil 40 mg treatment group were not significantly different compared to placebo.
357 patients from the placebo-controlled study entered a long-term extension study. Of these, 311 patients had been treated with tadalafil for at least 6 months and 293 for 1 year (median exposure 365 days; range 2 days to 415 days). For those patients for which there are data, the survival rate at 1 year is 96.4%. Additionally, 6 minute walk distance and WHO functional class status appeared to be stable in those treated with tadalafil for 1 year.
Tadalafil 20 mg administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical trials, reports of changes in colour vision were rare (<0.1%).
Three trials were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. In two of these trials decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters such as motility, morphology and FSH.
A total of 35 paediatric patients with PAH aged 6 to <18 years were treated in a 2-period add-on (in addition to patient's current endothelin receptor antagonist) study (H6D-MC-LVHV) to evaluate tadalafil efficacy, safety, and PK. In the 6-month double-blind period (Period 1), 17 patients received tadalafil and 18 patients received placebo.
Tadalafil dose was administered based on patient's weight at the screening visit. The majority of patients (25 [71.4%]) were ≥40 kg and received 40 mg, with the remainder (10 [28.6%]) weighing ≥25 kg to <40 kg and receiving 20 mg. There were 16 male and 19 female patients in this study; the median age for the overall population was 14.2 years (ranged from 6.2 to 17.9 years). No patient aged <6 years was enrolled in the study. Pulmonary arterial hypertension aetiologies were predominantly IPAH (74.3%) and PAH associated with persisting or recurrent pulmonary hypertension after repair of a congenital systemic to pulmonary shunt (25.7%). The majority of patients were in WHO functional Class II (80%).
The primary objective of period 1 was to evaluate the efficacy of tadalafil compared with placebo in improving 6MWD from baseline to Week 24, as assessed in patients ≥6 to <18 years of age who were developmentally capable of performing a 6MW test. For the primary analysis (MMRM), the LS mean (Standard Error: SE) change from baseline to 24 weeks in 6MWD was 60 (SE: 20.4) metres for tadalafil and 37 (SE: 20.8) metres for placebo.
Additionally, in paediatric patients with PAH aged ≥2 to <18 years, an exposure-response (ER) model was used to predict 6MWD based upon paediatric exposure following 20 or 40 mg daily doses estimated using a Population PK model and an established adult ER model (H6D-MC-LVGY). The model demonstrated similarity of response between model-predicted and the actual observed 6MWD in paediatric patients aged 6 to <18 years from Study H6D-MC-LVHV.
There were no confirmed cases of clinical worsening in either treatment group during period 1. The proportion of patients with improvement in WHO functional class from baseline to week 24 was 40% in the tadalafil group compared to 20% in the placebo group. Additionally, a positive trend of potential efficacy in tadalafil versus placebo group was also observed in measurements like NT-Pro- BNP (treatment difference: -127.4, 95% CI, -247.05 to -7.80), echocardiographic parameters (TAPSE: treatment difference 0.43, 95% CI, 0.14 to 0.71; left ventricular EI-systolic: treatment difference -0.40, 95% CI, -0.87 to 0.07; left ventricular EI-diastolic: treatment difference -0.17, 95% CI, -0.43 to 0.09; 2 patients with reported pericardial effusion from placebo group and none from tadalafil group), and CGI-I (improved in tadalafil 64.3%, placebo 46.7%).
A total of 32 patients from the placebo-controlled study (H6D-MC-LVHV) entered the open-label 2- year extension period (period 2) during which all patients received tadalafil at their appropriate weight cohort-related dose. The primary objective of period 2 was to evaluate the long-term safety of tadalafil.
In total, 26 patients completed the follow-up, during which time no new safety signals were observed. Clinical worsening was experienced in 5 patients; 1 had new onset syncope, 2 had an increase in endothelin receptor antagonist dose, 1 had addition of new PAH-specific concomitant therapy and 1 was hospitalized for PAH progression. WHO functional class was maintained or improved in the majority of patients at the end of period 2.
Due to limited availability of pharmacodynamic measures and lack of a suitable and approved clinical endpoint in children younger than age 6 years, efficacy is extrapolated in this population based upon exposure-matching to the adult efficacious dose range.
Dosing and efficacy of ADCIRCA has not been established for children aged less than 2 years.
A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of tadalafil was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy in slowing the decline in ambulation as measured by the primary 6-minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p=0.307) and -59.1 m in the tadalafil 0.6 mg/kg group (p=0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids.
Pharmacokinetic studies have shown that ADCIRCA tablets and oral suspension are bioequivalent based upon AUC(0-∞) in the fasted state. The tmax of the oral suspension is approximately 1 hour later than the tablets, however the difference was not considered clinically relevant. While the tablets may be taken with or without food, the oral suspension should be taken on an empty stomach at least 1 hour before or 2 hours after a meal.
Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 4 hours after dosing. Pharmacokinetic studies have shown that ADCIRCA tablets and oral suspension are bioequivalent based upon AUC(0-∞). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil film-coated tablets are not influenced by food, thus ADCIRCA tablets may be taken with or without food. The effect of food on the rate and extent of absorption with the tadalafil oral suspension has not been investigated; therefore, tadalafil suspension should be taken on an empty stomach at least 1 hour before or 2 hours after a meal. The time of dosing (morning versus evening after a single 10 mg administration) had no clinically relevant effects on the rate and extent of absorption. For children, tadalafil was dosed in clinical trials and post-marketing trials without regard to food with no safety concerns.
The mean volume of distribution is approximately 77 L at steady state, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13 000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
The mean oral clearance for tadalafil is 3.4 L/h at steady state and the mean terminal half-life is 16 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Between 20 mg to 40 mg, a less than proportional increase in exposure is observed. During tadalafil 20 mg and 40 mg once daily dosing, steady-state plasma concentrations are attained within 5 days, and exposure is approximately 1.5 fold of that after a single dose.
In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. There were no clinically relevant differences in Cmax compared to healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.
Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years after a 10 mg dose. This effect of age is not clinically significant and does not warrant a dose adjustment.
In clinical pharmacology studies using single-dose tadalafil (5 to 20 mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.
Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.
Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil in these patients is not recommended.
Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects after a 10 mg dose. This difference in exposure does not warrant a dose adjustment.
Pharmacokinetic studies have included subjects and patients from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.
In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure were observed. No dose adjustment is warranted.
Based on data from 36 paediatric patients with PAH aged 2 to <18 years, body weight did not have an impact on the clearance of tadalafil; the AUC values in all paediatric weight groups are similar to those in adult patients at the same dose. Body weight was shown to be a predictor of peak exposure in children; due to this weight effect, the dose is 20 mg daily for paediatric patients ≥2 years and weighing <40 kg, and the Cmax is expected to be similar to paediatric patients weighing ≥40 kg taking 40 mg daily. Tmax for the tablet formulation was estimated at approximately 4 hours and was independent of body weight. Tadalafil half-life values were estimated to range from 13.6 to 24.2 hours for a range of 10 to 80 kg of body weight and did not show any clinically relevant differences.
Non-clinical data reveal no special hazard for humans based on conventional trials of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1 000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free active substance at this dose was approximately 18 times the human AUC at a 20 mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7 – 18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.
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