4.1. Therapeutic indications

Adults

Treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1).

Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.

Paediatric population

Treatment of paediatric patients aged 2 years and above with pulmonary arterial hypertension (PAH) classified as WHO functional class II and III.

4.2. Posology and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Posology

Adults

The recommended dose is 40 mg (two x 20 mg film-coated tablets) taken once daily.

Paediatric population (age 2 years to 17 years)

The recommended once daily doses based on age and weight categories in paediatric patients are shown below.

Paediatric patient's age and/or weight

Recommended daily dose and dosing regimen

Age ≥ 2 years old

Body weight ≥ 40 kg

Body weight < 40 kg

40 mg (two 20 mg tablets) once daily

20 mg (one 20 mg tablet or 10 mL of oral suspension (OS), 2 mg/mL tadalafil*) once daily

* Oral suspension is available for administration to paediatric patients who require 20 mg and are not able to swallow tablets.

For patients < 2 years old no PK or efficacy data are available from clinical trials. The most appropriate dose of ADCIRCA in children aged between 6 months to < 2 years has not been established. Therefore, ADCIRCA is not recommended in this age subset.

Delayed dose, missed dose, or vomiting

If there is a delay in the administration of ADCIRCA, but yet within the same day, the dose should be taken with no changes to the subsequent dose schedules. Patients should not take an extra dose if a dose is missed.

Patients should not take an extra dose if vomiting occurs.

Special populations

Elderly patients

Dose adjustments are not required in elderly patients.

Renal impairment

Adults and paediatric population (2 to 17 years, weighing at least 40 kg)

In patients with mild to moderate renal impairment a starting dose of 20 mg once per day is recommended. The dose may be increased to 40 mg once per day, based on individual efficacy and tolerability. In patients with severe renal impairment the use of tadalafil is not recommended (see sections 4.4 and 5.2).

Paediatric population (2 to 17 years, weighing less than 40 kg)

In patients < 40 kg and with mild to moderate renal impairment a starting dose of 10 mg once per day is recommended. The dose may be increased to 20 mg once per day, based on individual efficacy and tolerability. In patients with severe renal impairment the use of tadalafil is not recommended (see sections 4.4 and 5.2).

Hepatic impairment

Adults and paediatric population (2 to 17 years, weighing at least 40 kg)

Due to limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B), a starting dose of 20 mg once per day may be considered.

Paediatric population (2 to 17 years, weighing less than 40 kg)

In patients < 40 kg and with mild to moderate hepatic impairment, a starting dose of 10 mg once per day may be considered.

For patients of all ages, if tadalafil is prescribed, a careful individual benefit/risk assessment should be undertaken by the prescribing physician. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended (see sections 4.4 and 5.2).

Paediatric population (age < 2 years)

Dosing and efficacy of ADCIRCA has not been established for children aged < 2 years. Currently available data are described in sections 4.8 and 5.1.

Method of administration

ADCIRCA is for oral use.

The film-coated tablets should be swallowed whole with water, with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Acute myocardial infarction within the last 90 days.

Severe hypotension (< 90/50 mm Hg).

In clinical trials, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

The co-administration of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).

Patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).

4.4. Special warnings and precautions for use

Cardiovascular diseases

The following groups of patients with cardiovascular disease were not included in PAH clinical trials:

- Patients with clinically significant aortic and mitral valve disease

- Patients with pericardial constriction

- Patients with restrictive or congestive cardiomyopathy

- Patients with significant left ventricular dysfunction

- Patients with life-threatening arrhythmias

- Patients with symptomatic coronary artery disease

- Patients with uncontrolled hypertension.

Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility of associated PVOD should be considered.

Tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects.

In patients who are taking alpha1 blockers concomitant administration of tadalafil may lead to symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil and doxazosin is not recommended.

Vision

Visual defects, including Central Serous Chorioretinopathy (CSCR), and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. Most cases of CSCR resolved spontaneously after stopping tadalafil. Regarding NAION, analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, visual acuity impairment and/or visual distortion, he should stop taking ADCIRCA and consult a physician immediately (see section 4.3). Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Decreased or sudden hearing loss

Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factors were present in some cases (such as age, diabetes, hypertension, previous hearing loss history and associated connective tissue diseases) patients should be advised to seek prompt medical attention in the event of sudden decrease or loss of hearing.

Renal and hepatic impairment

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.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and, therefore, dosing of tadalafil is not recommended.

Priapism and anatomical deformation of the penis

Priapism has been reported in men treated with PDE5 inhibitors. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Tadalafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Use with CYP3A4 inducers or inhibitors

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended (see section 4.5).

For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended (see section 4.5).

Treatments for erectile dysfunction

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take ADCIRCA with these medicinal products.

Prostacyclin and its analogues

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

Bosentan

The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).

Lactose

ADCIRCA contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on tadalafil

Cytochrome P450 inhibitors

Azole antifungals (e.g. ketoconazole)

Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose exposure (AUC) 2-fold and Cmax by 15 %, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single dose exposure (AUC) 4-fold and Cmax by 22 %.

Protease inhibitors (e.g. ritonavir)

Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32 % and decreased Cmax by 30 %.

Cytochrome P450 inducers

Endothelin-1 receptor antagonists (e.g. bosentan)

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42 % and Cmax by 27 % following multiple dose co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.4 and 5.1). Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.

The safety and efficacy of combinations of tadalafil and other endothelin-1 receptor antagonists have not been studied.

Antimycobacterials (e.g. rifampicin)

A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and Cmax by 46 %, relative to the AUC and Cmax values for tadalafil alone (10 mg).

Effects of tadalafil on other medicinal products

Nitrates

In clinical trials, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.3).

Anti-hypertensives (including Calcium channel blockers)

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended (see section 4.4).

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin.

In clinical pharmacology studies, the potential for tadalafil (10 and 20 mg) to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied either as monotherapy or as part of combination therapy. In patients taking multiple antihypertensive medicinal products whose hypertension was not well controlled, greater reductions in blood pressure were observed compared to patients whose blood pressure was well controlled, where the reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of doxazosin -see above) is, in general, minor and not likely to be clinically relevant.

Riociguat

Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical trials, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section 4.3).

CYP1A2 substrates (e.g. theophylline)

When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 beats per minutes [bpm]) increase in heart rate.

CYP2C9 substrates (e.g.R-warfarin)

Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

Acetylsalicylic acid

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

P-glycoprotein substrates (e.g. digoxin)

Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.

Oral contraceptive

At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26 % and Cmax by 70 % relative to oral contraceptive administered with placebo. There was no statistically significant effect of tadalafil on levonorgestrel which suggests the effect of ethinylestradiol is due to inhibition of intestinal sulphation by tadalafil. The clinical relevance of this finding is uncertain.

Terbutaline

A similar increase in AUC and Cmax seen with ethinylestradiol may be expected with oral administration of terbutaline, probably due to inhibition of intestinal sulphation by tadalafil. The clinical relevance of this finding is uncertain.

Alcohol

Alcohol concentrations were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen after co-administration with alcohol. Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 mL of 40 % alcohol [vodka] in an 80 kg male), but in some subjects, postural dizziness and orthostatic hypotension were observed. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

Paediatric population

Interaction studies have only been performed in adults.

Based upon population PK analysis, the estimates of apparent clearance (CL/F) and the effect of bosentan on CL/F in paediatric patients are similar to those in adult patients with PAH. No dose adjustment is considered necessary for tadalafil with bosentan use.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tadalafil during pregnancy.

Breast‑feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the breastfed child cannot be excluded. ADCIRCA should not be used during breast feeding.

Fertility

Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical trials suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men (see sections 5.1 and 5.3).

4.7. Effects on ability to drive and use machines

ADCIRCA has negligible influence on the ability to drive or use machines. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to ADCIRCA, before driving or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions, occurring in ≥ 10 % of patients in the tadalafil 40 mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.

In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (ADCIRCA 11 %, placebo 16 %). Three hundred and fifty-seven (357) patients who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily.

Tabulated list of adverse reactions

The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with ADCIRCA. Also included in the table are some adverse reactions which have been reported in clinical trials and/or post-marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not known,” as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA.

Frequency estimate: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

System Organ Class

Very common

Common

Uncommon

Rare

Not known1

Immune system disorders

Hypersensitivity reactions5

Angioedema

Nervous system disorders

Headache6

Syncope, Migraine5

Seizures5, Transient amnesia5

Stroke2 (including haemorrhagic events)

Eye disorders

Blurred vision

Non-arteritic anterior ischemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect, Central serous chorioretinopathy

Ear and labyrinth disorders

Tinnitus

Sudden hearing loss

Cardiac disorders

Palpitations2, 5

Sudden cardiac death2, 5, Tachycardia2, 5

Unstable angina pectoris, Ventricular arrhythmia, Myocardial Infarction2

Vascular disorders

Flushing

Hypotension

Hypertension

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis (including nasal congestion, sinus congestion and rhinitis)

Epistaxis

Gastrointestinal disorders

Nausea, Dyspepsia (including abdominal pain/discomfort3)

Vomiting, Gastroesophageal reflux

Skin and subcutaneous tissue disorders

Rash

Urticaria5, Hyperhydrosis (sweating)5

Stevens-Johnson Syndrome, Exfoliative dermatitis

Musculoskeletal, connective tissue and bone disorders

Myalgia, Back pain Pain in extremity (including limb discomfort)

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Increased uterine bleeding4

Priapism5, Penile haemorrhage, Haematospermia

Prolonged erections

General disorders and administration site conditions

Facial oedema, Chest pain2

(1) Events not reported in registration trials and cannot be estimated from the available data. The adverse reactions have been included in the table as a result of post-marketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction.

(2) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors.

(3) Actual MedDRA terms included are abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and stomach discomfort.

(4) Clinical non-MedDRA term to include reports of abnormal/excessive menstrual bleeding conditions such as menorrhagia, metrorrhagia, menometrorrhagia, or vaginal haemorrhage.

(5) The adverse reactions have been included in the table as a result of post-marketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction; and in addition, the frequency estimates are based on only 1 or 2 patients experiencing the adverse reaction in the pivotal placebo-controlled study of ADCIRCA.

(6) Headache was the most commonly reported adverse reaction. Headache may occur at the beginning of therapy; and decreases over time even if treatment is continued.

Paediatric population

A total of 51 paediatric patients aged from 2.5 to 17 years with PAH were treated with tadalafil in clinical trials (H6D-MC-LVHV, H6D-MC-LVIG). A total of 391 paediatric patients with PAH, from new-born to < 18 years, were treated with tadalafil in an observational post-marketing study (H6D-JE-TD01). Following tadalafil administration, the frequency, type and severity of adverse reactions in children and adolescents were similar to that seen for adults. Due to differences in study design, sample size, gender, age range, and doses, safety findings from these trials are detailed separately below.

Placebo-controlled clinical trial in paediatric patients (H6D-MC-LVHV)

In a randomised, placebo‑controlled study in 35 patients aged 6.2 to 17.9 years (median age of 14.2 years) with PAH, a total of 17 patients were treated once daily with ADCIRCA 20 mg (middle‑weight cohort, ≥ 25 kg to < 40 kg) or 40 mg (heavy-weight cohort, ≥ 40 kg), and 18 patients were treated with placebo, for 24 weeks. The most common AEs, occurring in ≥ 2 patients treated with tadalafil, were headache (29.4 %), upper respiratory tract infection and influenza (17.6 % each), and arthralgia and epistaxis (11.8 % each). No deaths or SAEs were reported. Of the 35 paediatric patients treated in the short‑term, placebo-controlled study, 32 entered the 24 month long‑term open-label extension and 26 patients completed the follow‑up. No new safety signals were observed.

Uncontrolled pharmacokinetic study in paediatric patients (H6D‑MC‑LVIG)

In a paediatric multiple ascending dose study, 19 patients with a median age of 10.9 years [range 2.5 - 17 years] received once daily ADCIRCA, for an open-label treatment duration of 10 weeks (Period 1) and for up to a further 24 months in an extension (Period 2). SAEs were reported in 8 patients (42.1 %). These were pulmonary hypertension (21.0 %), viral infection (10.5 %), and cardiac failure, gastritis, pyrexia, type 1 diabetes mellitus, febrile convulsion, presyncope, seizure, and ovarian cyst (5.3 % each). No patient was discontinued due to AEs. TEAEs were reported in 18 patients (94.7 %) and the most frequent TEAEs (occurring in ≥ 5 patients) were headache, pyrexia, viral upper respiratory tract infection, and vomiting. Two deaths were reported.

Post-marketing study in paediatric patients (H6D-JE-TD01)

Safety data were collected during an observational post-marketing study in Japan including 391 paediatric PAH patients (2 years maximum observational period). The mean age of patients in the study was 5.7 ± 5.3 years, including 79 patients aged < 1 year, 41 aged 1 to < 2 years, 122 aged 2 to 6 years, 110 aged 7 to 14 years, and 39 aged 15 to 17 years. AEs were reported in 123 patients (31.5 %). The incidences of AEs (≥ 5 patients) were pulmonary hypertension (3.6 %); headache (2.8 %); heart failure and decreased platelet count (2.0 % each); epistaxis and upper respiratory tract infection (1.8 % each); bronchitis, diarrhoea, and abnormal hepatic function (1.5 % each); and gastroenteritis, protein losing gastroenteropathy, and increased aspartate aminotransferase (1.3 % each). The incidence of SAEs was 12.0 % (≥ 3 patients), including pulmonary hypertension (3.6 %), heart failure (1.5 %), and pneumonia (0.8 %). Sixteen deaths (4.1 %) were reported; none were related to tadalafil.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses.

In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis contributes negligibly to tadalafil elimination.