tadalafil: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Adcirca (previously Tadalafil Lilly)

4.1 Therapeutic indications

Applies to: ADCIRCA 20 mg film-coated tablets · ADCIRCA 2 mg/mL oral suspension

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

Applies to: ADCIRCA 20 mg film-coated tablets

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.

Applies to: ADCIRCA 2 mg/mL oral suspension

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 * Tablets are available for patients able to swallow them and taking a 20 or 40 mg dose.

Patients should not take an extra dose if vomiting occurs.

Special populations

Elderly patients
Dose adjustments are not required in elderly patients.

Renal impairment

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

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.

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

Method of administration

Oral use.

The oral suspension should be taken on an empty stomach at least 1 hour before or 2 hours after a meal.

For instructions on preparation of the medicinal product before administration, see section 6.6.

The prescribed dose of ADCIRCA oral suspension can be administered via nasogastric (NG) tube.
Follow the manufacturer’s instructions for the NG tube to administer the medicinal product. To ensure adequate dosing, after administration of the oral suspension, the enteral feeding tube must be flushed with at least 3 mL of water or sodium chloride 9 mg/ml (0.9 %) solution for infusion.

4.3 Contraindications

Applies to: ADCIRCA 20 mg film-coated tablets · ADCIRCA 2 mg/mL oral suspension

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).

4.8 Undesirable effects

Applies to: ADCIRCA 20 mg film-coated tablets

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,
Gastroesophage al 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 national reporting system listed in Appendix V.

Applies to: ADCIRCA 2 mg/mL oral suspension

Summary of the safety profile

Tabulated list of adverse reactions

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

Paediatric population

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, 19patients 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 8patients (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 < 1year, 41 aged1 to < 2years, 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

4.4 Special warnings and precautions for use

Applies to: ADCIRCA 20 mg film-coated tablets

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’.

Applies to: ADCIRCA 2 mg/mL oral suspension

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.

Vision

Decreased or sudden hearing loss

Renal and hepatic 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

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

Prostacyclin and its analogues

Bosentan

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

Excipients

Sodium benzoate
This medicinal product contains 2.1 mg sodium benzoate in each mL of oral suspension.

Sorbitol
This medicinal product contains 110.25 mg sorbitol in each mL. Sorbitol is a source of fructose. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary.

Propylene glycol
This medicinal product contains 3.1 mg propylene glycol in each mL.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg)per 1 mL, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: ADCIRCA 20 mg film-coated tablets

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.

Applies to: ADCIRCA 2 mg/mL oral suspension

Effects of other medicinal products on tadalafil

Cytochrome P450 inhibitors

Cytochrome P450 inducers

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

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

In clinical pharmacology trials, 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 trials 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).

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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Applies to: ADCIRCA 20 mg film-coated tablets

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).

Applies to: ADCIRCA 2 mg/mL oral suspension

Pregnancy

There are limited data from the use of tadalafil in pregnant women. Animal trials 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

4.7 Effects on ability to drive and use machines

Applies to: ADCIRCA 20 mg film-coated tablets · ADCIRCA 2 mg/mL oral suspension

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.

4.9 Overdose

Applies to: ADCIRCA 20 mg film-coated tablets · ADCIRCA 2 mg/mL oral suspension

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.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: ADCIRCA 20 mg film-coated tablets · ADCIRCA 2 mg/mL oral suspension

Pharmacotherapeutic group: Urologicals, drugs used in erectile dysfunction, ATC code: G04BE08.

Mechanism of action

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

Pulmonary arterial hypertension in adults
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.

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: ADCIRCA 20 mg film-coated tablets

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.

Absorption

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.

Distribution

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.

Biotransformation

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: ADCIRCA 2 mg/mL oral suspension

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.

Absorption

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 studies without regard to food with no safety concerns.

Distribution

Less than 0.0005 % of the administered dose appeared in the semen of healthy subjects.

Biotransformation

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Cialis

4.1 Therapeutic indications

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, sexual stimulation is required.

CIALIS is not indicated for use by women.

Applies to: CIALIS 5 mg film-coated tablets

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.

CIALIS is not indicated for use by women.

4.2 Posology and method of administration

Applies to: CIALIS 2.5 mg film-coated tablets

Posology

Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen with the lowest doses of CIALIS might be considered suitable, based on patient choice and the physician’s judgement.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Men with renal impairment
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment (see sections 4.4 and 5.2).

Men with hepatic impairment
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of CIALIS in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.

Applies to: CIALIS 5 mg film-coated tablets

Posology

Erectile dysfunction in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Benign prostatic hyperplasia in adult men
The recommended dose is 5 mg, taken at approximately the same time every day with or without food.
For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5 mg taken at approximately the same time every day. Patients who are unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an alternative therapy as the efficacy of tadalafil 2.5mg for the treatment of benign prostatic hyperplasia has not been demonstrated.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benign prostatic hyperplasia is not recommended in patients with severe renal impairment (see sections 4. 4 and 5.2).

Men with hepatic impairment
For the treatment of erectile dysfunction using on-demand CIALIS the recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh Class C); if 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.

Once-a-day dosing of CIALIS both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of CIALIS in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.

Applies to: CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Posology

Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried.
It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Men with hepatic impairment
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of CIALIS in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.

4.3 Contraindications

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

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

In clinical studies, 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 CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

CIALIS, must not be used in men with cardiac disease for whom sexual activity is inadvisable.
Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
- patients with myocardial infarction within the last 90 days,
- patients with unstable angina or angina occurring during sexual intercourse,
- patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
- patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled hypertension,
- patients with a stroke within the last 6 months.

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

The co-administration of 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).

4.8 Undesirable effects

Applies to: CIALIS 2.5 mg film-coated tablets

Summary of the safety profile

The most commonly reported adverse reactions in patients taking CIALIS for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of CIALIS. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with CIALIS once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated summary of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo- controlled clinical trials (comprising a total of 8022 patients on CIALIS and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

Very common

Common

Uncommon

Rare

Not known
Immune system disorders

Hypersensitivity reactions
Angioedema2

Nervous system disorders

Headache
Dizziness
Stroke1 (including haemorrhagic events), Syncope,
Transient ischaemic attacks1, Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect,
Swelling of eyelids,
Conjunctival hyperaemia, Non- arteritic anterior ischemic optic neuropathy
(NAION)2, Retinal vascular occlusion2
Central serous chorioretinopathy
Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction, Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Dyspnoea,
Epistaxis

Gastrointestinal disorders

Dyspepsia

Abdominal pain,
Vomiting, Nausea,
Gastro-oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria,
Stevens-Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosis
(sweating)

Musculoskeletal, connective tissue and bone disorders

Back pain,
Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism, Penile haemorrhage,
Haematospermia

General disorders and administration site conditions

Chest pain1,
Peripheral oedema,
Fatigue
Facial oedema2,
Sudden cardiac death1, 2

(1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).
(2) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
(3) More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.

Description of selected adverse reactions

A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions

Applies to: CIALIS 5 mg film-coated tablets

Summary of the safety profile

Tabulated summary of adverse reactions

Very common

Common

Uncommon

Rare

Not known
Immune system disorders

Hypersensitivity reactions
Angioedema2

Nervous system disorders

Headache
Dizziness
Stroke1 (including haemorrhagic events), Syncope,
Transient ischaemic attacks1,
Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect,
Swelling of eyelids,
Conjunctival hyperaemia, Non- arteritic anterior ischemic optic neuropathy
(NAION)2,
Retinal vascular occlusion2
Central serous chorioretinopathy

Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction, Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Dyspnoea,
Epistaxis

Gastrointestinal disorders

Dyspepsia

Abdominal pain,
Vomiting, Nausea,
Gastro-oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria, Stevens-
Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosis
(sweating)

Musculoskeletal, connective tissue and bone disorders

Back pain,
Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism, Penile haemorrhage,
Haematospermia

General disorders and administration site conditions

Chest pain1,
Peripheral oedema,
Fatigue
Facial oedema2,
Sudden cardiac death1, 2

Description of selected adverse reactions

Other special populations

Reporting of suspected adverse reactions

Applies to: CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Summary of the safety profile

Tabulated summary of adverse reactions

Very common
Common
Uncommon
Rare

Not known
Immune system disorders

Hypersensitivity reactions
Angioedema2

Nervous system disorders

Headache
Dizziness
Stroke1 (including haemorrhagic events), Syncope,
Transient ischaemic attacks1, Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect,
Swelling of eyelids,
Conjunctival hyperaemia, Non- arteritic anterior ischemic optic neuropathy
(NAION) 2,
Retinal vascular occlusion2
Central serous chorioretinopathy
Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction, Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Dyspnoea,
Epistaxis

Gastrointestinal disorders

Dyspepsia

Abdominal pain,
Vomiting, Nausea,
Gastro-oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria, Stevens-
Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosis
(sweating)

Musculoskeletal, connective tissue and bone disorders

Back pain,

Myalgia, Pain in extremity
Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism, Penile haemorrhage,
Haematospermia

General disorders and administration site conditions

Chest pain1,
Peripheral oedema,
Fatigue

Facial oedema2,
Sudden cardiac death1,2

Description of selected adverse reactions

Other special populations

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: CIALIS 2.5 mg film-coated tablets

Before treatment with CIALIS

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1) and as such potentiates the hypotensive effect of nitrates (see section 4.3).

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve- sparing prostatectomy.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to CIALIS, to sexual activity, or to a combination of these or other factors.

In patients receiving concomitant antihypertensive medicinal products, tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.

In patients who are taking alpha1 blockers, concomitant administration of CIALIS may lead to symptomatic hypotension in some patients (see section 4.5). 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 CIALIS 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 CIALIS and consult a physician immediately (see section 4.3).

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 and previous hearing loss history) patients should be advised to stop taking tadalafil and 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, once-a-day dosing of CIALIS is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

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.

CIALIS, 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 inhibitors

Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined (see section 4.5).

CIALIS and other treatments for erectile dysfunction

The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take CIALIS in such combinations.

Lactose

CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Applies to: CIALIS 5 mg film-coated tablets

Before treatment with CIALIS

A medical history and physical examination should be undertaken to diagnose erectile dysfunction or benign prostatic hyperplasia and determine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examined to rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascular conditions (see section 4.3).

Cardiovascular

Vision

Decreased or sudden hearing loss

Renal and hepatic impairment

There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration either for the treatment of erectile dysfunction or benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Use with CYP3A4 inhibitors

CIALIS and other treatments for erectile dysfunction

Lactose

CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Applies to: CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Before treatment with CIALIS

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

Cardiovascular

Vision

Decreased or sudden hearing loss

Hepatic impairment

There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C). If CIALIS is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Use with CYP3A4 inhibitors

CIALIS and other treatments for erectile dysfunction

Lactose

CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine 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

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets

Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.

Effects of other substances on tadalafil

Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) 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) exposure (AUC) 4-fold and Cmax by 22 %. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg)

exposure (AUC) 2-fold with no change in Cmax. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would be expected to increase plasma concentrations of tadalafil (see section 4.4).
Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.

Transporters
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
Therefore there is the potential of drug interactions mediated by inhibition of transporters.

Cytochrome P450 inducers
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;
the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.

Effects of tadalafil on other medicinal products

Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg-20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

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. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood-pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant. Analysis of phase 3 clinical trial data showed no difference in

adverse events in patients taking tadalafil with or without antihypertensive medicinal products.
However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.

Riociguat
Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, 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).

5- alpha reductase inhibitors
In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co- administered with 5-ARIs.

CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.

Ethinylestradiol and terbutaline
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.

Alcohol
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co- administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

Cytochrome P450 metabolised medicinal products
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.

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.

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

Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.

Applies to: CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Effects of other substances on tadalafil

AUC and Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and Cmax by 22 %. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in Cmax. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would be expected to increase plasma concentrations of tadalafil (see section 4.4).
Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.

Effects of tadalafil on other medicinal products

Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg – 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant. Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products.
However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.

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.

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

Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.

4.6 Fertility, pregnancy and lactation

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

CIALIS is not indicated for use by women.

Pregnancy

Breastfeeding

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

Fertility

Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies 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

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

CIALIS 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 CIALIS, before driving or using machines.

4.9 Overdose

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

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. Adverse events 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.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: CIALIS 2.5 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.

Pharmacodynamic effects

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.

Clinical efficacy and safety

Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to CIALIS on demand. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

Tadalafil 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 studies, reports of changes in colour vision were rare (< 0.1 %).

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: CIALIS 5 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.

Pharmacodynamic effects

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.

Clinical efficacy and safety

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Pharmacodynamic effects

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.

Clinical efficacy and safety

Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to CIALIS. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: CIALIS 2.5 mg film-coated tablets · CIALIS 5 mg film-coated tablets · CIALIS 10 mg film-coated tablets / CIALIS 20 mg film-coated tablets

Absorption

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus CIALIS may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 63 l, 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.

Biotransformation

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.

Elimination

The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 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).

Linearity/non-linearity

Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing.

Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.

Special populations

Elderly

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Tadalafil Lilly

4.1 Therapeutic indications

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, sexual stimulation is required.

Tadalafil Lilly is not indicated for use by women.

Applies to: Tadalafil Lilly 5 mg film-coated tablets

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.

Tadalafil Lilly is not indicated for use by women.

4.2 Posology and method of administration

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets

Posology

Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In patients who anticipate a frequent use of Tadalafil Lilly (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil Lilly might be considered suitable, based on patient choice and the physician’s judgement.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Men with hepatic impairment
The recommended dose of Tadalafil Lilly is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil Lilly in patients with severe hepatic impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of Tadalafil Lilly in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Oral use.

Tadalafil Lilly is available as 2.5, 5, 10, and 20 mg film-coated tablets.

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

Applies to: Tadalafil Lilly 5 mg film-coated tablets

Posology

Erectile dysfunction in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Benign prostatic hyperplasia in adult men
The recommended dose is 5 mg, taken at approximately the same time every day with or without food.
For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5 mg taken at approximately the same time every day. Patients who are unable to tolerate tadalafil 5 mg for the treatment of benign prostatic hyperplasia should consider an alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic hyperplasia has not been demonstrated.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Men with hepatic impairment
For the treatment of erectile dysfunction using on-demand Tadalafil Lilly the recommended dose of Tadalafil Lilly is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil Lilly in patients with severe hepatic impairment (Child-Pugh Class C); if 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.

Once-a-day dosing of Tadalafil Lilly both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of Tadalafil Lilly in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Oral use.

Tadalafil Lilly is available as 2.5, 5, 10, and 20 mg film-coated tablets.

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

Applies to: Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Posology

Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.

In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried.

It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.

In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Special populations

Elderly men
Dose adjustments are not required in elderly patients.

Men with hepatic impairment
The recommended dose of Tadalafil Lilly is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil Lilly in patients with severe hepatic impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see sections 4.4 and 5.2).

Men with diabetes
Dose adjustments are not required in diabetic patients.

Paediatric population
There is no relevant use of Tadalafil Lilly in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

Oral use.

Tadalafil Lilly is available as 2.5, 5, 10, and 20 mg film-coated tablets.

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

4.3 Contraindications

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets

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

In clinical studies, 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 Lilly to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

Tadalafil Lilly, must not be used in men with cardiac disease for whom sexual activity is inadvisable.
Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

Tadalafil Lilly is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous Phosphodiesterase-5 (PDE5) inhibitor exposure (see section 4.4).

Applies to: Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

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

Therefore, administration of Tadalafil Lilly to patients who are using any form of organic nitrate is contraindicated (see section 4.5).

Tadalafil Lilly is contraindicated in patients who have loss of vision in one eye because of non- arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous Phosphodiesterase-5 (PDE5) inhibitor exposure (see section 4.4).

4.8 Undesirable effects

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets

Summary of the safety profile

The most commonly reported adverse reactions in patients taking Tadalafil Lilly for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of Tadalafil Lilly. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with Tadalafil Lilly once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated list of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8 022 patients on Tadalafil Lilly and

4 422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

Frequency convention: 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) and very rare (<1/10 000) and not known (cannot be estimated from the available data).

System Organ
Class
Very common

Common

Uncommon

Rare

Not known
Immune system disorders

Hypersensitivity reactions
Angioedema2

Nervous system disorders

Headache Dizziness
Stroke1
(including haemorrhagic events),
Syncope,
Transient ischaemic attacks1,
Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect,
Swelling of eyelids,
Conjunctival hyperaemia,
Non-arteritic anterior ischemic optic neuropathy
(NAION)2,
Retinal vascular occlusion2
Central serous chorioretinopathy
Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction,
Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestio n
Dyspnoea,
Epistaxis

Gastrointestinal disorders

Dyspepsi a

Abdominal pain,
Vomiting,
Nausea, Gastro- oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria,
Stevens-
Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosis
(sweating)

Musculoskeletal
, connective tissue and bone disorders

Back pain,
Myalgia,
Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism,
Penile haemorrhage,
Haematosper mia

General disorders and administration site conditions

Chest pain1,
Peripheral oedema, Fatigue
Facial oedema2,
Sudden cardiac death1, 2

Description of selected adverse reactions

Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

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 national reporting system listed in Appendix V.

Applies to: Tadalafil Lilly 5 mg film-coated tablets

Summary of the safety profile

Tabulated list of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8 022 patients on Tadalafil Lilly and 4 422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

System organ class
Very commo n

Common

Uncommon

Rare

Not known
Immune system disorders

Hypersensitivit y reactions
Angioedema2

Nervous system disorders

Headache
Dizziness
Stroke1
(including haemorrhagic events),
Syncope,
Transient ischaemic attacks1,
Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect, Swelling of eyelids,
Conjunctival hyperaemia,
Non-arteritic anterior ischemic optic neuropathy
(NAION)2,
Retinal vascular occlusion2
Central serous chorioretinopath y
Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction,
Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestio n
Dyspnoea,
Epistaxis

Gastrointestinal disorders

Dyspepsia

Abdominal pain, Vomiting,
Nausea, Gastro- oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria,
Stevens-
Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosis
(sweating)

Musculoskeletal
, connective tissue and bone disorders

Back pain,
Myalgia,
Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism, Penile haemorrhage,
Haematospermi a

General disorders and administration site conditions

Chest pain1,
Peripheral oedema,
Fatigue
Facial oedema2,
Sudden cardiac death1, 2

(1) Most of the patients had pre-existing cardiovascular risk factors (see section 4.4).

(2) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
(3) More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.

Description of selected adverse reactions

Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions

Applies to: Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Summary of the safety profile

Tabulated list of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8 022 patients on Tadalafil Lilly and

4 422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

System organ class
Very common
Common
Uncommon
Rare

Not known
Immune system disorders

Hypersensitivi ty reactions
Angioedema2

Nervous system disorders

Headache
Dizziness
Stroke1
(including haemorrhagic events),
Syncope,
Transient ischaemic attacks1,
Migraine2,
Seizures2,
Transient amnesia

Eye disorders

Blurred vision,
Sensations described as eye pain

Visual field defect,
Swelling of eyelids,
Conjunctival hyperaemia,
Non-arteritic anterior ischemic optic neuropathy
(NAION) 2,
Retinal vascular occlusion2
Central serous chorioretinop athy
Ear and labyrinth disorders

Tinnitus
Sudden hearing loss

Cardiac disorders1

Tachycardia,
Palpitations
Myocardial infarction,
Unstable angina pectoris2,
Ventricular arrhythmia2

Vascular disorders

Flushing
Hypotension3,
Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Dyspnoea,
Epistaxis

Gastrointestin al disorders

Dyspepsia

Abdominal pain,
Vomiting,
Nausea,
Gastro- oesophageal reflux

Skin and subcutaneous tissue disorders

Rash
Urticaria,
Stevens-
Johnson syndrome2,
Exfoliative dermatitis2,
Hyperhydrosi s (sweating)

Musculoskele tal, connective tissue and bone disorders

Back pain,
Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Prolonged erections
Priapism,
Penile haemorrhage,
Haematosper mia

General disorders and administration site conditions

Chest pain1,
Peripheral oedema,
Fatigue

Facial oedema2,
Sudden cardiac death1,2

Description of selected adverse reactions

Other special populations

Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets

Before treatment with Tadalafil Lilly

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if Tadalafil Lilly is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to Tadalafil Lilly, to sexual activity, or to a combination of these or other factors.

In patients who are taking alpha1 blockers, concomitant administration of Tadalafil Lilly may lead to symptomatic hypotension in some patients (see section 4.5). 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 Lilly 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 Tadalafil Lilly and consult a physician immediately (see section 4.3).

Decreased or sudden hearing loss

patients should be advised to stop taking tadalafil and 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, once-a-day dosing of Tadalafil Lilly is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of Tadalafil Lilly in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If Tadalafil Lilly is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Tadalafil Lilly, 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 inhibitors

Caution should be exercised when prescribing Tadalafil Lilly to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined (see section 4.5).

Tadalafil Lilly and other treatments for erectile dysfunction

The safety and efficacy of combinations of Tadalafil Lilly and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take Tadalafil Lilly in such combinations.

Lactose

Tadalafil Lilly contains lactose. 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’.

Applies to: Tadalafil Lilly 5 mg film-coated tablets

Before treatment with Tadalafil Lilly

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if Tadalafil Lilly is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Cardiovascular

possible to definitively determine whether these events are related directly to these risk factors, to Tadalafil Lilly, to sexual activity, or to a combination of these or other factors.

Vision

Decreased or sudden hearing loss

Renal and hepatic impairment

There is limited clinical data on the safety of single-dose administration of Tadalafil Lilly in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration either for the treatment of erectile dysfunction or benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. If Tadalafil Lilly is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Use with CYP3A4 inhibitors

Tadalafil Lilly and other treatments for erectile dysfunction

Lactose

Tadalafil Lilly contains lactose. 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’.

Applies to: Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Before treatment with Tadalafil Lilly

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if Tadalafil Lilly is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Cardiovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to Tadalafil Lilly, to sexual activity, or to a combination of these or other factors.

Vision

Visual defects, including Central Serous Chorioretinopathy (CSCR), and cases of NAION have been reported in connection with the intake of Tadalafil Lilly 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 Tadalafil Lilly and consult a physician immediately (see section 4.3).

Decreased or sudden hearing loss

Hepatic impairment

There is limited clinical data on the safety of single-dose administration of Tadalafil Lilly in patients with severe hepatic insufficiency (Child-Pugh Class C). If Tadalafil Lilly is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Priapism and anatomical deformation of the penis

Use with CYP3A4 inhibitors

Tadalafil Lilly and other treatments for erectile dysfunction

Lactose

Tadalafil Lilly contains lactose. 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

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Effects of other substances on tadalafil

Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.

Transporters
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
Therefore there is the potential of medicinal product interactions mediated by inhibition of transporters.

Effects of tadalafil on other medicinal products

Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of Tadalafil Lilly to patients who are using any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical trial in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of Tadalafil Lilly (2.5 mg - 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil Lilly before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dose and progressively adjusted.

blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant. Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products.
However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.

5- alpha reductase inhibitors
In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.

Alcohol
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

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.

Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.

4.6 Fertility, pregnancy and lactation

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Tadalafil Lilly is not indicated for use by women.

Pregnancy

Breast-feeding

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

Fertility

4.7 Effects on ability to drive and use machines

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Tadalafil Lilly 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 Tadalafil Lilly, before driving or using machines.

4.9 Overdose

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Pharmacodynamic effects

Clinical efficacy and safety

Three clinical studies were conducted in 1 054 patients in an at-home setting to define the period of responsiveness to Tadalafil Lilly on demand. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil Lilly 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Tadalafil Lilly 5 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Pharmacodynamic effects

Clinical efficacy and safety

Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil Lilly 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC Code: G04BE08.

Mechanism of action

Pharmacodynamic effects

Clinical efficacy and safety

Three clinical studies were conducted in 1 054 patients in an at-home setting to define the period of responsiveness to Tadalafil Lilly. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.

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 studies, reports of changes in colour vision were rare (< 0.1 %).

Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil Lilly 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily.

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Tadalafil Lilly 2.5 mg film-coated tablets · Tadalafil Lilly 5 mg film-coated tablets · Tadalafil Lilly 10 mg film-coated tablets / Tadalafil Lilly 20 mg film-coated tablets

Absorption

The rate and extent of absorption of tadalafil are not influenced by food, thus Tadalafil Lilly may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.

Distribution

Less than 0.0005 % of the administered dose appeared in the semen of healthy subjects.

Biotransformation

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.

Elimination

Linearity/non-linearity

Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.

Special populations

Elderly

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.