4.1. Therapeutic indications

Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, sexual stimulation is required. Tadalafil is not indicated for use by women.

4.2. Posology and method of administration

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 mg 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 (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil 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 Tadalafil is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil 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 in the paediatric population with regard to the treatment of erectile dysfunction.

Method of administration

For oral use.

4.3. Contraindications

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 to patients who are using any form of organic nitrate is contraindicated. (See section 4.5).

Tadalafil 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.

Tadalafil 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).

4.4. Special warnings and precautions for use

Before treatment with Tadalafil

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 Tadalafil 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, 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 Tadalafil 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 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 otherPDE5 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 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 tadalafil is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of Tadalafil 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 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.

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 inhibitors

Caution should be exercised when prescribing Tadalafil 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 and other 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. The patients should be informed not to take Tadalafil in such combinations.

Lactose

Tadalafil 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 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

Effects of other substances 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.

Antimicrobial medicinal products (e.g. rifampicin)

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

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. 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 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).

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 bpm) increase in heart rate.

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).

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.

P-glycoprotein substrates (e.g. digoxin)

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

Oral contraceptive pill

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 gut 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 gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.

4.6. Fertility, pregnancy and lactation

Tadalafil is not indicated for use by women.

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.

Breastfeeding

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk.

A risk to the suckling child cannot be excluded. Tadalafil 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

Tadalafil 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, before driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in patients taking Tadalafil 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. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with Tadalafil 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 Tadalafil 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) Post marketing 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

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

4.9. Overdose

Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. 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.