Tadalafil is used to treat adult men with:

Erectile dysfunction. This is when a man cannot get, or keep a hard, erect penis suitable for sexual activity. Tadalafil has been shown to significantly improve the ability of obtaining a hard erect penis suitable for sexual activity.

Following sexual stimulation Tadalafil works by helping the blood vessels in your penis to relax, allowing the flow of blood into your penis. The result of this is improved erectile function. Tadalafil will not help you if you do not have erectile dysfunction. It is important to note that Tadalafil does not work if there is no sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you were not taking a medicine for erectile dysfunction.

Tadalafil 5 mg is also indicated for:

Urinary symptoms associated with a common condition called benign prostatic hyperplasia, this is when the prostate gland gets bigger with age. Symptoms include difficulty in starting to pass water, a feeling of not completely emptying the bladder and a more frequent need to pass water even at night. Tadalafil improves blood flow to, and relaxes the muscles of, the prostate and bladder which may reduce symptoms of benign prostatic hyperplasia. Tadalafil has been shown to improve these urinary symptoms as early as 1-2 weeks after starting treatment

Posology

Erectile dysfunction in adult men

Flexible dose, on demand: 10 mg and 20 mg should be used; the recommended starting dose is one 10 mg tablet before sexual activity. However, if you have been given the dose of one 20mg tablet is because your doctor has decided that the recommended dose of 10mg is too weak. You may take a tablet at least 30 minutes before sexual activity, may still be effective up to 36 hours after taking the tablet. 10 mg and 20 mg are intended for use prior to anticipated sexual activity and is not recommended for continuous daily use.

Once a day dosing: 5 mg should be used; the recommended dose is one 5 mg tablet taken once a day at approximately the same time of the day. When taken once a day 5 mg allows you to obtain an erection, when sexually stimulated, at any time point during the 24 hours of the day. Once a day dosing of may be useful to men who anticipate having sexual activity two or more times per week.

It is important to note that does not work if there is no sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you were not taking a medicine for erectile dysfunction. Drinking alcohol may affect your ability to get an erection.

Benign prostatic hyperplasia in adult men

The dose is one 5 mg tablet taken once a day at approximately the same time of the day. If you have benign prostatic hyperplasia and erectile dysfunction, the dose remains one 5 mg tablet taken once a day. Do not take more than once a day.

Pulmonary arterial hypertension (PAH) in adult men

The usual dose is two 20 mg tablets taken once a day. You should take both tablets at the same time, one after the other. If you have a mild or moderate liver or kidney problem, your doctor may advise you to take only 20 mg per day.

Special population:

Elderly patients

Dose adjustments are not required in elderly patients.

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)

Hepatic impairment

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 10mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing of tadalafil 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).

Pediatric population

The safety and efficacy of a pivotal placebo-controlled study of tadalafil in individuals below 18 years of age has not yet been established. No data are available.

Method of administration

Tablets for oral use.

- 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 (<90/50mmHg), 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 ischemic 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)

Before treatment with tadalafil tablets

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 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.

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

·         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). The combination of tadalafil and doxazosin is not recommended.

Tadalafil - 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.

Vision

Visual defects and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, 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). 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).

Prostacyclin and its analogues

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical studies. 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction studies were conducted with 10mg and/or 20mg tadalafil, as indicated below. Regarding those interaction studies where only the 10mg 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 metabolized by CYP3A4.

·         A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone.

·         Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%.

·         Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) 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 %.

·         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

Antimicrobial medicinal products (e.g. rifampicin)

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

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.

Effects of tadalafil on Other Medicinal Products

Nitrates

In clinical studies, tadalafil (5mg, 10mg and 20mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of tadalafil 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 received daily doses of tadalafil 20mg for 7 days and 0.4mg 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 (5mg - 20mg), 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 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 8mg daily) and tadalafil (5mg daily dose and 20mg 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 (10mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20mg) 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 20mg 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 co-administered 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 10mg 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 (10mg or 20mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180ml 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 (0.6g/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 (10mg).

Cytochrome P450 metabolized medicinal products

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolized 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 (10mg and 20mg) 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 (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.

P-glycoprotein substrates (e.g. digoxin)

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

Antidiabetic medicinal products

Specific interaction studies with antidiabetic medicinal products were not conducted.

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.

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 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).

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.

Summary of the safety profile of tadalafil in pulmonary arterial hypertension

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, nasopharyngitis 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 a pivotal placebo-controlled study of tadalafil for the treatment of PAH, a total of 323 patients were treated with tadalafil 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 (tadalafil 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 summary of adverse reactions

The table below lists the adverse reactions reported during the placebo-controlled clinical study in patients with PAH treated with tadalafil. Also included in the table are some adverse reactions which have been reported in clinical studies 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 study data from the pivotal placebo-controlled study of tadalafil.

Frequency convention:

·         Very common (≥1/10),

·         Common (≥1/100 to <1/10),

·         Uncommon (≥1/1000 to <1/100),

·         Rare (≥1/10,000 to<1/1000),

·         Very Rare (<1/10,000) and

·         Not known (cannot be estimated from the available data)

Very common	Common	Uncommon	Rare	Not known1
Immune system disorders
	Hypersensitivity reactions5			Angioedema
Nervous system disorders
Headache6	Syncope, Migraine5	Seizures5, Transient amnesia5		Stroke2 (including hemorrhagic events)
Eye disorders
	Blurred vision,			Non-arteritic anterior ischemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect
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
Renal and urinary disorders
		Haematuria
Musculoskeletal, connective tissue and bone disorders
Myalgia, Back pain Pain in extremity (including limb discomfort)
Reproductive system and breast disorders
	Increased uterine bleeding4	Priapism5, Penile haemorrhage, Haematospermia		Prolonged erections
General disorders and administration site conditions
	Facial   oedema, Chest pain2

Description of selected adverse reactions

1.      Events not reported in registration studies 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 study 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 hemorrhage.

5.      The adverse reactions have been included in the table as a result of postmarketing or clinical study 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 a pivotal placebo- controlled study of tadalafil.

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.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

To report any side effect(s):

•          Saudi Arabia:

-      The National Pharmacovigilance Centre (NPC) o  Fax: +966-11-205-7662 o  SFDA Call Center: 19999 o  E-mail: npc.drug@sfda.gov.sa o  Website: https://ade.sfda.gov.sa

•          Other GCC States:

Please contact the relevant competent authority.

Single doses of up to 500mg have been given to healthy subjects, and multiple daily doses up to 100mg 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. Hemodialysis contributes negligibly to tadalafil elimination.

Pharmacotherapeutic group: Urologicals, ATC code: G04BE08.

Mechanism of action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Pulmonary arterial hypertension

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 (PAH)

A randomized, double-blind, placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension. Allowed background therapy included bosentan (stable maintenance dose up to 125 mg twice daily) and chronic anticoagulation, digoxin, diuretics and oxygen. More than half (53.3%) of the patients in the study were receiving concomitant bosentan therapy.

Patients were randomized to one of five treatment groups (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or placebo). Patients were at least 12 years of age and had a diagnosis of PAH that was idiopathic, related to collagen disease, related to anorexigen use, related to human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of at least 1 year in duration of a congenital systemic-to-pulmonary shunt (for example, ventricular septal defect, patent ductus arteriosus). The mean age of all patients was 54 years (range 14 to 90 years) with the majority of patients being Caucasian (80.5 %) and female (78.3 %). Pulmonary arterial hypertension (PAH) etiologies were predominantly idiopathic PAH (61.0 %) and related to collagen vascular disease (23.5%). The majority of patients had a World Health Organization (WHO) Functional Class III (65.2 %) or II (32.1 %). The mean baseline 6-minute-walk-distance (6MWD) was 343.6 meters.

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance (6MWD). Only tadalafil 40 mg achieved the protocol defined level of significance with a placebo- adjusted median increase in 6MWD of 26 metres (p=0.0004; 95 % CI: 9.5, 44.0; Pre-specified Hodges-Lehman method) (mean 33 metres, 95 % CI: 15.2, 50.3). The improvement in walk distance was apparent from 8 weeks of treatment. Significant improvement (p<0.01) in the 6MWD was demonstrated at week 12 when the patients were asked to delay taking study medicinal product in order to reflect trough active substance concentration. Results were generally consistent in subgroups according to age, gender, PAH aetiology and baseline WHO functional class and 6MWD. The placebo-adjusted median increase in 6MWD was 17 metres (p=0.09; 95 % CI: : -7.1, 43.0; Pre- specified Hodges-Lehman method) (mean 23 metres, 95 % CI; -2.4, 47.8) in those patients who received tadalafil 40 mg in addition to their concomitant bosentan (n=39), and was 39 metres (p<0.01, 95 % CI:13.0, 66.0; Pre-specified Hodges-Lehman method) (mean 44 metres, 95 % CI: 19.7, 69.0) in those patients who received tadalafil 40 mg alone (n=37).

The proportion of patients with improvement in WHO functional class by week 16 was similar in the tadalafil 40 mg and placebo groups (23 % vs. 21 %). The incidence of clinical worsening by week 16 in patients treated with tadalafil 40 mg (5 %; 4 of 79 patients) was less than placebo (16 %; 13 of 82 patients). Changes in the Borg dyspnoea score were small and non-significant with both placebo and tadalafil 40 mg.

Additionally, improvements compared to placebo were observed with tadalafil 40 mg in the physical functioning, role-physical, bodily pain, general health, vitality and social functioning domains of the SF-36. No improvements were observed in the role emotional and mental health domains of the SF-36. Improvements compared to placebo were observed with tadalafil 40 mg in the EuroQol (EQ-5D) US and UK index scores comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression components, and in the visual analogue scale (VAS).

Cardiopulmonary hemodynamics was performed in 93 patients. Tadalafil 40 mg increased cardiac output (0.6 L/min) and reduced pulmonary artery pressures (-4.3 mmHg) and pulmonary vascular resistance (-209 dyn.s/cm5) compared to baseline (p<0.05). However, post hoc analyses demonstrated that changes from baseline in cardiopulmonary hemodynamic parameters for the tadalafil 40 mg treatment group were not significantly different compared to placebo.

Erectile dysfunction

Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to tadalafil 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.

In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo.

Tadalafil at doses of 2 to 100mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that tadalafil improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking tadalafil (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in tadalafil-treated patients as compared to 32% with placebo.

Long-term treatment

357 patients from the placebo-controlled study entered a long-term extension study. Of these, 311 patients had been treated with tadalafil for at least 6 months and 293 for 1 year (median exposure 365 days; range 2 days to 415 days). For those patients for which there are data, the survival rate at 1 year is 96.4 %. Additionally, 6-minute walk distance and WHO functional class status appeared to be stable in those treated with tadalafil for 1 year.

Tadalafil 20 mg administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6mmHg, respectively), and no significant change in heart rate.

In a study to assess the effects of tadalafil on vision, no impairment of color 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 color vision were rare (<0.1%).

Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters, such as motility, morphology, and FSH.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the pediatric population in the treatment of pulmonary arterial hypertension. See section 4.2 for information on pediatric use.

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 it 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 77 liters 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

Tadalafil is predominantly metabolized 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 3.4 l/h at steady state and the mean half-life is 16 hours in healthy subjects.

Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Linearity/non-linearity

Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5mg to 20mg, exposure (AUC) increases proportionally with dose. Between 20 mg to 40 mg, a less than proportional increase in exposure is observed. During tadalafil 20 mg and 40 mg once daily dosing, steady-state plasma concentrations are attained within 5 days of once daily dosing and exposure is approximately 1.5 fold of that after a single dose.

Population pharmacokinetics

In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26 % higher when compared to those of healthy volunteers. There were no clinically relevant differences in Cmax compared to healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.

Special Populations

Elderly

Healthy elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.

Renal Insufficiency

In clinical pharmacology studies using single dose tadalafil (5mg-20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In hemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Hemodialysis contributes negligibly to tadalafil elimination. Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.

Hepatic Insufficiency

Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10mg is administered.

There is limited clinical data on the safety of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). If FONTAX is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If FONTAX is prescribed once-a-day, a careful individual benefit/risk evaluation 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 in these patients is not recommended.

Patients with Diabetes

Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.

Race

Pharmacokinetic studies have included subjects and patients from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.

Gender

In healthy female and male subjects following single and multiple doses of tadalafil, no clinically relevant differences in exposure were observed. No dose adjustment is warranted.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20mg dose.

There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.

Tablet Core:

·   Lactose monohydrate (Spray Dried),

·   Lactose monohydrate,

·   Hydroxypropylcellulose,

·   Croscarmellose sodium,

·   Sodium laurilsulphate,

·   Cellulose microcrystalline,

·   Magnesium stearate,

·   Purified water

Film coating

·   Hypromellose

·   Lactose monohydrate

·   Triacetin

·   Titanium dioxide (E171)

·   Talc

·   Purified water

•          FONTAX 5mg: iron oxide red (E172)

Not applicable.

Fontax 5 mg: 48 months.

     Keep this medicine out of the sight and reach of children and in original packages

     Do not store above 30°C

     Do not use this medicine after the expiry date which is stated on the carton and blister after ‘EXP’.   The expiry date refers to the last day of that month.

     Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Fontax 5 mg: PVC/PE/PVDC-Alu blister packs each containing 30 tablets.

No special requirements.