EDYSTA

Edysta®(Tadalafil)

Presentation

Edysta 5 tablet : Orange, round shaped, film coated tablet; each tablet contains Tadalafil INN5mg.

Edysta 10 tablet : Yellow, diamond shaped, film coated tablet; each tablet contains Tadalafil INN10mg.

Edysta 20 tablet : Orange, diamond shaped, film coated tablet; each tablet contains Tadalafil INN20mg.

Indications

Edysta is a phosphodiesterase type 5 (PDE5) inhibitor indicated for the treatment of:

• erectile dysfunction (ED)

• the signs and symptoms of benign prostatic hyperplasia (BPH)

• ED and the signs and symptoms of BPH (ED/BPH) Dosage and administration Edysta for use as needed:

• ED: Starting dose: 10mg (one Edysta 10 tablet) as needed prior to sexual activity. Increase to 20mg (one Edysta 20 tablet) or decrease to 5mg (one Edysta 5 tablet) based upon efficacy/tolerability. Improves erectile function compared to placebo up to 36 hours post dose. Not to be taken more than once per day. Edysta for once daily use:

• ED: 2.5mg taken once daily, without regard to timing of sexual activity. May increase to 5mg (one Edysta 5 tablet) based upon efficacy and tolerability.

• BPH: 5mg (one Edysta 5 tablet), taken at approximately the same time every day.

• ED and BPH: 5mg (one Edysta 5 tablet), taken at approximately the same time every day. Edysta may be taken without regard to food.

Use in Elderly Men: Dose adjustments are not required in elderly patients. Use in Men with Impaired Renal Function: Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10mg is the maximum recommended dose. Once-a-day dosing of Tadalafil is not recommended in patients with severe renal impairment. Use in Men with Impaired Hepatic Function: The recommended dose of Tadalafil is 10mg 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 10mg 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. Use in Men with Diabetes: Dose adjustments are not required in diabetic patients. Paediatric population: Tadalafil should not be used in individuals below 18 years of age.

Contra-indications, warnings, etc

Contra-indications: Tadalafil is contra-indicated in hypersensitivity to the active substance or to any of the excipients, patients who are using any form of organic nitrate, 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 contra-indicated:

• 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 contra-indicated in patients who have loss of vision in one eye because of nonarteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. Precautions and warnings: Before treatment with Edysta: A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potentialunderlying 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, and as such potentiates the hypotensive effect of nitrates. 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 Edysta 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 ischaemic 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 Edysta, to sexual activity, or to a combination

of these or other factors. Tadalafil (2.5mg and 5mg) – In patients receiving concomitant antihypertensive medicines, 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 Edysta may lead to symptomatic hypotension in some patients. The combination of tadalafil and doxazosin is not recommended. Vision: Visual defects and cases

of NAION have been reported in connection with the intake of Edysta 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. 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 Edysta in patients with severe hepatic insufficiency (Child-Pugh class C). Once-a-day administration has not

been evaluated in patients with hepatic insufficiency. If Edysta 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. Edysta, 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 Edysta 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. Edysta and other treatments for erectile dysfunction: The safety and efficacy of combinations of Edysta and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take Edysta in such combinations. Lactose: Tadalafil contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Drug interactions: Interaction studies were conducted with 10mg and/or 20mg Tadalafil, as indicated below. With regard to 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: Tadalafil is principally metabolised 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. 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. The role of transporters (for example, p-glycoprotein) in the  disposition of tadalafil is not known. There is thus the potential of drug interactions mediated by inhibition of transporters. A CYP3A4 inducer, rifampicin, 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. Effects of Tadalafil on Other Medicinal Products: In clinical studies, tadalafil (5mg, 10mg and 20mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of Edysta to patients who are using any form of organic nitrate is contra-indicated. 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 Edysta (2.5mg – 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 Edysta before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.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. 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 agents was examined. Major classes of antihypertensive agents 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 medicines, tadalafil 20mg may induce a blood pressure decrease, which (with the exception of alpha-blockers) 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 medicines. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicines. 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 coadministering these medicines. 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 concentrations (mean maximum blood concentration 0.08%) were not affected by coadministration 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 maximise 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). 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. 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. Tadalafil (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid. Specific interaction studies with antidiabetic agents were not conducted. Use in pregnancy and lactation: Tadalafil is not indicated for use by women. 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. As a precautionary measure, it is preferable to avoid the use of Tadalafil during pregnancy. 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.

Effect on ability to drive and use machine: No studies of the effect on the ability to drive and use machines have been performed. 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 operating machinery.

Side effects: The most commonly reported adverse reactions were headache and dyspepsia. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age. The below lists the adverse reactions reported

in erectile dysfunction placebo-controlled clinical trials in patients treated with Edysta on demand and daily dosing with doses within the currently approved dosing range for Edysta. Adverse reactions that have been reported from post marketing surveillance in patients taking

Edysta are also included. Frequency convention: Very common (³1/10), Common (³1/100 to <1/10), Uncommon (³1/1000 to <1/100), Rare (³1/10,000 to <1/1000), Very Rare (<1/10,000) and Not known (cannot be estimated from the available data). Immune system disorders:

Uncommon: Hypersensitivity reactions, Rare: Angioedema. Nervous system disorders: Very common: Headache, Common: Dizziness, Rare: Stroke (including haemorrhagic events), syncope, transient ischaemic attacks, migraine, seizures, transient amnesia. Eye disorders: Uncommon: Blurred vision, sensations described as eye pain, Rare: Visual field defect, swelling of eyelids, Conjunctival hyperaemia, Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion. Ear and labyrinth disorders: Rare: Sudden hearing loss. Cardiac disorders: Uncommon: Tachycardia, palpitations, Rare: Myocardial infarction, unstable angina pectoris, ventricular arrhythmia. Vascular disorders: Common: Flushing, Uncommon: Hypotension, hypertension. Respiratory, thoracic and mediastinal disorders: Common: Nasal congestion, Uncommon: Dyspnoea, Rare: Epistaxis. Gastrointestinal disorders: Common: Dyspepsia, gastrooesophageal reflux, Uncommon: Abdominal pain. Skin and subcutaneous tissue disorders: Uncommon: Rash, hyperhydrosis (sweating), Rare: Urticaria, stevens-Johnson syndrome, exfoliative dermatitis. Musculoskeletal, connective tissue and bone disorders: Common: Back pain, myalgia. Reproductive system and breast disorders: Rare: Prolonged erections, priapism. General disorders and administration site conditions: Uncommon: Chest pain, Rare: Facial oedema, sudden cardiac death.

Overdose: Single doses of up to 500mg have been given to volunteer, 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.

Haemodialysis contributes negligibly to Tadalafil elimination.

Pharmaceutical precautions

Store in a cool and dry place protected from light.

Packaging quantities

Edysta 5 tablet : Cartons containing 10 tablets in blisters.

Edysta 10 tablet : Cartons containing 4 tablets in blisters.

Edysta 20 tablet : Cartons containing 4 tablets in blisters.