Public Assessment Report Decentralised Procedure - …

1 PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5; UK/H/4673/001-3/DC 1 Public Assessment Report Decentralised Procedure Sildenafil 25 mg film -coated tablets Sildenafil 50 mg film -coated Tablets Sildenafil 100 mg film -coated tablets UK/H/4673/001-3/DC UK licence numbers: PL 34771/0143-5 Macleods Pharma UK Limited PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5; UK/H/4673/001-3/DC 2 LAY SUMMARY On 02 July 2012, the MHRA granted Macleods Pharma UK Limited Marketing Authorisations (licences) for the medicinal products, Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets (PL 34771/0143-5). These are prescription-only medicines (POM). Sildenafil belongs to a group of medicines called phosphodiesterase type 5 (PDE5) inhibitors. It works by helping to relax the blood vessels in your penis, allowing blood to flow into your penis when you get sexually excited.

2 Sildenafil will only help you to get an erection if you are sexually stimulated. You should not take sildenafil if you do not have erectile dysfunction. You should not take sildenafil if you are a woman. Sildenafil is a treatment for men with erectile dysfunction, which is also sometimes known as impotence. This is when a man cannot get, or keep a hard, erect penis suitable for sexual activity. Based on the data submitted by Macleods Pharma UK Limited, Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets were considered to be generic versions of the innovator products, Viagra 25 mg, 50 mg and 100 mg film -coated tablets (Pfizer Limited). No new or unexpected safety concerns arose from these applications. It was judged that the benefits of Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets outweigh the risks; hence Marketing Authorisations have been granted. PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5.

3 UK/H/4673/001-3/DC 3 TABLE OF CONTENTS Module 1: Information about initial Procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 14 Module 4: Labelling Page 16 Module 5: Scientific discussion during initial Procedure Page 22 I Introduction Page 22 II About the product Page 24 III Scientific Overview and discussion Page 25 Quality aspects Page 25 Non-clinical aspects Page

4 29 Clinical aspects Page 29 IV Overall conclusions and benefit-risk Assessment Page 33 Module 6: Steps taken after initial Procedure Page 34 PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5; UK/H/4673/001-3/DC 4 Module 1 Information about Initial Procedure Product Name Sildenafil 25 mg film -coated tablets Sildenafil 50 mg film -coated tablets Sildenafil 100 mg film -coated tablets Type of Application Generic, Article 10(1) Active Substance Sildenafil (as sildenafil citrate) Form film -coated tablets Strength 25 mg, 50 mg, 100 mg MA Holder Macleods Pharma UK Limited Golden Gate Lodge, Crewe Hall, Crewe, Cheshire, CW1 6UL, United Kingdom Reference Member State (RMS) UK Concerned Member States (CMS) Germany, Hungary, Italy, Poland, Romania, Spain Procedure Number UK/H/4673/001-3/DC Timetable End of Procedure : Day 210 10 May 2012 PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5.

5 UK/H/4673/001-3/DC 5 Module 2 Summary of Product Characteristics The UK Summary of Product Characteristics (SmPC) for Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets (PL 34771/0143-5) is as follows. Differences between the individual SmPCs are highlighted: 1 NAME OF THE MEDICINAL PRODUCT Sildenafil 25 mg film -coated tablets Sildenafil 50 mg film -coated tablets Sildenafil 100 mg film -coated tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each film -coated tablet contains sildenafil citrate equivalent to 25/50/100 mg of sildenafil. For a full list of excipients, see Section 3 PHARMACEUTICAL FORM film -coated tablet. Blue coloured, diamond shaped, film coated tablets debossed with CL 35/36/37 on one side and plain on the other side. 4 CLINICAL PARTICULARS Therapeutic indications Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.

6 In order for Sildenafil film -coated Tablets to be effective, sexual stimulation is required. Posology and method of administration For oral use. Use in adults The recommended dose is 50mg taken as needed approximately one hour before sexual activity. Based on efficacy and toleration, the dose may be increased to 100mg or decreased to 25mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day. If Sildenafil film -coated Tablets is taken with food, the onset of activity may be delayed compared to the fasted state (see Section ). Use in the elderly Dosage adjustments are not required in elderly patients. Use in patients with impaired renal function The dosing recommendations described in Use in adults apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min). Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min) a 25mg dose should be considered.

7 Based on efficacy and toleration, the dose may be increased to 50mg and 100mg. Use in patients with impaired hepatic function Since sildenafil clearance is reduced in patients with hepatic impairment ( cirrhosis) a 25mg dose should be considered. Based on efficacy and toleration, the dose may be increased to 50mg and 100mg. Use in children and adolescents Sildenafil film -coated Tablets is not indicated for individuals below 18 years of age. PAR Sildenafil 25 mg, 50 mg and 100 mg film -coated tablets PL 34771/0143-5; UK/H/4673/001-3/DC 6 Use in patients using other medicines With the exception of ritonavir for which co-administration with sildenafil is not advised (see Section ) a starting dose of 25mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see Section ). In order to minimise the potential for developing postural hypotension, patients should be stable on alpha-blocker therapy prior to initiating sildenafil treatment.

8 In addition, initiation of sildenafil at a dose of 25 mg should be considered (see Sections and ). Contraindications Hypersensitivity to the active substance or to any of the excipients. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway (see Section ), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable ( patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure). Sildenafil film -coated Tablets 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 ).

9 The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure < 90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases). Special warnings and precautions for use 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. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see Section ).

10 Prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction ( , aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure. Sildenafil film -coated Tablets potentiates the hypotensive effect of nitrates (see Section ). Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of Sildenafil film -coated Tablets.