New Medicines Committee Briefing: Avanafil July 2015

New Medicines Committee Briefing July 2015 Avanafil (Spedra®) 50mg, 100mg and 200mg oral tablets for treatment of in adult males.

Avanafil® is to be reviewed for use Primary Care  within: Secondary Care 

Summary:  Avanafil (Spedra®) is an oral PDE5 inhibitor for erectile dysfunction  There is currently no oral alternative to listed in the Joint Formulary  Avanafil would provide an alternative to sildenafil and could be used for patients who fail first line sildenafil  There are no head to head trials of avanafil vs alternative PDE5 inhibitor; meta analyses provide some evidence that avanafil is likely to be as effective as other PDE5 inhibitors  Avanafil has a 15 minute onset of action compared to sildenafil’s 1 hour onset  Department of Health restrictions on prescribing will limit the use of avanafil to certain patient groups and/or specialist clinics  Avanafil is significantly more expensive than generic sildenafil (e.g. £3.52 vs 29p per dose at typical treatment dosage) and similarly priced to other branded PDE5 inhibitors.

Formulary application

Consultant submitting application: Mr Samson Liu (Consultant Urological Surgeon)

Supported by: Mr A Golash, Mr L Gommersall, Mr C Luscombe, Mr Mark Saxby, Mr H Fernando, Mr RL James and Mr YR Rao (Consultant Urological Surgeons) with Mr H Nair (Associate Specialist in Urology) and Dr VS Chadalavada (Clinical Assistant in Urology)

Clinical Director supporting application: Miss A Walsh

(Clinical Director for General Surgery and Urology)

The application is a request for avanafil to be considered for inclusion in the North Staffordshire Joint Formulary for the treatment of erectile dysfunction in adult males.

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In support, the applicant states that avanafil is well suited for the on demand treatment of mild to severe erectile dysfunction and:  is effective in men with erectile dysfunction, including those with diabetes and nerve sparing radical prostatectomy  has been shown to be generally well tolerated over 52 weeks  demonstrates long term tolerability and improvement in sexual function and  has rapid onset of action Mr Liu estimates that 200 new patients will be treated per year with avanafil at a cost of £167.28 per patient and that the treatment will be long term. Avanafil provides a second line option for patients who have failed sildenafil. The application states that the new drug cost will be accompanied by a reduction in the use of currently prescribed PDE5 inhibitor erectile dysfunction drugs – ether generic sildenafil or nonformulary and . Background Erectile dysfunction (ED) is defined as the consistent or recurrent inability to achieve and/or maintain an erection sufficient to permit satisfactory sexual performance. Normal erectile function requires the coordination of psychological, hormonal, neurological, vascular and anatomic factors. Alteration of any of these is sufficient to cause ED. The main causes of ED are chronic systemic illnesses (diabetes mellitus, heart disease, hypertension and peripheral vascular disease), neurological disorders (post- traumatic spinal-cord injuries, multiple sclerosis) or post-surgical lesions (after radical prostatectomy)1. The European guidelines on male sexual dysfunction2 advise that first‑line therapy is usually oral treatment with selective type 5 (PDE5) inhibitors (e.g. sildenafil). NICE guidelines on multiple sclerosis3, type 1 diabetes4, type 2 diabetes5 and myocardial infarction6 advise that men with erectile dysfunction should be offered PDE5 inhibitors. Men with prostate cancer should have early and ongoing access to specialist erectile dysfunction services7. The majority of drug treatments for erectile dysfunction may only be prescribed on the NHS under certain circumstances. In addition, the Department of Health recommends that treatment should also be available from specialist services when the condition is causing severe distress. Following a consultation, in June 20148, the Department of Health has amended the regulations to allow unrestricted prescribing of generic sildenafil for men with erectile dysfunction. Avanafil has been added to the list of treatments for erectile dysfunction that are still restricted including tadalafil, vardenafil, branded sildenafil and alprostadil. Avanafil (brand name Spedra®), a new PDE5 inhibitor, is licensed for the treatment of erectile dysfunction in adult men9. The product received a European Marketing Authorisation for the treatment of erectile dysfunction in adult men in June 2013 and was launched in the UK in March 2014. Current formulary status Avanafil is not listed in the current North Staffordshire Joint Formulary. The drugs listed for erectile dysfunction are listed in the table, below (colour codes added in text) 7.4.5 Drugs for erectile dysfunction Alprostadil (Caverject®) Green  MTRAC Alprostadil (MUSE®) Green  MTRAC Green Sildenafil Green  MTRAC

Therapeutic class and mode of action9 Avanafil is a highly selective and potent, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by avanafil produces increased levels of cGMP in the corpus cavernosum of

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the penis. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Licensed indication Treatment of erectile dysfunction in adult men. In order for Spedra® (avanafil) to be effective, sexual stimulation is required. Dosage and administration The recommended dose is 100 mg taken as needed approximately 15 to 30 minutes before sexual activity. Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment. Avanafil has not been evaluated in patients with erectile dysfunction due to spinal cord injury or other neurological disorders and in subjects with severe renal or hepatic impairment. Safety and adverse effects9 Contraindications Hypersensitivity to the active substance or to any of the excipients The use of avanafil is contraindicated in:  Patients who are using any form of organic nitrate or nitric oxide donors (such as amyl nitrite)  Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;  Patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood pressure > 170/100 mmHg);  Patients with unstable angina, angina with sexual intercourse, or congestive heart failure categorised as New York Heart Association Class 2 or greater.  Patients with severe hepatic impairment (Child-Pugh C).  Patients with severe renal impairment (creatinine clearance < 30 mL/min).  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 type 5 phosphodiesterase (PDE5) inhibitor exposure.  Patients with known hereditary degenerative retinal disorders.  Patients who are using potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease before prescribing avanafil. Adverse Events The safety profile of avanafil is based on 2436 subjects exposed to avanafil during the clinical development program. The most common adverse reactions reported in clinical studies were headache, flushing, nasal and sinus congestion and back pain (≥ 1/100 to < 1/10). Overall adverse events and adverse reactions for avanafil-treated subjects were more frequent in subjects with a Body Mass Index (BMI) <25 (normal BMI subjects). In the long term clinical study, the percentage of patients who experienced adverse reactions decreased with increasing length of exposure.

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Drug Interactions Potential for pharmacodynamic interactions with avanafil Nitrates - administration with any form of organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. Alpha-blockers - in patients receiving stable doxazosin treatment, mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing were 2.5 mmHg and 6.0 mmHg, respectively. In patients receiving stable tamsulosin treatment, mean maximum decreases in standing and supine systolic blood pressure following avanafil dosing were 3.6 mmHg and 3.1 mmHg, respectively Antihypertensives other than alpha-blockers - mean maximum decrease in supine blood pressure of 2/3 mmHg with enalapril and 1/-1 mmHg with amlodipine. Amlodipine increases the maximum and total exposure of avanafil by 28% and 60%, respectively. Alcohol - concurrent use of avanafil and alcohol may increase the likelihood of hypotension, dizziness, or syncope. The safety and efficacy of combinations of avanafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Effects of other substances on avanafil Avanafil is a substrate of and predominantly metabolised by CYP3A4. CYP3A4 Inhibitors - co-administration of avanafil with potent CYP3A4 inhibitors is contraindicated – e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, nefazadone, saquinavir, nelfinavir, indinavir, atanazavir, and telithromycin Moderate CYP3A4 inhibitors - e.g. erythromycin amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil - the maximum recommended dose of avanafil is 100 mg, not to exceed once every 48 hours. Patients should be advised to avoid grapefruit juice within 24 hours prior to taking avanafil. CYP3A4 substrates - e.g. amlodipine, rivaroxabin and apixiban - a clinically significant interaction is not expected Cytochrome P450 Inducers - concomitant use of CYP inducers, especially inducers of CYP3A4 (e.g. bosentan, carbamazepine, efavirenz, phenobarbital and rifampin) is not recommended as it may decrease the efficacy of avanafil although this has not been evaluated. Effects of avanafil on other medicinal products Cytochrome P450 Inhibition - negligible potential for drug-drug interactions including metabolites of avanafil, no clinically relevant interactions with omeprazole, rosiglitazone and desipramine Cytochrome P450 Induction - in vitro studies did not reveal any potential interaction at clinically relevant interactions. Transporters - avanafil has a modest potential for acting as P-gp substrate and P-gp inhibitor – relevant for digoxin but only tested in vitro as interaction potential was felt to be remote by the CHMP who did not require in vivo testing10. Presentation9 50 mg tablets: PVC/PCTFE/Aluminium blisters in cartons of 4, 8 and 12 tablets. 100 mg tablets: PVC/PCTFE/Aluminium blisters in cartons of 2, 4, 8 and 12 tablets. 200 mg tablets: PVC/PCTFE/Aluminium blisters in cartons of 4, 8 and 12 tablets. This medicinal product does not require any special storage conditions.

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Guidance and Evidence Summary

NICE Guidance published NO NICE Advice published YES NICE advice [ESNM45] Erectile dysfunction: avanafil11 Published date: August 2014 NICE advice is not NICE Guidance: it reviews the strengths and weaknesses of the relevant evidence to provide useful information for those working on the managed entry of new medicines for the NHS. Summary of NICE advice [ESNM45] Erectile dysfunction: avanafil Efficacy This evidence summary is based on 4 phase III studies that have evaluated the efficacy and safety of avanafil in men with erectile dysfunction. Three of the studies are double-blind, RCTs of 12 weeks' duration (1 in a general population with erectile dysfunction [without diabetes or post-prostatectomy12, n=646]; 1 in men with type 1 or type 2 diabetes13, (n=390) and 1 in men with erectile dysfunction following bilateral nerve-sparing radical prostatectomy14, n=298]. Men were instructed to take placebo or avanafil 50 mg (Goldstein et al. 2012a12 only), 100 mg or 200 mg as needed approximately 30 minutes before initiation of sexual activity. In addition, 712 men from 2 of the RCTs12,13 enrolled in a 52-week open-label extension study15. All men were initially assigned to avanafil 100 mg but could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. Overall, in the 3 RCTs, compared with placebo, avanafil 50 mg, 100 mg and 200 mg statistically significantly improved all 3 co-primary outcomes (percentage of sexual attempts in which an erection of sufficient duration was maintained to enable successful intercourse; percentage of sexual attempts in which vaginal penetration was achieved; and International Index of Erectile Function16 erectile function domain scores). Avanafil 100 mg and 200 mg were statistically significantly better than avanafil 50 mg12 but there were no significant differences between avanafil 100 mg and 200 mg12,13; comparison not reported in Mulhall et al. 201314. The 3 RCTs are placebo-controlled and it is not known how avanafil compares to other PDE5 inhibitors. Limitations of the open-label extension study include the lack of a comparator and blinding, and the possibility that responders to avanafil in the qualifying studies may have been more likely to enrol than non-responders, potentially over estimating the benefits of avanafil. The open-label long-term extension study suggests that the effects of avanafil are maintained for up to 52 weeks. In this study, about two-thirds of men responded to avanafil 100 mg and, of those who did not, a further two-thirds responded to 200 mg. However, only 24.0% of men remained on the 100 mg dose, with 75.3% of men voluntarily increasing their dose to 200mg17. Safety From the studies, the overall safety profile of avanafil appears to be similar to that of other PDE5 inhibitors and no new safety concerns have been raised. The majority of adverse events seen were mild‑moderate in severity and resulted in infrequent discontinuations (2.8% with avanafil 100 mg17). However, it is not known how the efficacy, tolerability and safety of avanafil compare with the other PDE5 inhibitors sildenafil, tadalafil and vardenafil.

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The safety and efficacy results are summarised, in the table, below

Efficacy Safety  The mean percentage of attempts resulting in  Across the 3 RCTs, adverse events were reported successful intercourse was: in around 30−40% taking avanafil and around 25% of men taking placebo (no statistical o 41.3%, 57.1%, and 57.0% for avanafil 50 mg, analyses reported). 100 mg, and 200 mg respectively in the general population with erectile  The summary of product characteristics9 states dysfunction, compared with 27.0% for that the most common adverse events reported placebo (all p≤0.000212). in clinical studies (n=2144) were headache, flushing, nasal and sinus congestion (all with an o 34.4% and 40.0% for avanafil 100 mg and incidence of between 1 in 10 and 1 in 100), and 200 mg respectively in men with diabetes back pain (incidence between 1 in 100 and (89.5% type 2), compared with 20.5% for 1 in 1000). placebo (both p<0.000113).  Men should be aware of how they react to o 23.4% and 26.4% for avanafil 100 mg and avanafil before driving or using machines 200 mg respectively in men post- because dizziness, somnolence and altered prostatectomy, compared with 8.9% for vision were reported in clinical studies placebo (both p≤0.000414). (incidence ≥ 1/1000 to < 1/100).  There are no direct head-to-head comparisons of PDE5 inhibitors and indirect comparisons are limited by differences in study design  According to European guidelines on male sexual dysfunction16, erections sufficient for intercourse have been reported in 60−80% of men taking sildenafil, tadalafil and vardenafil.

Meta-analyses Yuan et al18 performed a systematic literature review and network meta-analysis of PDE5 inhibitors versus placebo as treatments for erectile dysfunction. Of the 118 studies included, there were two avanafil trials. Using the self-administered Global Assessment Questionnaire, avanafil was reported as less effective based on question 1 (while using the study medication, did you feel that your erections improved?) as compared to tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI]: 0.33–0.9) and vardenafil (RR: 0.63; 95% CI: 0.35–0.92). For all efficacy outcomes, the absolute effects and rank tests indicated that tadalafil and vardenafil were the most effective agents. Wang et al19 published a systematic review and meta-analysis to compare the effectiveness and safety among different dosages of avanafil for the treatment of erectile dysfunction, comparing against placebo. Results from the meta analyses were summarised by the All Wales Medicines Strategy Group in their assessment report20 and are presented in the table, below. SEP3, mean SEP2, mean IIEF-EF domain score, difference from difference from mean difference from baseline (95% CI) baseline (95% CI) baseline (95% CI) Sildenafil 17.3 (5.9–28.6) 8.7 (1.9–15.5) 6.0 (5.3–6.7) Tadalafil 36.2 (31.9–39.9) 27.7 (24.1–31.4) 7.5 (6.6–8.3) Vardenafil 36.3 (4.0–41.3) 27.4 (23.3–31.5) 7.1 (6.0–8.2) Avanafil 22.8 (16.5–28.9) 20.7 (15.2–25.9) 5.2 (3.9–6.5) IIEF-EF: International Index of Erectile Function-Erectile Function; SEP3: percentage of sexual attempts in which an erection of sufficient duration was maintained to enable successful intercourse; SEP2: percentage of sexual attempts in which vaginal penetration was achieved

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Considerations European guidelines2 advise that the choice of PDE5 inhibitor depends on the frequency of intercourse and the man's personal experience of these drugs, avanafil has similar contraindications, cautions and interactions to other PDE5 inhibitors9. Avanafil, tadalafil, sildenafil and vardenafil are taken on-demand. At lower doses, tadalafil is also licensed to be taken daily. According to the summaries of product characteristics, sildenafil should be taken 1 hour before sexual activity, whereas tadalafil and vardenafil should be taken 25−30 minutes before sexual activity. Since the publication from NICE, the licence for avanafil states that it should be taken 15 to 30 minutes before sexual activity. SMC recommended use within NHS Scotland NO On 9 May 2014 did not recommend as “The holder of the marketing authorisation has not made a submission”21 The SMC will be reviewing a fill submission on 4 August and will provide advice on 7 September 201522 All Wales Medicines Strategy Group (AWSG) NO Currently under review; the AWMSG met on 17 June 201523 Regional Drug and Therapeutic Centre (RDTC): NO Not reviewed MTRAC24 YES Category B: suitable for restricted prescribing under defined conditions Avanafil is suitable for prescribing in Primary Care under the restrictions imposed by the Department of Health for the funding of drugs for erectile dysfunction. Cochrane Review: NO Not reviewed Cost analysis: Costs When usual starting doses are considered, avanafil costs significantly more than generic sildenafil. See table, below for comparative costs of ‘on demand’ drugs in same class.

Drug BNF cost1 Cost per dose Avanafil 50mg 4 tablets £10.94 £2.74 Avanafil 100mg 4 tablets £14.08 £3.52 Avanafil 200mg 4 tablets £21.90 £5.48 Sildenafil 25 mg 4 tablets £1.09 £0.27 Viagra 25 mg 4 tablets £14.08 £3.52 Sildenafil 50 mg 4 tablets £1.15 £0.29 Viagra 50 mg 4 tablets £21.27 £5.32 Sildenafil 100 mg 4 tablets £1.23 £0.31 Viagra 100 mg 4 tablets £23.50 £5.88 Tadalafil 10mg 4 tablets £26.99 £6.75

1 All prices taken from BNF June 2015

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Drug BNF cost1 Cost per dose Tadalafil 20mg 4 tablets £26.99 £6.75 Vardenafil 5 mg 4 tablets £7.56 £1.89 Vardenafil 10 mg 4 tablets £14.08 £3.52 Vardenafil 20 mg 4 tablets £23.48 £5.87

The Department of Health has amended regulations25 to allow unrestricted prescribing of generic sildenafil for men with erectile dysfunction. Avanafil tadalafil, vardenafil, branded sildenafil and alprostadil may only be prescribed on the NHS to patients who are suffering from any of the following conditions26:  diabetes  multiple sclerosis  Parkinson’s disease  poliomyelitis  prostate cancer  severe pelvic injury  single gene neurological disease  spina bifida  spinal cord injury  renal failure treated by dialysis or transplant  have had prostatectomy  have had radical pelvic surgery Additionally, patients were receiving NHS prescriptions for one of these drugs on 14th September 1998 are eligible for continued use of the drug. Additionally, men who are not eligible for NHS prescriptions of drugs for erectile dysfunction from their GP can receive treatment from specialist services where their impotence is causing severe psychological distress27. It is recommended that the following criteria be taken into account –  significant disruption to normal social and occupational activity  marked effect on mood, behaviour, social and environmental awareness  marked effect on interpersonal relationships Specialist services should operate their usual arrangements for prescribing and dispensing these treatments, which should be on a hospital prescription form or form FP10(HP), which can be dispensed at a community pharmacy. Men in this category who are prescribed treatment for impotence on the NHS should continue to receive their treatment through the specialist services. Arrangements should be made for men to receive repeat prescriptions from the specialist service; this may or may not involve an outpatient appointment. GPs may not issue ongoing prescriptions.

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Avanafil (Spedra®) NMC Review July 2015: Usage and Expenditure for May14-Apr15

Expenditure for May14-Apr15:

NORTH UHNS Acute STOKE ON Brand Name Medicine Description STAFFORDSHIRE TRENT CCG Trust TOTAL CCG

Spedra® Avanafil Tab 50mg £0.00 £18.19 £30.35 Spedra® Avanafil Tab 100mg £24.32 £216.32 £52.14 Spedra® Avanafil Tab 200mg £0.00 £40.47 £40.56 Viagra®/Generic Sildenafil Tab 25mg £1.95 £565.39 £1,165.80 Viagra®/Generic Sildenafil Tab 50mg £1.05 £4,671.12 £6,037.07 Viagra®/Generic Sildenafil Tab 100mg £0.00 £11,797.36 £12,559.31 Viagra®/Generic Sildenafil Chewable Tab 25mg £0.00 £0.98 £5.84 Viagra®/Generic Sildenafil Chewable Tab 50mg £0.00 £1.93 £37.69 Viagra®/Generic Sildenafil Chewable Tab 100mg £0.00 £2.07 £16.73 Viagra®/Generic Sildenafil Oral Soln/Susp 10mg/5ml £0.00 £717.38 £525.50 Viagra®/Generic Sildenafil Oral Soln/Susp 25mg/5ml £0.00 £4,089.29 £5,633.11 Cialis® Tadalafil Tab 2.5mg £0.00 £3,791.20 £5,306.76 Cialis® Tadalafil Tab 5mg £212.88 £33,128.04 £32,596.06 Cialis® Tadalafil Tab 10mg £43.78 £24,393.76 £37,817.66 Cialis® Tadalafil Tab 20mg £0.00 £68,848.10 £64,181.28 Levitra® Vardenafil Tab 5mg £0.00 £713.03 £252.28 Levitra® Vardenafil Tab 10mg £0.00 £2,525.68 £3,535.61 Levitra® Vardenafil Tab 20mg £0.00 £9,725.04 £15,434.81 Levitra® Vardenafil Orodisper Tab 10mg S/F £0.00 £33.07 £181.88 TOTAL £283.98 £165,278.42 £185,410.44

References

1 Extract from Spedra : EPAR - Public assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Public_assessment_report/human/002581/WC500145207.pdf 2 http://uroweb.org/guideline/male-sexual-dysfunction/# 3 NICE clinical guideline 8 http://www.nice.org.uk/Guidance/cg8 4 NICE clinical guideline 15 http://www.nice.org.uk/Guidance/cg15 5 NICE clinical guideline 87 http://www.nice.org.uk/Guidance/cg87 6 NICE clinical guideline 172 http://www.nice.org.uk/Guidance/cg172 7 NICE clinical guideline 175 http://www.nice.org.uk/guidance/CG175 8 SI 2014 No. 1625 The National Health Service (General Medical Services Contracts) (Prescription of Drugs etc.) (Amendment) Regulations 2014 9 SMPC for Avanafil (Spedra) https://www.medicines.org.uk/emc/medicine/28729

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10 CHMP Assessment report, p55 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Public_assessment_report/human/002581/WC500145207.pdf 11 NICE advice [ESNM45] Erectile dysfunction: avanafil http://www.nice.org.uk/advice/esnm45/chapter/Key- points-from-the-evidence 12 http://onlinelibrary.wiley.com/doi/10.1111/j.1743- 6109.2011.02629.x/abstract;jsessionid=E99274BF512CB013D31C22A86FD26198.f04t03 13 http://www.mayoclinicproceedings.org/article/S0025-6196(12)00668-4/abstract 14 http://www.jurology.com/article/S0022-5347(12)05809-0/abstract 15 http://onlinelibrary.wiley.com/doi/10.1111/ijcp.12065/abstract 16 http://www.ncbi.nlm.nih.gov/books/NBK38717/#B172635 17 http://onlinelibrary.wiley.com/doi/10.1111/j.1743- 6109.2011.02629.x/abstract;jsessionid=E99274BF512CB013D31C22A86FD26198.f04t03 18 Yuan J, Zhang R, Yang Z et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. European Urology 2013; 63 (2): 902-12 19 Wang H, Yuan J, Hu X et al. The effectiveness and safety of avanafil for erectile dysfunction: a systematic review and meta-analysis. Current Medical Research & Opinion 2014; 30 (8): 1565-71 20 http://www.awmsg.org/awmsgonline/grabber?resId=File%2F1779 21 https://www.scottishmedicines.org.uk/files/advice/M__Scottish_Medicine_Consortium_Web_Data_Audit_advic e_Advice_by_Year_2014_No.6_- _June_2014_avanafil__Spedra__Non_Submission_FINAL_May_2014_for_website.pdf 22 https://www.scottishmedicines.org.uk/SMC_Advice/Forthcoming_Submissions/avanafil_Spedra 23 http://www.awmsg.org/awmsgonline/app/appraisalinfo/1261 24 http://centreformedicinesoptimisation.co.uk/download/09a8d8c94c0817f50c705bda112e8401/Avanafil- update-summary-August-2014.pdf 25 http://www.legislation.gov.uk/uksi/2014/1625/contents/made 26 Schedule 2 of the National Health Service (General Medical Services Contracts) (Prescription of Drugs etc.) Regulations 2004 27 Health Service Circular 1999/177. Treatment for impotence, patients with severe distress

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