New Medicines Committee Briefing: Avanafil July 2015 New Medicines Committee Briefing July 2015 Avanafil (Spedra®) 50mg, 100mg and 200mg oral tablets for treatment of erectile dysfunction 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 sildenafil 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. Page 1 of 10 Written by David Prayle New Medicines Committee Briefing: Avanafil July 2015 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 tadalafil and vardenafil. 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 phosphodiesterase 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 Apomorphine 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 Page 2 of 10 Written by David Prayle New Medicines Committee Briefing: Avanafil July 2015 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. Page 3 of 10 Written by David Prayle New Medicines Committee Briefing: Avanafil July 2015 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