Testosterone: overlooked and undervalued?

A Trends supplement commissioned and sponsored by Ferring Pharmaceuticals Ltd (see back page) Prescribing information appears on pages 7 and 8 TESTOSTERONE: OVERLOOKED AND UNDERVALUED? 2

Introduction ROGER KIRBY treatment of many male disorders; however, Hence the need for this supplement, the benefts and risks of testosterone which contains sections on testosterone estosterone is a focal point of men’s replacement therapy (TRT) do need to be defciency syndrome (TDS) and erectile Thealth, but its importance is too carefully balanced, although worries about dysfunction (ED). Also discussed is the often underestimated. Testosterone is induction or progression of cancer importance of strict testosterone control responsible for all male characteristics, have now largely been allayed.1 and measurement in androgen deprivation and testosterone defciency results in therapy (ADT) for advanced hormone- hypogonadism, which has an impact on Unfortunately, the opportunity to detect dependent . It is in essence the entire male organism. Testosterone and correct testosterone defciency a call to action for clinicians to become also plays an important role in male is too often neglected. Measurement more aware of testosterone control, and ageing. Many diseases, especially mood of testosterone levels in the blood is to encourage them to measure serum disorders, cardiovascular disease and simple to do and hypogonadism is easy testosterone levels more regularly – to the metabolic syndrome, not to mention to treat; however, family practitioners look after the whole man, rather than just sexual dysfunction, can be caused or and urologists alike seem strangely his heart or his prostate, by managing exacerbated by testosterone defciency. reluctant to engage with this increasingly androgen levels as well as counselling him Testosterone is a key factor in the important component of men’s health. about a healthier lifestyle.

Authors Professor Roger Kirby, Consultant Urologist, Director of The Prostate Centre, Professor Geoffrey Hackett, Consultant in and Andrology, Good Hope Hospital, Sutton Coldfeld, Birmingham Professor Mike Kirby, Visiting Professor to the Faculty of Health and Human Sciences, University of Hertfordshire, and The Prostate Centre, London Mr Derek Rosario, Clinical Senior Lecturer, University of Sheffeld and Honorary Consultant Urological Surgeon to Sheffeld Teaching Hospitals Trust

Writing assistance was provided by Steve Chaplin, medical writer

Declaration of interests Roger Kirby has been involved in educational activities on behalf of Pfzer in the Middle and Far East. Geoffrey Hackett is an occasional speaker for Bayer, Lilly, Menarini and Besins. Mike Kirby has received funding for research, conference attendance, lecturing and advice from the pharmaceutical industry including Ferring, Astellas, Pfzer, Takeda, Bayer, MSD, BI, Lilly, GSK, AZ and Menarini. Derek Rosario has acted as advisor for Ferring, Bayer and Astellas and is in receipt of an unrestricted educational grant from Bayer.

TRENDS IN UROLOGY & MEN’S HEALTH: SUPPLEMENT TESTOSTERONE: OVERLOOKED AND UNDERVALUED? 3

Testosterone defciency syndrome

GEOFFREY HACKETT prevalence), prediabetes, obesity and be checked at three to six months along those on repeat prescriptions for opiate with FBC and PSA, and thereafter at DS is defned as: ‘a clinical syndrome analgesics. Current guidelines recommend 12-monthly intervals. With gels, testing Tcaused by androgen defciency which mandatory testosterone measurement should be carried out two to four hours may adversely affect the multiple organ in all men presenting with ED or reduced after morning application, being careful to functions and quality of life.’2 sexual desire.4 Appropriate management exclude contamination of the venesection of these common associated conditions is site by gel. The dose is then adjusted The most prevalent symptoms of TDS usually the responsibility of the primary as necessary to reach the therapeutic are reduced sexual desire, ED, loss of care physician. range. For long-acting injections, trough morning erections and hot fushes;2 levels (timing of day unimportant) less frequent symptoms associated Diagnosis of TDS is confrmed by a fasting should be taken immediately before the with low testosterone include increased morning (8–11am) TT.2–4 If low or borderline fourth injection, with dose adjustment waist circumference, obesity, metabolic levels are detected then a repeat test is in two-week increments to achieve syndrome and impaired health status. suggested at least two weeks later, plus trough levels in the mid-upper range. TDS is also associated with less specifc sex hormone-binding globulin (SHBG) to Follow-up and monitoring are the duty symptoms such as loss of physical calculate FT, plus luteinising hormone (LH), of the prescribing physician (usually the strength and muscle mass, fatigue, full blood count (FBC) and prostate-specifc GP), sometimes as part of a local shared changes in mood, anger, sleep disturbance antigen (PSA) after appropriate counselling. care protocol. PSA levels may show and cognitive impairment. Severe TDS If TT is <5.2nmol/L, serum prolactin is physiological normalisation with a rise is associated with increased risk of required and if combined with low LH, then from baseline by up to 20%, usually osteoporosis and chronic anaemia. pituitary MRI should be considered. settling within 6–12 months. There is no evidence that TRT is associated with any Current EAU, ISSM and BSSM guidelines Appropriate medication is decided by increase in prostate cancer and may even suggest that men with total testosterone detailed discussion with the patient.2–4 2–4 (TT) <8nmol/L should be offered TRT Some men prefer to start with gel, knowing TAKE-HOME MESSAGES: TDS and those between 8 and 11nmol/L (free that they could stop immediately in the testosterone [FT] 180–225pmol/L) may, event of side-effects. Skin reactions can • Appropriate management should be depending on severity, beneft from a six- occur in some men and care is required the responsibility of primary care month trial.3 Laboratories quote reference to minimise the risk of partner transfer. physicians as they currently manage ranges based on health populations, but Other patients may opt for long-acting the associated comorbidities clinical guidelines defne ‘action levels’ that injections of testosterone undecanoate, • Target groups: type 2 diabetes; should dictate best practice. with the reassurance that 12 weeks of prediabetes; obesity; repeat opioid therapy is delivered in a single dose. With prescriptions; ED; reduced sexual desire The risk of hypogonadism is raised long-acting injections, raised haematocrit • Measure and monitor testosterone levels among men with comorbidities. In one occurs in around 6% at 3–12 months; • Patients need to be informed that TRT primary care population, the odds ratios this can be managed by increasing the is long term for hypogonadism were: hypertension dose interval, venesection or switching to • Aim to normalise testosterone for 1.84 (95% CI 1.53–2.22), dyslipidaemia transdermal administration. Short-acting symptom improvement 1.47 (1.23–1.76), type 2 diabetes 2.09 testosterone enanthate injections, although • A trial of TRT should be a minimum of (1.70–2.58), obesity 2.38 (1.93–2.93), inexpensive, require frequent clinic visits, six months for maximal symptomatic lower urinary tract syndrome/benign may cause unacceptable mood swings beneft prostatic hyperplasia 1.29 (1.03–1.62) and fuctuations in blood levels, and are • There is no evidence that TRT is associated and chronic obstructive pulmonary not recommended. with increased cardiovascular risk – current disease/asthma 1.40 (1.04–1.86).5 evidence favours a reduction in risk The goal of therapy is to return the serum • There is no evidence that TRT is associated Target groups for primary care include testosterone level to the upper normal with an increase in prostate cancer men with type 2 diabetes (40% range, ideally above 15nmol/L.4 This should

TRENDS IN UROLOGY & MEN’S HEALTH: SUPPLEMENT TESTOSTERONE: OVERLOOKED AND UNDERVALUED? 4

be associated with a reduction in long-term with associated comorbidities, such as Low serum testosterone has been shown rates and a reduction in cardiovascular and hypertension, dyslipidaemia and diabetes. in many studies to be associated with all-cause mortality.6 Reduction in visceral fat and increase increased cardiovascular and all-cause in lean muscle mass is seen beyond 12 mortality2 and an increased risk of Improvement in libido and energy may be months of therapy.2 Weight loss alone in developing type 2 diabetes.8 Well conducted seen within a few weeks. Improvement in men with TDS results in loss of fat and lean studies with long-term treatment to erectile function may take 6–12 months. muscle, but with co-administration of TRT, therapeutic levels suggest a reduction in ED therapy is often required in men weight loss is almost exclusively fat.7 cardiovascular and all-cause mortality.6 Erectile dysfunction

MIKE KIRBY surgery, depression, neurological disorders, about ED during monitoring. Remember, if smoking, obesity and physical inactivity. we don’t ask, patients don’t tell! D is the persistent inability to attain ED can be a predictor of coronary artery Eand/or maintain an erection suffcient for disease and may be an early warning sign The assessment of ED should include a sexual performance. Estimates of prevalence of more widespread vascular disease.9 comprehensive sexual, medical, psychiatric based on published studies range from 2–9% It may also be an adverse reaction to and surgical history, including lifestyle factors among men under 40 to 10–71% in the medication. The risk factors for ED are such as alcohol use and smoking. A physical over-70s. The English Longitudinal Study of similar to those for cardiovascular disease examination should include blood pressure, Ageing found that 28% of men aged 50 to and it may be ED that brings a patient with heart rate, waist circumference and weight. >90 reported ED or used treatment for it. comorbidities to the attention of their GP. A genital examination is recommended and NICE guidance recommends giving men with a digital rectal examination should be carried ED is often associated with a wide range of diabetes the opportunity to discuss ED in out if urinary or ejaculatory symptoms are comorbidities, including diabetes, peripheral their annual review and men with previously present. Laboratory measurements should arterial disease, , bowel diagnosed heart disease should be asked include lipids, testosterone, fasting plasma glucose or HbA1c. Male with ED Male with ED, failure of PDE5I First-time presentation No previous T testing The aim of management is to enable the individual and couple to enjoy a satisfactory sexual experience by Screen all ED patients for T Screen all ED patients for T identifying and treating the underlying T normal T low T low T normal cause, modifying risk factors and introducing lifestyle change. The treatment of comorbidities should be optimised as ED therapies, eg T therapy Combination Alternative PDE5I therapy, ED therapies, part of the management of ED and this eg T + PDE5I eg injections, includes addressing psychosocial issues. intraurethral alprostadil, Unsatisfactory Satisfactory Unsatisfactory prosthesis Phosphodiesterase type 5 inhibitors (PDE5Is) response response response are the initial treatment of choice. If a PDE5I is not effective, alprostadil (as a cream, a Alternative Continue T therapy pellet or an injection) or a vacuum device therapies, eg may be suitable. In such patients check injections, Continue testosterone – correcting hypogonadism can intraurethral Unsatisfactory Satisfactory combination 10 alprostadil, response response convert them to a responder. therapy prosthesis Measurement of serum TT is advised in The BSSM guidelines include topical alprostadil in the alternative ED therapies. T, testosterone. national guidelines as an initial step in the treatment pathway (Figure 1).11 For those Figure 1. BSSM guideline for the management of ED11 with a level of <12nmol/L, a trial of TRT

TRENDS IN UROLOGY & MEN’S HEALTH: SUPPLEMENT TESTOSTERONE: OVERLOOKED AND UNDERVALUED? 5

should be considered. If this does not activity, once per day; daily dosing with TAKE-HOME MESSAGES: ED improve ED, a PDE5I should be added. tadalafl, which has a longer half-life, or generic sildenafl is an option if • ED is common in older men Involve the partner wherever possible. intercourse is frequent or the couple wish • It is a marker of underlying vascular disease Penile prostheses are the last resort, but to avoid planning the event. Between 24% • Treatment is effective and improves the have a high satisfaction rate. and 50% of patients discontinue PDE5I quality of life of men and their partners 12,13 use, when one of the other therapeutic • A careful clinical review is essential to PDE5Is offer the convenience of oral options can be offered. detect comorbidity, including a search for administration and effcacy in most cardiovascular risk factors and hypogonadism subgroups of patients. Sildenafl is Alprostadil is a local vasodilator and is • Involve the partner wherever possible available as a generic; it is the most cost- effective even in neurogenic ED. It is • Explain the treatment options and make effective PDE5I and can be prescribed on recommended as second-line therapy a shared decision the NHS. These agents are vasodilators and and can be administered via a topical • PDE5Is are frst line, but effective second should be prescribed cautiously for men cream, an intracavernosal injection or an and third line options are available with signifcant cardiovascular disease, intraurethral pellet. Topical alprostadil • PDE5Is are contraindicated for men many of whom were excluded from cream is a safe second-line therapy for ED, taking nitrates clinical trials. PDE5Is are contraindicated indicated for those who cannot tolerate, • Provide lifestyle advice for all for men taking nitrates – an alternative cannot take or are not satisfed with, oral ED therapy (such as alprostadil) can be PDE5I therapy.14 More than half of men The opportunity to target lifestyle factors prescribed for these men or an alternative discontinue alprostadil injection therapy.15–17 associated with cardiovascular disease and antianginal prescribed, and the nitrates Discontinuation rates may be lower with metabolic disorders should not be missed. discontinued as they have no prognostic the cream.18 There is no contraindication to This can lead to an improvement in erectile beneft. The PDE5I dose should be taken using alprostadil preparations with TRT, but function, increase testosterone levels and 0.5–1.0 hour before anticipated sexual published studies are lacking. reduce cardiovascular risk.19 ADT in advanced hormone-dependent prostate cancer DEREK J ROSARIO ACHIEVING AND MAINTAINING In some men, treatment with LHRH CASTRATION agonists is associated with ‘microsurges’ ndrogens are essential for prostate Surgical castration is rarely practised today, of testosterone that exceed the target Adevelopment and function. In with medical castration using a luteinising level; this is associated with earlier PSA prostate cancer, androgenic stimulation hormone-releasing hormone (LHRH) agonist progression.22,23 This could explain why drives malignant proliferation. Where or a gonadotrophin-releasing hormone the antagonist degarelix is associated with clinical response to ADT induced by (GnRH) antagonist (degarelix) being the norm. signifcantly longer PSA progression-free medical or surgical castration is seen, the survival and a lower risk of death at 3 or 12 disease is termed castrate-sensitive. The LHRH agonists cause an initial surge in months compared with an LHRH agonist lethal form of prostate cancer is usually LH, increasing testosterone synthesis and (Figure 2).24,25 termed castration-resistant (CRPC), provoking transient tumour fare. Between where disease progression occurs despite two and four weeks later, tachyphylaxis In the event of a rising PSA or clinical castrate levels of circulating testosterone. results in downregulation of LH receptors disease progression on ADT, it is essential to It has become evident that in almost all and LHRH agonists achieve castrate levels measure testosterone to confrm castrate cases of CRPC, androgenic stimulation is of testosterone (defned as 0.5ng/ml for levels before labelling the disease CRPC. still active via a number of mechanisms.20 regulatory purposes). By contrast, the Serum PSA should routinely be measured Thus effective testosterone suppression GnRH antagonist degarelix suppresses on a three-monthly basis during long-term (ADT) is essential to optimise outcomes in testosterone to below 0.5ng/ml within ADT; nadir PSA levels at six months is highly advanced prostate cancer. three days without any initial surge.21 prognostic of disease outcome.

TRENDS IN UROLOGY & MEN’S HEALTH: SUPPLEMENT TESTOSTERONE: OVERLOOKED AND UNDERVALUED? 6

TAKE-HOME MESSAGES: ADT in advanced 100 hormone-dependent prostate cancer 95 • LHRH agonists and GnRH antagonists have different profles of effcacy 90 and adverse events, so consider them carefully before initiating treatment. 85 • Measure serum testosterone to confrm castrate levels before labelling the Probability (%) 80 disease CRPC Degarelix 75 • Cardiovascular risk during ADT should LHRH agonist be managed actively 70 0 28 56 84 112 140 168 196 224 252 280 308 336 364 MINIMISING CARDIOVASCULAR RISK Time (days) ADT is associated with serious adverse At risk number effects including fatigue, hot fushes, Degarelix 1263 1253 1234 1186 958 933 911 891 864 836 816 792 770 710 sexual dysfunction, gynaecomastia, LHRH agonist 657 653 645 615 489 483 470 460 449 445 429 418 408 375 osteoporosis, obesity, metabolic syndrome and diabetes. It has long been recognised Figure 2. Probability of PSA progression-free survival in all patients. Reproduced with permission from Klotz L et al, Eur Urol 2014;66:1101–825 that ADT might be associated with an increased cardiovascular risk: treatment was reduced by over half by treatment risk calculator and managed in primary care with an LHRH agonist is associated with with degarelix compared with the LHRH with standard treatments, including lifestyle an increased risk of coronary artery agonist (HR 0.44; 95% CI 0.26–0.74; change through smoking reduction, diet and disease (HR 1.11; 95% CI 1.07–1.15), acute number needed to treat 12).27 exercise. Men who may be at increased risk myocardial infarction (HR 1.09; 95% CI should therefore be identifed to their GP, 1.04–1.15) and sudden cardiac death The adverse effects of ADT can be mitigated who should also be aware of the value of (HR 1.18; 95% CI 1.12–1.24) compared by suitable treatment. The NICE guideline for monitoring testosterone levels for improved with orchidectomy.26 This risk appears to prostate cancer recommends a 12-week prostate cancer outcomes. In secondary be due to excess mortality in men with supervised exercise intervention that care, the difference in risk associated with pre-existing cardiovascular disease. In this improves disease-specifc quality of degarelix and LHRH agonists should be group of men, the risk of cardiac events life28,29 and reduces cardiovascular risk.30 considered when choosing ADT for men within the frst year of treatment on ADT Cardiovascular risk can be estimated using a with existing heart disease. Conclusion

ROGER KIRBY ED or other non-specifc symptoms. process of ageing. Patient education Low testosterone is, conversely, a is therefore important: men, and their lthough management strategies desired outcome of ADT in advanced partners, should understand the nature Aare very different, monitoring and hormone-dependent prostate cancer of their problem and have realistic controlling testosterone levels plays a and it is important that testosterone is expectations of what can be achieved valuable role in managing men across a measured to ensure patients remain at with TRT. Careful follow-up is important number of men’s health disorders. Low castrate levels. Most patients can easily to ensure that serum testosterone levels testosterone is an important underlying be managed in primary care, as there are controlled. Comorbidities such as cause of the signs and symptoms of TDS is usually no need to refer them on for obesity, diabetes and hyperlipidaemia and ED, and GPs should remember to more specialist investigations. Many men (the metabolic syndrome) may need to be ‘tick testosterone’ when evaluating men presenting with testosterone defciency addressed with lifestyle advice about diet of middle age and beyond who present consider the signs and symptoms of and exercise, as well as other forms of to their doctor with tiredness, lassitude, hypogonadism as simply the natural pharmacotherapy.

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REFERENCES 9. Kirby M, Jackson G. Trends Urol Mens 17. Sung HH, et al. Andrology 2014;2:45–50. 1. Boyle P, et al. BJU Int 2016;118:731–41. Health 2011;2(4):19–23. 18. Rooney M, et al. J Sex Med 2009;6:520–34. 2. Dohle G, et al. EAU guidelines on male 10. Aversa A, et al. Clin Endocrinol 2003; 19. Kirby M. Sex Med Rev 2015;3:169–82. hypogonadism. March 2015 (https:// 58:632–8. 20. Greasley R, et al. Cancer Manag Res uroweb.org/guideline/male-hypogonadism; 11. BSSM. Guidelines on the management of 2015;7:153–64. accessed 30 November 2016). erectile dysfunction. July 2009, updated 21. Klotz L, et al. BJU Int 2008;102:1531–8. 3. Dean JD, et al. J Sex Med 2015;12:1660–86. September 2013 (https://www.guidelines. 22. Morote J, et al. J Urol 2007;178:1290–5. 4. BSSM. Guidelines on the management co.uk/bssm/erectile-dysfunction; accessed 23. Pickles T, et al. BJU Int 2012;110:E500–7. of sexual problems in men: the role of 30 November 2016). 24. Tombal B, et al. Eur Urol 2010;57:836–42. androgens. December 2010 (https://www. 12. Kim SC, et al. Int J Impot Res 2013;26: 25. Klotz L, et al. Eur Urol 2014;66:1101–8. guidelines.co.uk/bssm/androgens; accessed 87–93. 26. Gandaglia G, et al. BJU Int 2014;114:E82–9. 30 November 2016). 13. Corona G, et al. Andrology 2016; doi: 27. Albertsen PC, et al. Eur Urol 2014;65: 5. Mulligan T, et al. Int J Clin Pract 2006;60:762–9. 10.1111/andr.12255 (Epub ahead of print). 565–73. 6. Wallis CJ, et al. Lancet Diabetes Endocrinol 14. Anaissie J, Hellstrom WJ. Res Rep Urol 28. NICE. Prostate cancer: diagnosis and 2016;4:498–506. 2016;8:123–31. management. Clinical guideline 175 7. Ng Tang Fui M, et al. BMC Medicine 15. Raina R, et al. Int J Impot Res 2005;17: (www.nice.org.uk/guidance/cg175; 2016;14:153. 86–90. accessed 30 November 2016). 8. Holmboe SA, et al. J Clin Endocrinol Metab 16. Raina R, et al. Int J Impot Res 2003;15: 29. Bourke L, et al. Eur Urol 2014;65:865–72. 2016;101:3180–90. 318–22. 30. Stephen E, et al. Br J Cancer 2016;114:401–8.

Prescribing Information: Testim® (testosterone) 50mg Gel use in women. The gel may be transferred to others by skin to skin contact, Please consult the full Summary of Product Characteristics before prescribing. which could lead to adverse reactions (inadvertent androgenisation) by repeated contact. Inform the patient about the transfer risk, which can be prevented by Name of Product: Testim® (testosterone) 50mg Gel. covering or washing the site before contact. Testim® gel should not be prescribed Composition: One tube of 5 g gel contains 50 mg testosterone. Testim® is a for patients who may not comply with safety instructions (e.g. severe alcoholism, clear to translucent gel. drug abuse, severe psychiatric disorders). The content of the tube is fammable. Indications: Testosterone replacement therapy for male hypogonadism when Testim ® contains propylene glycol which may cause skin irritation. testosterone defciency has been confrmed by clinical features and biochemical Side effects: Common (1% to <10%): Application site reactions (rash, tests. erythema, pruritus), increased PSA, hypertension worsened, acne, headache, Dosage and administration: Recommended starting dose: One tube of 5 g increased haematocrit, increased red blood cell count and increased gel daily. If serum testosterone levels are below the normal range, the dose may haemoglobin. Uncommon (0.1% to <1%): Hot fushes/fushing, pruritus and be increased from 50 mg (one tube) to 100 mg (two tubes) once daily. Once peripheral oedema, gynecomastia (may develop and persist in patients being opened apply the entire content of the tube immediately to clean dry intact skin treated for hypogonadism with testosterone). Very rare (<0.01% to not known): of the shoulders and/or upper arms, preferably in the morning. Wash hands Azoospermia. Other known reactions to testosterone are: Prostate cancer, immediately after use. Do not apply to the genital area. Not for use in children. electrolyte changes, decreased libido, anxiety, emotional liability, generalized Not clinically evaluated in males less than 18 years of age. paresthesia, nausea, jaundice and liver function test abnormalities, hirsutism, Contraindications: Androgens are contraindicated in men with carcinoma of alopecia, seborrhoea, hypertension, muscle cramps, increased frequency of the breast or known or suspected carcinoma of the prostate. Hypersensitivity erections, priapism, prostate abnormalities, altered blood lipid levels (including to testosterone (synthesised from soy) or to any of the excipients. Testim® is not reduction of HDL cholesterol), and weight gain. indicated for women and must not be used in pregnant or breastfeeding women. Nature and contents of container: Testim ® is supplied as a Carton containing Pregnant women must avoid skin contact with Testim® application sites. 30 x 5g tubes. Special Warnings and Precautions: Prior to therapy, the risk of prostate Marketing Authorisation Number: 03194/0105. cancer must be excluded. Examine breast and prostate gland at least yearly Marketing Authorisation Holder: Ferring Pharmaceuticals Ltd., Drayton Hall, and twice yearly in elderly or at risk patients (those with clinical or familial Church Road, West Drayton, UB7 7PS. factors). Monitor serum calcium levels in patients with skeletal metastases at Legal category: POM. risk of hypercalcaemia/hypercalcuria. Testosterone may cause oedema with Basic NHS price: £32.00. or without congestive cardiac failure in patients with severe cardiac, hepatic or Date of preparation: April 2014. renal insuffciency. In this case, stop treatment immediately. Use with caution Testim ® is a registered trademark. in patients with hypertension, ischemic heart disease, epilepsy, and migraine. TM/005/2016/UK(1) Possible increased risk of sleep apnoea in patients who are obese or with chronic respiratory disease. Improved insulin sensitivity may occur. Irritability, nervousness, weight gain, prolonged or frequent erections may indicate Adverse events should be reported. Reporting forms and information excessive androgen exposure requiring dosage adjustment. If severe application can be found at www.mhra.gov.uk/yellowcard. site reaction occurs, discontinue treatment if necessary. Periodically monitor Adverse events should also be reported to Ferring Pharmaceuticals Ltd. testosterone concentrations, full blood count, lipid profle, and liver function. Tel: 0844 931 0050. Email: [email protected] Testosterone may produce a positive reaction in an anti-doping test. Not for

TRENDS IN UROLOGY & MEN’S HEALTH: SUPPLEMENT Prescribing Information the condom. Interactions: Based on the nature of the metabolism of Vitaros® drug-drug interactions are considered unlikely. Not recommended for use with Vitaros® Refer to Summary of Product Characteristics (SmPC) before phosphodiesterase-5 (PDE-5) inhibitors as an additive increased cardiovascular prescribing. Presentation: Alprostadil 300 micrograms in 100mg of cream risk cannot be excluded. Possible risk of priapism if used in combination with a (3mg/g). Indication: Treatment of men ≥18 years of age with erectile dysfunction. penile implant or smooth muscle relaxant. Possible increased risk of hypotension Dosage & Administration: Vitaros® is applied to the tip of the penis (meatus) (especially in elderly) when administered in combination with antihypertensive 5-30 minutes prior to attempting intercourse. Do not insert the tip of the drugs and vasoactive medications. The effect of Vitaros® may be reduced if AccuDose™ container into the opening of the penis. Use as needed to achieve administered concomitantly with sympathomimetics, decongestants and an erection to a maximum frequency of once every 24 hours and no more appetite suppressants. When used in combination with anticoagulants and than 2-3 times per week. Vitaros® Accudose™ container is for single use only. platelet aggregation inhibitors, there may be an increased risk of urethral Contraindications: Should not be used in patients with orthostatic hypotension, bleeding, haematuria. Fertility, Pregnancy & Lactation: Pregnant women myocardial infarction, syncope, abnormal penile anatomy, urethritis, balanitis, should not be exposed to Vitaros®. It is not recommended to use Vitaros® while tendency to thrombosis, hyperviscosity syndrome, underlying conditions that breastfeeding. It is not known whether Vitaros® has an effect on human male may predispose them to priapism, known hypersensitivity to alprostadil or any fertility. Undesirable Effects: Common (≥1/100 to <1/10): rash, urethral pain, excipients. Should not be used in patients for whom sexual activity is inadvisable penile pain, burning erythema tingling, throbbing or numbness, genital pain, (men with unstable cardiovascular or cerebrovascular conditions). A condom erythema or discomfort, balantitis, penile oedema, erection increased, in partner: must be worn for sexual intercourse with a woman who has child bearing vulvovaginal burning sensation and vaginitis. Other Serious Undesirable potential. Warnings & Precautions: Treatable causes of erectile dysfunction Effects: Uncommon (≥1/1000, <1/100): hypotension, priapism, dizziness, should be excluded before initiation of Vitaros®. If priapism occurs, the patient syncope, urinary tract infection. Refer to the SmPC for details on full side effect should seek medical assistance immediately. Avoid driving or hazardous tasks profle and interactions. Basic NHS Price: £40 per pack of 4 doses. Legal due to risk of hypotension or syncope after administration, dose may need to be Classifcation: POM. Marketing Authorisation Number: PL 03194/0125. lowered in patients with hepatic and/or renal impairment. Inadvertent intraurethral Marketing Authorisation Holder: Ferring Pharmaceuticals Ltd. Drayton Hall, exposure may result in penile burning, tingling sensation and pain. Vitaros® offers Church Road, West Drayton, UB7 7PS, UK. PI Approval Code: VIT/2000/2016/ no protection from the transmission of sexually transmitted diseases, partners UK Date of preparation: August 2016. of Vitaros® users can experience adverse effects such as vaginal irritation. Adverse events should be reported. Reporting forms and information The effects of Vitaros® on the oral or anal mucosa have not been studied. A can be found at www.mhra.gov.uk/yellowcard. condom barrier is recommended for use with Vitaros®, including use during Adverse events should also be reported to Ferring Pharmaceuticals Ltd. oral or anal sex. Only latex material based condoms have been investigated for Tel: 0844 931 0050. Email: [email protected] use with Vitaros®. Other materials may not exclude possible risk of damage to

Prescribing Information: Firmagon® (degarelix) 120mg and 80mg powder musculoskeletal pain and discomfort, gynaecomastia, testicular atrophy, and solvent for solution for injection. erectile dysfunction, chills, pyrexia, fatigue, Infuenza-like illness. Uncommon: Please consult the full Summary of Product Characteristics before hypersensitivity, hyperglycemia/ diabetes mellitus, cholesterol increased, weight prescribing. decreased, appetite decreased, changes in blood calcium, depression, libido Name of Product: Firmagon 120mg and 80mg powder and solvent for solution decreased, mental impairment, hypoaesthesia, vision blurred, cardiac arrhythmia for injection. (incl. atrial fbrillation), palpitations, QT prolongation, hypertension, vasovagal Composition: Each vial contains 120mg or 80mg degarelix (as acetate). reaction (incl. hypotension), dyspnoea, constipation, vomiting, abdominal pain, Indication: Firmagon is a gonadotrophin releasing hormone (GnRH) antagonist abdominal discomfort, dry mouth, bilirubin increased, alkaline phosphatase indicated for treatment of adult male patients with advanced hormone- increased, urticaria, skin nodule, alopecia, pruritus, erythema, osteoporosis/ dependent prostate cancer. osteopenia, arthralgia, muscular weakness, muscle spasms, joint swelling/ Dosage and administration: For subcutaneous use only. Starting dose–240mg stiffness, pollakiuria, micturition urgency, dysuria, nocturia, renal impairment, administered as two subcutaneous injections of 120mg each. Maintenance dose incontinence, testicular pain, breast pain, pelvic pain, genital irritation, ejaculation – 80mg administered monthly as one subcutaneous injection. failure, malaise, peripheral oedema. Rare: neutropenic fever, anaphylactic Contraindications: Hypersensitivity to the active substance or to any of the reactions, myocardial infarction, cardiac failure. Please consult the full Summary excipients. of Product Characteristics for further information about side effects. Special Warnings and Precautions: Long-term androgen deprivation Presentation: Firmagon 120mg contains 2 vials of 120mg powder for solution therapy may prolong the QT interval. The beneft/risk ratio must be thoroughly for injection and 2 solvent pre-flled syringes, 2 vial adaptors and 2 administration appraised in patients with a history of a corrected QT interval over 450 msec, in needles. Firmagon 80mg contains 1 vial of 80mg powder for solution for injection patients with a history of or risk factors for torsades de pointes and in patients and 1 solvent pre-flled syringe, 1 vial adaptor and administration needle. Solvent receiving concomitant medicinal products that might prolong the QT interval as for both 120mg and 80mg: Water for injection. Firmagon has not been studied in these patients. A thorough QT study showed Marketing Authorisation Number: 80mg: EU/1/08/504/001, 120mg: that there was no intrinsic effect of Firmagon on QT/QTc interval. Monitoring of EU/1/08/504/002. liver function in patients with known or suspected hepatic disorder is advised Marketing Authorisation Holder: Ferring Pharmaceuticals A/S, Kay Fiskers during treatment. Firmagon has not been studied in patients with severe renal Plads 11, DK-2300 Copenhagen S, Denmark. impairment, patients with a history of severe untreated asthma, anaphylactic Legal category: POM. reactions or severe urticaria, or angioedema. It can be anticipated that long Basic NHS price: Firmagon 120mg - £260.00; Firmagon 80mg - £129.37 periods of testosterone suppression in men will have effects on bone density. Date of preparation: January 2014 Diabetic patients may require more frequent monitoring of blood glucose when Firmagon® is a registered trademark. receiving androgen deprivation therapy. Cardiovascular disease such as stroke PI Job Code: FN/648/2012/UK(3) and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all cardiovascular risk factors Adverse events should be reported. Reporting forms and information should be taken into account. can be found at www.mhra.gov.uk/yellowcard. Side effects: Very Common: hot fush, injection site adverse reactions. Adverse events should also be reported to Ferring Pharmaceuticals Common: anaemia, weight increase, insomnia, dizziness, headache, diarrhoea, Ltd. Tel: 0844 931 0050. Email: [email protected] nausea, liver transaminases increased, hyperhidrosis (incl. night sweats), rash,

Ferring Pharmaceuticals Ltd was involved in the outline development and medico-legal approval of this supplement and provided fnancial support for its publication. The supplement is peer reviewed and the authors and publisher retained fnal editorial control of the content. The opinions expressed in the supplement are not necessarily those of the publisher or Ferring Pharmaceuticals Ltd. Printed and published by John Wiley & Sons, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ © John Wiley & Sons 2017 Pr.1629 January 2017 GEN/3160/2016/UK