An overview of Benign Prostatic Hyperplasia (BPH)

Benign Prostatic Hyperplasia(BPH)Overview of BPHPrepared by GlaxoSmithKline Ireland Medical Department in April 2012IE/COM/0019/12 (1) Prepn Aug 2013

Abbreviations usedAbbreviationBPHIPSSAURLUTSPSAHRQoL/ QoLEAUAUA5ARIsDefinedBenign prostatic hyperplasiaInternational prostate symptom scoreAcute urinary retentionLower urinary tract symptomsProstate specific antigenHealth related quality of life/ Quality of lifeEuropean Association of UrologyAmerican Urology Association5-alpha reductase inhibitorsRoehrborn C et al. Eur Urol 2010;57:123–131; EAU: http://www.uroweb.org/; AUA: http://www.auanet.org/content/homepage/homepage.cfmIE/COM/0019/12 (1) Prepn Aug 2013

Contents• Disease impact in men with moderate LUTSdue to BPH• Diagnosis of BPHIE/COM/0019/12 (1) Prepn Aug 2013

What is BPH?• Benign prostatic hyperplasia (BPH) is a histologicaldiagnosis 1• It becomes a clinical problem when associated with:– Bothersome lower urinary tract symptoms (LUTS) 1– Prostate enlargement 1– Bladder outlet obstruction 1• Growth factors and pro-inflammatory cytokines havebeen implicated in the pathogenesis of BPH 1,21. Roehrborn C. Int J Impt Res 2008;20:S11–S18; 2. Lucia S et al. Curr Urol Rep 2008;9:272–278.IE/COM/0019/12 (1) Prepn Aug 2013

Symptoms of BPHLUTS- Lower urinary tract symptomsVoiding (obstructive)symptoms• Hesitancy• Weak stream• Straining to pass urine• Prolonged micturition• Feeling of incompletebladder emptying• Urinary retentionStorage (irritative or filling)symptoms• Urgency• Frequency• Nocturia• Urge incontinenceKirby& Gilling, Fast Facts, Benign prostatic hyperplasia, 6 th Edition, Health PressIE/COM/0019/12 (1) Prepn Aug 2013

Men with moderate LUTS due to BPH mayexperience a substantial health burdenToday• Bother• Interference withdaily activities• Sleep disturbance• Sexual dysfunction• Worry• Impact on physicaland mental health• Impact on personalrelationshipsTomorrow• BPH progressionmeans risk ofo Worsening ofsymptomso AURo need for surgeryIE/COM/0019/12 (1) Prepn Aug 2013

Most men with BPH worry about the potentiallong-term consequences of their diseasePatient concerns with risk for AUR and need for surgeryEmberton M et al. Int J Clin Pract 2008; 62: 18–26IE/COM/0019/12 (1) Prepn Aug 2013

Impact of BPH on daily activitiesPercentage of men in whom urinary symptoms affected living activities at least some of the timeAvoids visits to the theatre,cinema, church etc6.715.1With BPHAvoid outdoor sports6.212.8Without BPHAvoid place without toilets13.232.4Not getting enough sleep10.327.1Cannot drive for 2 hours821Limited fluid before bedtime18.434.7Limited fluid before travel13.429.90 10 20 30 40PercentageGarraway WM et al. Br J Gen Pract 1993;43:318–21IE/COM/0019/12 (1) Prepn Aug 2013

The presence and severity of LUTS are risk factors for sexualdysfunction• Sexual activity is common in a majority of men aged 50−80 years and is animportant component of quality of life• Men with moderate-to-severe LUTS are at increased risk for– Erectile dysfunction– Ejaculatory dysfunction– Hypoactive desireRosen R et al. Eur Urol 2003;44:637–49IE/COM/0019/12 (1) Prepn Aug 2013

Partners of men with LUTS due to BPH also experiencesignificant morbidity due to their husband’s condition• Factors mainly affecting partner’s QoL– Psychological burden– Inadequate sex life– Sleep disturbance– Disruption in social life*– Inability to take care of essential tasks inside and outsidethe house– Fear of prostate cancer– Fear of surgery*Significantly correlated with partner’s IPSSMitropoulos D et al. Eur Urol 2002;41:240−4512IE/COM/0019/12 (1) Prepn Aug 2013

Deterioration in symptoms is the mostcommon manifestation of BPH progression4.5 years mean follow up in MTOPS (Medical Therapy of ProstaticSymptoms study)McConnell JD et al. N Engl J Med 2003;349:2387−98IE/COM/0019/12 (1) Prepn Aug 2013

Impairment of HRQoL in men with moderate LUTS due to BPHis comparable with that associated with epilepsy or asthmaHRQoL (1= perfect health)*Moderate lower urinary tract symptoms (LUTS) = IPSS ≥8 and

Contents• Disease impact in men with moderate LUTSdue to BPH• Diagnosis of BPHIE/COM/0019/12 (1) Prepn Aug 2013

Diagnosis of BPH• Medical history• Symptom assessment• Physical examination including a digital rectal examination(DRE)• Urinalysis• Creatinine measurement• Measurement of PSA– considered for men with at least a 10-year life expectancyfor whom management would be changed by a diagnosis ofprostate cancer• UltrasoundOther useful tests include• Uroflowmetry• Post-void residual urineKirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Medical History• To assess symptoms and determine any differential diagnoses for LUTS• Examples of differential diagnoses– Neurological conditions eg. Parkinsons Disease, Multiple Sclerosis– Inflammatory disorders eg. urinary tract infection– Neoplastic disorders eg. prostate cancer– Polyuria causes eg. diabetes– Other causes of obstruction disordersKirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Symptom Assessmentto determine severity of LUTS in men with BPH• The International Prostate Symptom Score (IPSS) has become the internationalstandard to assess LUTS severity• It is an 8-item self-administered questionnaire for patients• The first 7 items quantitatively measure the level of symptoms, reported as a totalIPSS score• Total IPSS score can range from 0–35; three categories of symptom severity arerecognised based on this:– Mild (0–7 points)– Moderate (8–19 points)– Severe (20–35 points)• The last item is a separate assessment of quality of life based on a score rangefrom 0–6Barry MJ et al. J Urol 1992;148:1549–57; Madersbacher S et al. Eur Urol 2004;46:547–554; Kirby&McConnell, Fast Facts, Benign prostatic hyperplasia, 6 thEdition, Health Press18IE/COM/0019/12 (1) Prepn Aug 2013

Physical examination• Physical examination during the initial assessment of a man with LUTSsuggestive of BPH should include:– Focused neurological examination– Digital rectal examination (DRE)• To help evaluate prostate size• To help exclude the presence of prostate cancer, as well asprostatitis and other pelvic pathologiesEAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554Oelke M et al. EAU guidelines 2012, www.eau,europa.eu accessed April 2012Kirby&McConnell, Fast Facts, Benign prostatic hyperplasia, 6 th Edition, Health PressIE/COM/0019/12 (1) Prepn Aug 2013

Digital Rectal Examination (DRE)RectumProstateBladder• Useful in evaluating prostatesize − although tends tounderestimate compared withfindings on TRUS or MRI• Also allows clinician todetermine whether the prostatefeels consistently smooth andelastic as it should, or if hardand irregular areas are presentthat may suggest malignancyTRUS = transurethral ultrasound; MRI = magnetic resonance imagingMadersbacher S et al. Eur Urol 2004; 46: 547–554Oelke M et al. EAU guidelines 2012, www.eau.europa.eu accessed April 2012Roehrborn C et al. Urology 2001; 57:1087–1092Kirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 201020IE/COM/0019/12 (1) Prepn Aug 2013

Urinalysis• Although benign prostatic obstruction is afrequent cause of LUTS in men, LUTS can alsobe caused by urinary tract infection or bladdercancer• Guidelines recommend urinalysis to aiddifferential diagnosisMadersbacher S et al. Eur Urol 2004; 46: 547–554Oelke M et al. EAU guidelines 2012, www.eau.europa.eu accessed April 2012Kirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Creatinine measurement• Whilst not recommended by the AUA guidelines, creatinine measurementis recommended by the EAU guidelines :– Benign prostatic obstruction may cause upper urinary tract dilatationand renal failure– When renal impairment is present, diabetes and hypertension are alsothe most probable underlying causes of creatinine elevation– Data from the MTOPS trial have shown that the risk of developing denovo renal failure in men with LUTS is minimal (

PSA: clinical utility of PSAin assessing men with LUTS suggestive of BPH• In the absence of prostate cancer, serum PSA measurement is auseful indicator of prostate volume• As such, a PSA test can be useful in determining patients mostlikely to experience BPH progression and thus patients most likelyto benefit for treatment with 5ARIs which can reduce prostatevolumeKirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Ultrasound• Aids differential diagnosis• EAU guidelines include a recommendation of ultrasound ofprostate, bladder, kidneys– In BPH, transrectal (preferred) or transabdominalultrasonography of the prostate are appropriateinvestigations to assess prostate volume and shapeMadersbacher S et al. Eur Urol 2004; 46: 547–554Oelke M et al. EAU guidelines 2012, www.eau,europa.eu accessed April 2012Kirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Uroflowmetry• Uroflowmetry is a simple non-invasive test that can reveal abnormalvoiding• Serial flows (two or more) with a voided volume exceeding 150 ml arerecommended to obtain a representative flow test• LUTS in the presence of a normal peak flow rate are more likely to have anon-BPH-related cause, and men with a reduced flow rate (eg Q max

Abnormal voiding recorded by uroflowmetryNormalElderly man with LUTSdue to BPEVoided volume: 399 mLQ max : 27 mL/secAverage flow rate: 17 mL/secFlow time: 23 secondsVoided volume: 424 mLQ max : 12 mL/secAverage flow rate: 8 mL/secFlow time: 51 secondsKirby&McConnell, Fast Facts, Benign prostatic hyperplasia, 6 th Edition, Health PressIE/COM/0019/12 (1) Prepn Aug 2013

Post-void residual (PVR) volume• Measurement of PVR urine is recommended by the EAU guidelines• PVR volume is calculated by measurement of bladder height, width andlength obtained by transabdominal ultrasonography– This is a simple, accurate and non-invasive methodMadersbacher S et al. Eur Urol 2004; 46: 547–554Oelke M et al. EAU guidelines 2012, www.eau.europa.eu accessed April 2012Kirby RS and Gilling PJ. Fast Facts: Benign Prostatic Hyperplasia 6 th Edition 2010IE/COM/0019/12 (1) Prepn Aug 2013

Summary• The initial assessment of a man presenting with LUTS suggestive of BPH should determine theseverity of symptoms and the degree of bother being caused– The IPSS is the standard international instrument for the evaluation of symptom severity andincludes a question on global quality of life• Physical examination including DRE helps evaluate the size of the prostate and helps exclude thepresence of prostate cancer• Serum PSA provides a reliable surrogate for prostate volume as well as prognostic informationconcerning disease progression– PSA testing can assist in discriminating benign prostate growth from prostate cancer• Further diagnostic tests recommended by guidelines as part of the initial assessment includeurinalysis, creatinine measurement, and determination of flow rate and post-void residual volume• Initially, the burden of disease in a man with BPH largely reflects the severity of his symptoms– Men with moderate LUTS due to BPH may experience a substantial reduction in their quality oflife across multiple dimensions• In many men the progressive course of BPH raises the prospect of worsening symptoms, as well asAUR and the need for surgeryIE/COM/0019/12 (1) Prepn Aug 2013

Abbreviated prescribing information• COMBODART ABRIDGED PRESCRIBING INFORMATION (API). (Please refer to the full Summary of Product Characteristics before prescribing)• PRESENTATIONS: Each hard capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, (equivalent to 0.367 mg tamsulosin).INDICATION: Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH). Reduction in the risk of acute urinary retention (AUR)and surgery in patients with moderate to severe symptoms of BPH. POSOLOGY & ADMINISTRATION: Adults (including elderly): The recommended doseis one capsule (0.5 mg/ 0.4 mg) taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and notchewed or opened. Contact with the contents of the dutasteride capsule contained within the hard-shell capsule may result in irritation of theoropharyngeal mucosa. Where appropriate, Combodart may be used to substitute concomitant dutasteride and tamsulosin hydrochloride in existingdual therapy to simplify treatment. Where clinically appropriate, direct change from dutasteride or tamsulosin hydrochloride monotherapy toCombodart may be considered. Renal impairment: The effect of renal impairment on dutasteride-tamsulosin pharmacokinetics has not been studied.No adjustment in dosage is anticipated for patients with renal impairment. Hepatic impairment: The effect of hepatic impairment on dutasteridetamsulosinpharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment. In patients withsevere hepatic impairment, the use of Combodart is contraindicated. CONTRAINDICATIONS: Combodart is contraindicated in: women, children andadolescents; patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin (including tamsulosin-induced angio-edema),soya, peanut or any of the other excipients; patients with a history of orthostatic hypotension: patients with severe hepatic impairment. SPECIALWARNINGS & PRECAUTIONS: Combodart should be prescribed after careful benefit risk assessment and after consideration of alternative treatmentoptions including monotherapies. In two 4-year clinical study, the incidence of cardiac failure (a composite term of reported events, primarily cardiacfailure and congestive cardiac failure) was higher among subjects taking the combination of dutasteride and an alpha blocker, primarily tamsulosin, thanit was among subjects not taking the combination. Digital rectal examination, as well as other evaluations for prostate cancer or other conditions whichcan cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Combodart and periodically thereafter.Combodart causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment. Patients should have a new baselineestablished after 6 months of treatment with Combodart and PSA should be monitored regularly thereafter. Any confirmed increase from the lowestPSA levels while on Combodart may signal the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy withCombodart and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor (see SPCsection 5.1). The relationship between dutasteride and high grade prostate cancer is not clear. Men taking Combodart should be regularly evaluated forprostate cancer risk including PSA testing (see SPC section 5.1). Results of one clinical study (the REDUCE study) in men at increase risk of prostatecancer revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men compared to placebo. The relationship betweendutasteride and high grade prostate cancer is not clear. Men taking Combodart should be regularly evaluated for prostate cancer risk including PSAtesting (see SPC section 5.1). As with other alpha-blockers, a reduction in blood pressure can occur during treatment with tamsulosin, as a result ofwhich, rarely, syncope can occur. Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataractsurgery in some patients on or previously treated with tamsulosin and may lead to increased procedural complications during the operation. Breastcancer has been reported in men taking dutasteride. Physicians should instruct their patients to promptly report any changes in their breast tissue suchas lumps or nipple discharge. Dutasteride is absorbed through the skin, therefore, women, children & adolescents must avoid contact with leakingcapsules. Caution should be used in the administration of Combodart to patients with mild to moderate hepatic impairment. The treatment of severelyrenally impaired patients (creatinine clearance of less than 10 ml/min) should be approached with caution. This medicinal product contains thecolouring agent Sunset Yellow (E110), which may cause allergic reactions.IE/COM/0019/12 (1) Prepn Aug 2013

Abbreviated prescribing informationCOMBODART ABRIDGED PRESCRIBING INFORMATION (API) CONTINUED. (Please refer to the full Summary of Product Characteristics beforeprescribing)INTERACTIONS: There have been no drug interaction studies for Combodart. The following reflect information available on the individualcomponents. Dutasteride: is mainly eliminated via metabolism and studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. Longtermcombination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole,ketoconazole administered orally) may increase serum concentrations of dutasteride. Tamsulosin: Concomitant administration of tamsulosinhydrochloride with drugs which can reduce blood pressure, including anaesthetic agents and other alpha-1 adrenergic blockers could lead toenhanced hypotensive effects. Dutasteride-tamsulosin should not be used in combination with other alpha-1 adrenergic blockers. Caution should beused when dutasteride-tamsulosin is used in combination with cimetidine and with concomitant administration of warfarin and tamsulosinhydrochloride. Diclofenac may increase the elimination rate of tamsulosin. FERTILITY, PREGNANCY & LACTATION: Combodart is contraindicated foruse by women. There have been no studies to investigate the effect of Combodart on pregnancy, lactation and fertility - the following statementsreflect the information available from studies with the individual components; Fertility: Dutasteride has been reported to affect semencharacteristics in healthy men. The possibility of reduced male fertility cannot be excluded. Effects of tamsulosin hydrochloride on sperm counts orsperm function have not been evaluated. Pregnancy: As with other 5 alpha reductase inhibitors, dutasteride inhibits the conversion of testosteroneto dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus.It is not known whether a male foetus will be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride(the risk of which is greatest during the first 16 weeks of pregnancy). As with all 5 alpha reductase inhibitors, when the patient's partner is or maypotentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom. Lactation: It is not knownwhether dutasteride or tamsulosin are excreted in human milk. ABILITY TO DRIVE & USE MACHINES: No studies on the effects of Combodart on theability to drive and use machines have been performed. However, patients should be informed about the possible occurrence of symptoms relatedto orthostatic hypotension such as dizziness when taking Combodart. UNDESIRABLE EFFECTS: DUTASTERIDE AND TAMSULOSIN CO-ADMINISTRATION: The following adverse events have been reported with an incidence of ≥1% during the four years of treatment in the CombATStudy (Combination of Avodart and Tamsulosin-study, a comparison of dutasteride 0.5mg and tamsulosin 0.4mg once daily for four years as coadministrationor as monotherapy): Cardiac failure, impotence, altered (decreased) libido, ejaculation disorders, breast disorders (includes breastenlargement and/or breast tenderness), dizziness. Adverse Events identified through post-marketing experience (therefore the true incidence isunknown) with dutasteride monotherapy include allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema, skin andsubcutaneous tissue disorders. Uncommon: Alopecia (primarily body hair loss), hypertrichosis. The following adverse events related to tamsulosinmonotherapy have been reported from both clinical trials and post marketing data: Common ( ≥1/100