Dutasteride – Indian Experience Dr. Sunil Shroff Professor & HOD, Dept. of Urology & Renal Transplantation Sri Ramachandra Medical College & Research Institution, Chennai E-mail: sshroff@vsnl.com or srmc69@eth.net www.medindia.net / urology Dr.Sunil Shroff - Dutasteride 2004

BPH – Changing Patterns in Management Over the last 10 years Treatment of BPH has changed dramatically The emphasis is more towards symptom improvement and prevention of Clinical progression of BPH Medical Treatment with Alpha Blockers and 5-Alpha Reductase Inhibitors are now established alternative to ‘Invasive Therapy’ Dr.Sunil Shroff - Dutasteride 2004

Clinical Progression of BPH Determines if a patient with BPH develops any of the below mentioned symptoms on follow up during watchful waiting Period AUR Recurrent urinary tract infection or urosepsis, Four-point or greater increase in baseline AUA symptom, Incontinence Need for prostate surgery Renal insufficiency due to BPH Dr.Sunil Shroff - Dutasteride 2004

BPH – Age Related Morbidity Among 50 yrs old men, an estimated 35% lifetime incidence of surgical or medical intervention A 60 years old has a 23% chance of experiencing Acute Urinary Retention if he survives for additional 20 years Nearly 1 in 10 men in their 70’s will have Acute Urinary Retention in the subsequent 5 years OsterlingJE. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate Suppl.1996,667-73 Jacobson SJ et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997,158:481 -487 Dr.Sunil Shroff - Dutasteride 2004

Reduction in Surgical Treatment Decrease in NUMBER of Prostatectomies - 1987 ----- 250,000 1996 ----- 116,000 2000 ----- 88,000 55% Reduction in TURP The above decrease may be the result of safer and better medical therapies US Health care financing Administration 2000 Dr.Sunil Shroff - Dutasteride 2004

Medical Management of BPH The effectiveness of alpha-blockers and Androgen Suppression have validated the Hypothesis that the patho- physiology of BPH comprises of: - A Dynamic Component - related to prostate smooth muscle tension (Mechanism of Action for Alpha Blockers) A Static Component - related to prostate size (Mechanism of Action for 5 Alpha Reductase inhibitors) Dr.Sunil Shroff - Dutasteride 2004

Does Prostate Volume Reduction Help Prostate Volume does not have strong co-relation to prostate symptoms However Prostate volume is an important predictor of risk for developing acute urinary retention (AUR) Finasteride - decreases the risk of progression to acute urinary retention - benefit greatest in men with enlarged prostates Rev Urol. 2003;5(suppl 5):S28-S35]© 2003 Med Reviews Dr.Sunil Shroff - Dutasteride 2004

 - Blockers – Review of literature No long-term data available to prove that alpha blockers retard or prevent BPH progression Limitations Elderly age group: Dizziness, Postural Hypotension Younger age group: Ejaculatory Dysfunction Therapeutic results irrespective of gland size and BOO Symptom relief and urodynamic improvement Rapid onset of action Clifford GM et al. Eur Urol 2000;38: 2-19 Dr.Sunil Shroff - Dutasteride 2004

5-Reductase Inhibitors: Review of literature Reduce prostate volume Reduce risk of progression to AUR Reduce risk of prostatic surgery Effective for long-term therapies Improvement in QoL Clifford GM et al. Eur Urol 2000;38: 2-19 Dr.Sunil Shroff - Dutasteride 2004

5-Reductase Inhibitors : BPH Progression Data available from large PLESS (Proscar Long-term Efficacy & Safety Study) trail with Finasteride showed : Improvement in urinary flow (beginning from 4th month) Reduction in AUA SI score (by 3.3 vs 1.3 points in placebo) Decreased baseline prostate volume by 18% over placebo (+14%) Reduced PSA levels by half vs those in placebo group Reduced risk of AUR & Surgery PLESS Study – Double Blind and Placebo Controlled Source: McConnel JD (1998) NEJM Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Initial Indian Experience Dutasteride - Drug Profile Dutasteride – Results of Seven Centres Dutasteride – Comparison and Discussion Testosterone Dihydrotestosterone 5α-Reductase DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Dutasteride inhibits the conversion of testosterone to Dihydrotestosterone (DHT) Dr.Sunil Shroff - Dutasteride 2004

Dutasteride - History of Drug Dutasteride – Filed for treatment of BPH in 1995 Dutasteride Approved by FDA on 20th Nov 2001 Dutasteride Now available in India – Dr.Reddys Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Basis of Trail The trial designed around the theory that androgens drive prostate cell growth. 5 - Alpha Reductase Inhibitors meets the two key criteria for a preventive agents: Non-toxic Attacks a specific molecular step in the prostatic tissue to selectively achieve androgen suppression Testosterone Dihydrotestosterone 5α-Reductase Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 5α-Reductase Testosterone is converted to DHT by the enzyme 5α reductase, which exists as Two Isoforms: Type I and Type II The type I Isoenzyme is also responsible for testosterone conversion in the Skin and Liver. The type II - Isoenzyme is primarily active in the Reproductive Tissues Dutasteride a novel dual 5α-Reductase inhibitor Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – A Novel 5-ARI 4- azasteroid Selective and potent inhibitor of both type I & II 5-AR Unlike Finasteride, inhibits: *Type I - 5AR : 45 fold *Type II -5AR : 2.5 fold 5 times more rapid onset of action Source : Drugs Ageing ( 2003) Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Pharmacokinetics Rapid absorption on oral administration Tmax : 1 - 3hrs Bioavailability : Approx 60% Elimination t1/2 : 3-5 weeks Extensive hepatic metabolism Faecal excretion Dr.Sunil Shroff - Dutasteride 2004

Dutasteride on DHT and Testosterone Dutasteride showed appreciable reduction in serum DHT levels, even as early as 1 month 1 month : 87.5% 24 months : 90.2% Reductions in DHT are rapid & sustained Median increase in Testosterone 19% (within Physiologic Limits) Dr.Sunil Shroff - Dutasteride 2004

Inherited Type 2 - 5α-Reductase Deficiency Adult males have decreased DHT levels 5α-reductase deficient males have a small prostate gland throughout life and do not develop BPH Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5α-reductase deficiency have been observed in these individuals. Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Effect on PSA Levels Dutasteride decreased PSA levels in men with BPH PSA levels at 24 months Dutasteride (0.5mg/d) :  50% Placebo :  15% (Ref: Claus GR et al. (2002) Urology 60;434-41) Claus GR et al. (2002) Urology 60;434-41 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Effect on Prostate Volume Dutasteride decreases both TPV & TZV starting at 1 month and continuing through 24 months Significant reduction in both Total Prostate Volume (TPA) & Transition Zone Volume (TZV) Mean % change from baseline: TPV = -25.7% TZV = -20.4% Claus GR et al. (2002) Urology 60;434-41 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Effect on Peak Urinary Flow rate (PFR or Qmax) At 24 months change in Qmax, from baseline: Dutasteride : + 2.2 ml/sec Placebo : + 0.9 ml/sec Claus GR et al. (2002) Urology 60;434-41 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Effect on AUR Offers 57% risk reduction of AUR At 24 months - AUR Dutasteride group : 39 (1.8%) Placebo group : 90 (4.2%) Claus GR et al. (2002) Urology 60;434-41 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Special Population No dosage adjustment required in elderly & renal dysfunction Cautious use in hepatic dysfunction. Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Drug Interactions No interaction with : 1- adrenoreceptor antagonist (eg. Tamsulosin, Terazosin) Digoxin, warfarin Likelihood interactions with : Ketoconazole, Verapamil, Diltiazem, Cimetidine, Ciprofloxacin Dr.Sunil Shroff - Dutasteride 2004

Metabolism and Elimination Dutasteride is extensively metabolized in humans Dutasteride and its metabolites are excreted mainly in feces. Only trace amounts of unchanged Dutasteride can be found in urine (<1%). Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Side Effects Profile No Effect on Bone density (52 weeks trail period as measured using DEXA on healthy volunteers) The Plasma Lipid Profile was unaffected by Dutasteride (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n = 13) of the one-year healthy volunteer study Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 DUTAS (Dutasteride) The Indian Experience Dr.Sunil Shroff - Dutasteride 2004

DUTAS (Dutasteride) An open prospective Phase III study to evaluate The efficacy & safety of Dutasteride in men with Benign Prostatic Hyperplasia (BPH) Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Clinical Trial Setting Seven Centres St.John’s Medical College, Bangalore Nizam’s Institute of Med Sci., Hyderabad M.S.Ramaiah Hospital, Bangalore PSG Institute of Medical Sciences, Coimbatore Nair Hospital , Mumbai Sri Ramachandra Medical College ,Chennai Care Hospital, Hyderabad After approval of Institutional Ethics Commitee and informed consent Dr.Sunil Shroff - Dutasteride 2004

Dutas : Bioequivalence Study Dr.Sunil Shroff - Dutasteride 2004 Comparative BE study between Dutas (DRL) & Avodart caps ( GSK) Inference : * Dutas (DRL) bioequivalent to Avodart . * Meets International Quality. Dr.Sunil Shroff - Dutasteride 2004

Dutas : Bioequivalence Study Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Prescribing Information : Dutasteride Composition: Each soft gelatin capsule contains: Dutasteride O.5 mg Capsules should be swallowed whole Colour: Iron Oxide Black and Iron Oxide Red Warnings & Precautions: Women who are pregnant or may become pregnant should not handle Dutasteride capsules because of possible absorption thro’ skin and risk of anomaly to male foetus. Caution should be exercised in patients with liver disease Dr.Sunil Shroff - Dutasteride 2004

Patients Profile on Dutasteride Dr.Sunil Shroff - Dutasteride 2004 Screened : 234 men with symptoms of BPH Enrolled : 88 men with BPH fulfilling inclusion criteria Mean Age = 66.15 yrs Mean Body Wt. = 64.54 kg Mean duration of BPH = 2.67 yrs Dropout: 5 4 pts after 4 weeks 1pt after 8 weeks Reason - lost to follow up Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Inclusion Profile Age 50 years and older Clinical diagnosis of BPH based on History, Physical and DRE AUA-SI - of 12 points or more Maximum urinary flow rate ( Qmax ) of 15ml / sec or less Voided volume of 125ml or greater Prostate volume (TRUS) of 30 cm3 or greater Inclusion Criteria same as three trials with identical design - Two conducted in the USA and one in 19 countries. Dr.Sunil Shroff - Dutasteride 2004

Dutasteride - Exclusion Criteria Residual volume of greater than 250ml History of prostate cancer, prior prostate surgery, Acute urinary retention within 3 months of screening Prostate Specific Antigen (PSA) – Normal Range, if above normal but below 10ng/ml to exclude malignancy by Sextant Biopsies Medication history with an α-blocker or other 5α-Reductase inhibitor in the last four weeks. Dr.Sunil Shroff - Dutasteride 2004

Evaluation Parameters Dr.Sunil Shroff - Dutasteride 2004 AUA - SI - ( Week 0, 4, 8 and 12 ) TPV (TRUS) - ( Week 0, 4 and 12 ) Qmax - ( Week 0, 4 and 12 ) PSA - ( Week 0 and 12 ) Clinical Adverse Event - ( Week 0 –12 ) Hematological and Biochemical Adverse Events - ( Week 0 and 12 ) Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 RESULTS Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 AUA-SI * Significantly different from Week 0, p < 0.00001 Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Total Prostate Volume * Significantly different from Week 0, p < 0.00001 Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Maximum Flow Rate * Significantly different from Week 0, p < 0.0001 Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 PSA * Significantly different from Week 0, p < 0.01 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – SRMC Experience (n 31) AUA-SI came down on an average by 7 points ( P value .0001) Prostate Volume decrease by 24% ( P value .001) Uroflow – mean increase by 3.2 ml/sec Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Drug Safety Seven patients reported adverse events Loss of libido (3), Erectile dysfunction (3) Abdominal pain (1) One patient with edema had to discontinue therapy due to concomitant cardiovascular disorder. No significant changes in hematological and biochemical parameters at week 12 compared to baseline Dr.Sunil Shroff - Dutasteride 2004

Finasteride VS Dutasteride Finasteride and Dutasteride both Reduce Prostate Volume Both work on Prostate cells and reduce conversion of Testosterone to DHT by blocking action of 5α-Reductase Finasteride works on 5α-Reductase Isoenzyme Type II Dutasteride exhibit less inter-individual variation in the level of DHT suppression compared to Finasteride Dr.Sunil Shroff - Dutasteride 2004

Combination Therapy in BPH Combination therapy with Alpha1 blockers & 5-Reductase Inhibitors may provide > benefit than mono - Rx Rationale : * alpha blockers offer rapid symptom relief * 5 – ARIs provide long term risk reduction Above aspects currently evaluated in clinical trials Dr.Sunil Shroff - Dutasteride 2004

Dutasteride: Combination Rx with -adrenergic blockers Objective Examine short term combination treatment with 1 – blockers & Dutasteride Followed by removal of 1 – blockers and continuation with only Dutasteride Trial details Multicenteric : 32 sites in 6 countries Age : Men  45years Methodology 1st Phase: 24 weeks: Combination Rx of Dutasteride 0.5mg/d & Tamsulosin 0.4 mg/d 2nd Phase: (12 weeks) 50 % of patients on combination & 50% on Dutasteride mono-Rx SMART 1 (Symptom Management After Reducing Therapy) : European Urology, 2003 Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 SMART – I : Conclusions Dutasteride can be used for short-term in combination Rx with 1-blockers (Tamsulosin) Combination Rx achieves rapid symptomatic relief; maintained even after 1-blockers withdrawal (after 6 months) SMART 1 (Symptom Management After Reducing Therapy) : European Urology, 2003 Dr.Sunil Shroff - Dutasteride 2004

Medical therapy: Alone and in combination For BPH (Final Vs Baseline Comparison Data) Placebo Finasteride Doxazosin Combination IPSS - 5.7 -6.6 -8.3* -8.5* PFR (Qmax) 1.4 1.8 3.6* 3.8* AUR 1.5 1.1 0.0 * P < 0.05 vs placebo Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Conclusion Dr.Sunil Shroff - Dutasteride 2004 A potent Type I & II - 5--Redutase inhibitor Generally well-tolerated Safety and tolerability data suggestions that Dutasteride to be well-tolerated in long-term use. Offers rapid onset of action, Clinical improvement in symptoms seen as early as 1 month Improves QoL and delays progression of BPH Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 Dutasteride – Conclusion 45 and 2.5 times more potent in inhibiting type I & II – 5 AR respectively than Finasteride Can be given effectively in combination with 1 – adrenergic blockers Pilot Indian experience in phase 3 trials, matches with International data. Larger multi-centre study can substantiate the above conclusion in Indian Patients Dr.Sunil Shroff - Dutasteride 2004

Dr.Sunil Shroff - Dutasteride 2004 References - Dutasteride 1. OsterlingJE. Benign Prostatic Hyperplasia: A Review of its Histogenesis and Natural History. Prostate Suppl.1996,667-73 2. Jacobson S J et al. Natural History of Prostatism: Risk Factors for Acute Urinary Retention 3. J Urol. 1997,158:481 -487 4. US Health care Financing Administration 2000 5. Rev Urol. 2003;5 (suppl 5):S28-S35] © 2003 Med Reviews 6. Clifford GM et al. Eur Urol 2000;38: 2-19 7. PLESS Study – Double Blind and Placebo Controlled 8. McConnel JD (1998) NEJM 9. Claus GR et al. (2002) Urology 60;434-41 10. SMART 1 (Symptom Management After Reducing Therapy) : European Urology, 2003 11. PREDICT: Kirby et al J Urol 1999;161;266 Dr.Sunil Shroff - Dutasteride 2004

Dutasteride – Indian Experience Sunil Shroff Sri Ramachandra Hospital Chennai sshroff@vsnl.com THANK YOU Dr.Sunil Shroff - Dutasteride 2004