How to treat: TRT modalities and formulations

Transcription

1 How to treat: TRT modalities and formulations Paul PIETTE, PharmD Senior Research Fellow Clinique Antoine Depage - Belgium ppiette@besins-healthcare.com Bruges 2014, May 15 th

2 Testosterone-replacement therapy should only be started in men who have a confirmed diagnosis of hypogonadism. The goal of treatment is to establish and maintain secondary sexual characteristics, sexual function, body composition, and quality of life. Although target testosterone concentrations in serum might be individualised, generally the aim should be to achieve those in the mid-normal range provided by a local laboratory. Basaria et al. Lancet 2013 online October 10,

3 TRx Volume in '000s Volume of Prescriptions by Year, 2009 to TRx Volume Trend by Year NPA data: ,884 7, , ,875 4,

4 Number of TRT Prescriptions by Patient Age (2009 to May 2014) Age, yrs YTD < 25 15,124 (0.6%) 19,336 (0.7%) 27,773 (0.7%) 37,996 (0.7%) 49,897 (0.9%) 23,915 (1.1%) ,373 (2.0%) 63,723 (2.2%) 97,923 (2.5%) 147,697 (2.9%) 188,739 (3.4%) 85,818 (4.1%) ,815 (9.0%) 284,072 (9.9%) 429,511 (11.1%) 640,076 (12.6%) 788,504 (14.1%) 331,810 (15.9%) ,699 (23.9%) 726,187 (25.3%) 1,047,280 (26.9%) 1,448,439 (28.5%) 1,656,641 (29.6%) 634,818 (30.3%) ,676 (33.4%) 958,374 (33.4%) 1,266,599 (32.6%) 1,612,768 (31.7%) 1,736,868 (31.1%) 622,721 (29.8%) ,798 (22.3%) 599,739 (20.9%) 757,873 (19.5%) 908,099 (17.9%) 904,732 (16.2%) 308,748 (14.8%) > ,566 (8.7%) 219,073 (7.6%) 259,939 (6.7%) 287,115 (5.6%) 263,781 (4.7%) 84,600 (4.0%) Total 2,426,051 2,870,504 3,886,898 5,082,190 5,589,162 2,092,430 Data source: SHA s Integrated Dataverse, non projected claims counts YTD = Year to date from January to May 2014

5 First line therapeutic approach (gels) & indication Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests APPROVED by EMA & FDA Box of 5gr = 30 sachets or dosing pump

6 Increasing testosterone use, in selected countries (% = transdermal) 97% 78% 78% 23% 50% 58% Handelsman D et al. MJA 2013; 199 (8):

7 Therapeutic approach to LOH Formulation: Advantages Disadvantages/Side effects Gel de T 1 2% Flexible dose Long lasting injectable Flexible dose Predictable bioavailability, constant blood level Good skin tolerability, no irritation, dry quicly Available in sachets or tubes (easy to apply) rapid in T levels in the presence of adverse events AEs (can be interrupted immediately) Administration of dose every 10 to 14 weeks. Daily administration Risk of transfer by skin contact to women and children in absence of precaution of use Local reactions to applicatio only significant in case of presence of enhancers Pain at injection site (high volume injected) High volume of castor oil to be injected Prolonged in T levels in the presence of AEs risk of microembolism in lung (POME): 30 FU after inj Long latency time before reaching steady state Intermediate duration injectable Implants Low cost Flexible dose Administration every 2 to 3 weeks Treatment every 3 to 6 months IM administration Pain at injection site Peaks and valleys in T levels Fluctuations in mood and libido Higher occurrence of erythrocytosis in old people SC (subcutaneous) surgical insertion Pain and inflammation at implant site Risk of infection and extrusion of the implants Meirelles RMR, Endocrinologia Feminina e Andrologia (Feminine Endocrinology and Andrology), pp , Surampudi PN et al., Int J Endocrinol, 2012.: doi: /2012/ Lunenfeld B et al, Aging Health 2009; 5(2) :

8 Therapeutic approach to LOH Formulation: Advantages Disadvantages/Side effects Oral PO administration Variable levels of testosterone above and below the midrange (Irregular bioavailability ) Variable clinical response Need for several doses per day with intake of fatty food. Risk of hepatotoxicity Transdermal system Easy to administer rapid in T levels in the presence of adverse events Daily administration Local reactions to application are common Can need to administer 2 patches per day Transbuccal system Restore T levels in the majority of patients Short half-live, requiring change twice a day Impossible to adjust the dose Disagreeable flavor Mouth Irritation and pain at the site of application Meirelles RMR, Endocrinologia Feminina e Andrologia (Feminine Endocrinology and Andrology), pp , Surampudi PN et al., Int J Endocrinol, 2012.: doi: /2012/ Lunenfeld B et al, Aging Health 2009; 5(2) :

9 Finkelstein JS et al. N Engl J Med 2013; 369 (11):

10 Mean Serum Testosterone and Estradiol Levels from Weeks 4 to 16, According to Testosterone Dose and Cohort. Finkelstein JS et al. N Engl J Med 2013; 369 (11):

11 Results of the 6 Month AndroGel Trial Average serum hormone assays Day 180 compared to baseline T-gel 5g n = 73 T-gel 10 g n = 78 T-patch n = 76 Percent free-t / T SHBG No significant alteration Small decrease across 3 groups DHT [fold increase] Estradiol [% increase] LH suppression [%] Swerdloff RS, Wang C et al. J Clin Endo Metab 2000; 85:

12 Follow-up during and after TRT (risks management) Paul PIETTE, PharmD Senior Research Fellow Clinique Antoine Depage - Belgium ppiette@besins-healthcare.com

13 Potential risk and safety information with T therapy (TT) Cardiovascular disease Lipid alterations Erythrocytosis Fluid retention B.P.H. Prostate cancer Hepatotoxicity Sleep apnea Gynecomastia Neutral or beneficial effect Neutral if physiologic replacement doses 3 à 18% with transdermal administration up to 44% with injection, Rarely of clinical significance Rarely of clinical significance Controversial Limited to oral administrations infrequent rare, usually reversible Skin reactions HIGH INCIDENCE with patch (up to 66%) Testicular atrophy or infertility LOW INCIDENCE with gel (5%) rare with injections Common in young men, more with inj.* Reversible with cessation of treatment Adapted * from Rhoden E.L. et al. N Engl J Med 2004; 350:

14 Effects of T gel (after 3 months) on sperm characteristics in 18 hypogonadal men Similar data were obtained in another study, where treatment with IM testosterone injections led to a decline in LH, FSH and sperm concentration. Thus, treatment with IM testosterone forms should be avoided in patients who are planning to father a child in the next 2 years Mskhalaya et al. Gynecol Endocrinol Published online August 28th

15 Contra-indications of TT According to the 2008, ISA, ISSAM, EAU, EAA, and ASA Recommendations Absolute Contra-indications Men suspected of or having carcinoma of the prostate or breast [ant. of Sexual criminality, desire for fertility] Relative Contra-indications Men should not be treated with testosterone if High risk of developing prostate cancer Severe symptoms of lower urinary tract obstruction Significant erythrocytosis Untreated severe congestive heart failure Untreated obstructive sleep apnea Wang C, Nieschlag E et al. Aging Male 2008: 1-8.

16 Conditions in which testosterone administration is associated with a high risk of adverse outcome and for which we recommend against using T (According to the 2010 US Endocrine society guidelines) Very high risk of serious adverse outcomes Moderate to high risk of adverse outcomes Metastatic prostate cancer Breast cancer AUA/IPSS = American Urological Association / International Prostate Symptom Score Unevaluated prostate nodule or induration PSA > 4 ng/ml (>3 ng/ml in individuals at high risk for prostate cancer, such as African Americans or men with first-degree relatives who have prostate cancer) Hematocrit >50% Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by AUA/ IPSS score >19 Uncontrolled or poorly controlled congestive heart failure Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab. 2010; 95(6):

17 Additional Risks of TT According to the 2008, ISA, ISSAM, EAU, EAA, and ASA Recommendations Because the possible development of an adverse event during treatment (especially elevated hematocrit or prostate carcinoma) requires rapid discontinuation of testosterone substitution short-acting preparations may be preferred over long-acting depotpreparations in the initial treatment of patients with LOH 17-α-alkylated testosterone androgen preparations such as 17-α-methyl testosterone are obsolete because of their potential for liver toxicity and should be no longer prescribed Wang C, Nieschlag E et al. Aging Male 2008: 1-8.

18 TRT clinical monitoring 3 to 6 months after starting the treatment 3 to 6 months later on After each (6 to) 12 months Clinical efficacy and tolerance evaluation Symptoms Clinical Tolerance - After 6 months: if non response (stop or other causes) - Morning erection - Sexual desire - Energy - Physical performance - Waist circumference - BP - Breast - Compliance - DRE after 40 years Buvat J et al. J Sex Med 2013; 10:

19 T blood levels monitoring Enanthate/Cyp. T inj Between 2 injections, and/or after 2 or 3 weeks Undecanoate T inj Just before next injection Implants Just before next injection Patchs Daily: 6 to 12 hours after application Matricial (2 days): 13 to 36 hours after application Gels 2 to 8 hours after application more than 2 weeks after starting the treatment Axilar solution Same Undecanoate T per os 3 to 5 hours after ingestion Buvat J et al. J Sex Med 2013; 10:

20 EVOLUTION OF Prostate Specific Antigen (PSA) by Duration of Treatment in Long-Term Study (Final) 3.0 PSA (ng/ml) Baseline Treatment (months) Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:

21 PSA (ng/ml) MEAN PSA LEVELS in the PADAM study Baseline Time (months) Placebo/ testosterone gel following 6 months placebo Transdermal testosterone gel only Bouloux PM et al. Results presented at the EAU Congress, Italy 2008.

22 Seeking an Urological Consultation Biological monitoring: alert criteria Relative TT > 700 ng/dl < 50 yr - More especially when beteween 50 to 65 years old Absolute (ask for urologic advice) TT > 500 ng/dl in frailty or > 65y HCT > 52-54% (function lab value) PSA 1ng/mL in 12 months or >4ng/mL (abs. value) During 1 st 24months 0.75ng/mL in 12 months followed by additional increase in next 3-6 months After 24 months >0.4ng/mL in 12 months followed by additional increase in next 3-6 months Buvat J et al. J Sex Med 2013; 10:

23 Monitoring TT According to the 2008, ISA, ISSAM, EAU, EAA, and ASA Recommendations Testosterone and Sexual Function Determine serum T for all men with ED and/or diminished libido If low T (<320ng/dL) and treated but inadequate response, reassess the causal mechanisms responsible for the ED Evidence suggests therapeutic synergism with combined use of T and PD-5 inhibitors in hypogonadal or borderline eugonadal men Combination treatment should be considered in hypogonadal men with ED failing to respond to either treatment alone Wang C, Nieschlag E et al. Aging Male 2008: 1-8.

24 Why a «Physiological correction of T deficiency»? Testosterone therapy in gel Contains 1% body-identical hormone Consistent and constant testosterone blood levels for a duration of 24 hours Lead to lesser decline in sperm count compared to injections Predictable bioavailability (87% of patients always remains in the physiological range) Well tolerated locally as well as systemically No skin irritation, easy tailoring of the treatment Dry quickly Odorless, colorless, not painful Can be interrupted immediately at any time Lunenfeld B et al. Aging Health 2009;5(2) :