off-label use of medicines in sexual med

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Andrology, Sexology and sexual medicine

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“Off-Label” drug use in Sexual Dysfunction : 

“Off-Label” drug use in Sexual Dysfunction By Shedeed Ashour Shedeed,M.D. Assistant Professor of Andrology, Sexology & STDs. Cairo University- Cairo, Egypt Consultant Andrologist, Dr Erfan & Bagedo General Hospital Jeddah, KSA DAMMAM -KHOUBAR-2009

Introduction : 

Introduction The use of legally available drugs is the Good Medical Practice that all patients hope. If a medicinal is used for an indication which is not stated in the labeling , they’ll be responsible for: Well informed about the product Base its use on firm scientific rational Sound medical evidence Maintain records of the product’s use and effects1 Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008 1-US food and drug administration FDA. Off label and investigational use of marketed drugs, biologics and medical devices.

Introduction : 

Introduction FDA allows the off-label use of medicines in the medical practice without IRB review.1 “Off-label” use often means that efficacy, safety and tolerability data are not available for that specific use: Classes commonly used: Anticonvulsants Antipsychotics Antihistamines Antiasthmatics Cardiovascular agents Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008 1-US food and drug administration FDA. Off label and investigational use of marketed drugs, biologics and medical devices.

Introduction : 

Introduction According to one study, approximately 21% of all prescriptions are written for off-label indications in office practice, and approximately 73% of those off-label uses have little or no scientific support.1 The great majority of drug use in pediatric practice is off-label, as therapeutic trials are rarely conducted in pediatric patients. Likewise, drug treatment in oncology and HIV treatment is commonly off-label. US food and drug administration FDA. Off label and investigational use of marketed drugs, biologics and medical devices. 1-Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med; 166: 1021—1026,2006.

Drug manufacturers will not usually try to get FDA approval for off-label uses of their products because of the time and expense involved, and may be subject to legal action by the FDA if they market products for off-label uses.1 : 

Drug manufacturers will not usually try to get FDA approval for off-label uses of their products because of the time and expense involved, and may be subject to legal action by the FDA if they market products for off-label uses.1 1-Henry V. Off-label prescribing: legal implications. J Leg Med. 20: 365—384; 1999.

Slide 6: 

Of all drugs, commonly used in the treatment of sexual dysfunctions, phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are FDA-approved for treatment of male erectile dysfunction, and Testosterone is approved for the treatment of delayed puberty and hypogonadism in men. All other drug usage in the treatment of sexual dysfunctions is off-label, some with good evidence of efficacy, and some without. Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008

Dapoxetine (PriligyTM) : 

Dapoxetine (PriligyTM) 10th of Feb. 2009 received the first regulatory approval in Finland and Sweden. Now its approved in 7 European countries (EMEA). FDA approval is still bending for more studies as asked in 2006.

Commonly used drugs in SD : 

Commonly used drugs in SD

Slide 10: 

According to the Theme of the Conference, I will elaborate on the off label drug use of: Premature ejaculation (PME). Peyronie’s disease(PD).

Prevalence of PE in Representative Epidemiological Studies : 

Prevalence of PE in Representative Epidemiological Studies 15 1239 Internet population Ho (2003) 18 1320 US men (40+ yrs) Carson et al (2003 4 2810 Swedish (18–74 yrs) Fugl-Meyer (1999) 29 3159 US men (18–59 yrs) Laumann (1999) 14 439 Danish Solstad (1993) 36 423 English students Eysenck (1983) 42 100 US couples Frank (1976) PE (%) n Type (age) Study Adapted from Simons JS, Carey MP. Arch Sex Behav 2001;30(2):177–219.

Premature ejaculation (PME). : 

Premature ejaculation (PME). Drugs used extensively in the treatment of PME: SSRIs TCAs PDE5I Local anesthetics (sprays and Gels). Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008

Serotonergic control of ejaculation : 

Serotonergic control of ejaculation 5-HT neurotransmission is locally regulated by the 5-HT transporter re-uptake system As 5-HT is released, the transporter system is activated, removing 5-HT from the synaptic cleft and preventing over-stimulation of postsynaptic 5-HT receptors McMahon CG et al, Disorders of orgasm and ejaculation in men. In Sexual Medicine: Sexual dysfunctions in men and women. 2nd International Consultation on Sexual Dysfunctions, Paris, 2004

PE: animal studies : 

PE: animal studies Animal studies have revealed that mice lacking the gene for eNOS develop symptoms similar to PE, while mice lacking the gene for heme Oxygenase-2 develop DE or anejaculation. Kregisfeild et al., Pysiol Behav, 1999.

Premature ejaculation (PME). : 

Premature ejaculation (PME). Antidepressants SSRIs: Rat studies have found that SSRIs block the presynaptic membrane 5HT transporters, resulting in delayed ejaculation. Pts taking these drugs for depression noted a prominent delay of ejaculation. Clinical effects of SSRIs in PME treatment, first reported in 1994, with Paroxetine. IELT get longer with Paroxetine In meta-analysis of 35 studies only 8 met the EBM standards. 1.4 folds IELT increase for placebo Vs 8.8 folds for the treatment group. Waldinger MD, Hengeveld MW, Zwinderman AH. Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study. Am J Psychiatry 1994. Waldinger et al. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res 2004.

Premature ejaculation (PME). : 

Premature ejaculation (PME). Antidepressants SSRIs: Onset of action. For how long Acquired Vs life-long PME. Relapses1 and tachyphylaxis.2 On-demand Vs Daily dosing. Side effects.{common, uncommon and discontinuation syndrome}. 1-Arafa M, Shamloul R. Efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire. Int J Impot Res. 2006. 2-Waldinger et al. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res 2004.

Premature ejaculation (PME). : 

Premature ejaculation (PME). Antidepressants SSRIs: Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008

Premature ejaculation (PME). : 

Premature ejaculation (PME). Local anesthetics (sprays and Gels): Rational. Advantages. Disadvantages. Preps. Studies are not large enough. Despite the fact they are frequently used, convincing data about their effectiveness are not available. Drop-out rate is very high. -Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008 -Busato W, Galindo CC. Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlled study. BJU Int 2004.

Premature ejaculation (PME). : 

Premature ejaculation (PME). PDE5I: Rational Several studies many of them is a form of contemporary therapy. 14 studies between 2001-2006. Meta analysis could not be done Different methodologies Regarded unreliable McMahon CG, McMahon CN, Leow LJ, Winestock CG. Efficacy of type-5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review. BJU Int 2006. Abdel-Hamid IA, El Naggar EA, El Gilany A-H. Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. Int J Impot Res 2001.

Why is PDE5 Inhibitors Effective? : 

Why is PDE5 Inhibitors Effective? Decrease the contractility of Seminal vesicles, Vasa and the urethra due to Smooth Muscle relaxation. Reduction in performance anxiety Anxiety score reduction supports erection Maintenance of erection prolongs ejaculation latency time Learned behavior? Central effect NOS-1/PDE-5 present in spinal cord T-8/L-3 CNS “loaded” with NOS-1 Regulatory role of NOS? McMahon CG, Stuckey BG, Andersen M, Purvis K, Koppiker S, Haughie S et al. Efficacy of sildenafil citrate (Viagra) in men with premature ejaculation. J Sex Med 2005; 2: 368—375.

EDITS* Satisfaction Scores (median) : 

EDITS* Satisfaction Scores (median) Abdel-Hamid, et al., IJIR, 13: 41-45, 2001

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease Oral medications Transdermal Therapy Intralesional medications Corticosteroids, Collagenases and Interferons and Verapamil 8.9% of Men being affected Its natural history vary…from 1990.1 Non of all treatment modalities are FDA approved for the treatment of PD Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008 1- Gelbard MK, Dorey F, James K. The natural history of Peyronie's disease. J Urol 1990; 144: 1376—1379.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease No substantial RCT. Nevertheless Vit E and Potaba are still frequently used. Benefits Vs Drawbacks Placebo effect. Oral Medications: VitaminE, Colchicine, Tamoxifen, Carnitine and Potaba. Bernard Fallon. Off label drug use in sexual medicine. Int J Impot Resc. 20(2):127-134,2008 1- Gelbard MK, Dorey F, James K. The natural history of Peyronie's disease. J Urol 1990; 144: 1376—1379.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease Verapamil as a Ca Channel blocker, increases collagenase activity and fibroblasts activity. Decreases Pain with or without steroid therapy. ? Tunical Bx. found negative in 8 pts. pretreated with Verapamil. !!! Iontophoresis ? Recent studies*….. Superior to intralesional therapy? Transdermal Medications: Verapamil, Steroids, iontophoresis, Dexamethazone and ESWL. Martin DJ, Badwan K, Parker M, Mulhall JP. Transdermal application of verapamil gel to the penile shaft fails to infiltrate the tunica albuginea. J Urol 2002; 168: 2483—2485. *Fitch III WP, Easterling WJ, Talbert RL, Bordovsky MJ, Mosier M. Topical verapamil HCl, topical trifluoperazine, and topical magnesium sulfate for the treatment of Peyronie' disease- a placebo-controlled pilot study. J Sex Med 2007; 4: 477—484.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease Local high concentration and decrease incidence of systemic toxicity. Steroids can improve pain, curvature and claimed to reduce plaque size (97, 32 and 31% respectively) but in combination with hyaluronidase? Side effects. Recent PD less than 12 month and plaque size<2cm. Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. Lamprakopoulos A, Zorzos I, Lykourinas M. The use of betamethasone and hyaluronidase injections in the treatment of Peyronie's disease. Scand J Urol Nephrol 2000; 34: 355—360.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease Purified clostridial collagenase. Prospective double blind randomized study cross over retreatment arm. 49 pts, increasing doses according to curvature severity. Results are not satisfactory or reproduced, Numbers were inadequate Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. Gelbard MK, James K, Riach P, Dorey F. Collagenase versus placebo in the treatment of Peyronie's disease: a double-blind study. J Urol 1993; 149: 56—58.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease IFN-a and ß inhibit fibroblast and collagen production and increased collagenase production. Therapy is appealing. Clinical experience was not encouraging. Contradicting results of different studies. Supplementation in some studies. Some plaque size and pain improvement are the noticeable results Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. Judge IS, Wisniewski ZS. Intralesional interferon in the treatment of Peyronie's disease: a pilot study. Br J Urol 1997; 79: 40—42. Inal T, Tokatli Z, Akand M, Ozdiler E, Yaman O. Effect of intralesional interferon-alpha 2b combined with oral vitamin E for treatment of early stage Peyronie's disease: a randomized and prospective study.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease The first clinical report of intralesional verapamil therapy in PD used injections every 2 weeks in 14 patients for 6 months.1 Ten milligrams of verapamil in 10 ml were injected using a 25 G needle and 100—150 plaque punctures each time. Ten of 10 patients had pain resolution, 9 of 9 bottleneck deformities resolved and 5 of 12 had curvature improvement. Four patients had surgery later. Results are not satisfactory or reproduced. Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. 1-Levine LA, Merrick PF, Lee RC. Intralesional verapamil injection for the treatment of Peyronie's disease. J Urol 1994; 151: 1522—1524.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease A recent study 'Intralesional Verapamil Prevents the Progression of Peyronie's Disease' of 94 patients treated with six injections of 10 mg verapamil found improvement in curvature in 18%, with no change in 60% and worsening in 22%. Average curve was 50º at baseline and 47º after treatment. Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. Bennett NE, Guhring P, Mulhall JP. Intralesional verapamil prevents the progression of Peyronie's disease. Urology 2007; 1181—1184.

(PD) Peyronie’s disease : 

(PD) Peyronie’s disease A recent literature review of intralesional injection studies in PD found a total of 19 published studies, including: four verapamil studies. Sixteen of these were level 4 according to the Oxford Center for Evidence—Based Medicine criteria (case series—level 5 is the lowest, expert opinion). Three of the four verapamil reports were level 4, and the fourth study, noted above, had only 14 patients. Intralesional therapy: Corticosteroids, collagenases, Interferon and Verapamil. Russell S, Steers W, McVary KT. Systematic evidence-based analysis of plaque injection therapy for Peyronie's disease. Eur Urol 2007; 51: 601—603. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)

Slide 32: 

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)

Summary : 

Summary Off-label use of drugs is common in treating sexual disorders. It is reasonable to recommend the routine use of a particular treatment if there is high-level evidence of efficacy and safety. The quality of the evidence should be high-level 1 or 2, using the Oxford Center for Evidence-Based Medicine criteria The use of SSRIs (with daily dosing) in PE seems to have a reasonable evidence-based justification. None of the treatments for PD has evidence-based justification, as there are essentially no randomized controlled trials.

Slide 34: 

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