BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE. Bulletin 169: Daily Tadalafil (Cialis ) for penile rehabilitation following radical prostactectomy

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE September 2012 Review date: September 2014 Bulletin 169: Daily Tadalafil (Cialis ) for penile rehabilitation following radical prostactectomy JPC Recommendation: The use of daily tadalafil for the treatment of penile rehabilitation following radical prostatectomy is not recommended. New Medicine Review Medicine Document status Daily tadalafil (Cialis ) for penile rehabilitation following radical prostatectomy Final Date of last revision August 2012 Proposed Sector of Primary, Secondary and Tertiary Care prescribing The intervention Mechanism of action Licensed indications Usual dosage Tadalafil is a selective, reversible phosphodiesterase type-5 (PDE5) inhibitor. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cyclic GMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. The SPC notes that tadalafil has no effect in the absence of sexual stimulation (1). Tadalafil (Cialis ) is licensed in the UK for the treatment of erectile dysfunction (ED) in adult males (1). The regular use of daily tadalafil as part of penile rehabilitation strategies in the early post-operative period following radical prostatectomy (RP), which is being considered in this review, does not fall within the licensed indications of tadalafil or any of the currently available PDE5 inhibitors. Tadalafil (Cialis ) is available as 2.5mg, 5mg, 10mg and 20mg film-coated tablets for oral use. In general, the recommended dose is 10mg taken at least 30 minutes prior to anticipated sexual activity; 20mg may be tried in those who do not have an adequate response. The maximum frequency is once a day (1). In patients who anticipate a frequent use of tadalafil (at least twice weekly) a once daily regimen might be considered suitable, based on patient choice and the physician's judgement. In these patients, the recommended dose is 5mg once daily; this may be decreased to 2.5mg once daily based on individual tolerability. The 10mg and 20mg doses of tadalafil are not recommended for continuous daily use. The appropriateness of continued use of the daily regimen should be reassessed periodically (1). Page 1 of 11

2 Treatment alternatives/ place in therapy Future alternatives National guidance The data for tadalafil in the setting of penile rehabilitation post-prostatectomy is very limited and no prospective, controlled studies are currently available (see below). Various doses have been described in the lower quality research (for example 20mg three times a week, 10mg every other day, 20mg every three days). The use of the daily regimen of tadalafil in this setting has not been described in the published literature. The other licensed PDE5 inhibitors (sildenafil, vardenafil) have been studied for this indication. Other interventions that have been used or investigated for penile rehabilitation include intracavernous injections, vacuum devices, and intraurethral alprostadil (2). The International Consensus of Sexual Medicine committee were unable to make any specific recommendation regarding the optimal rehabilitation regimen, due to the lack of good quality evidence (2). Unknown No national guidance or recommendations from any official bodies regarding the use of PDE-5 inhibitors as part of penile rehabilitation were located. In its clinical guideline on prostate cancer (published 2008), NICE recommends the use of PDE-5 inhibitors for men with prostate cancer who experience loss of erectile function, in order to improve their chance of spontaneous erections. No reference to the use of chronic therapy in the early post-operative period is however made (3). This guideline is currently being updated (4). The Department of Health issued guidance on the treatment of impotence (HSC 1999/148), recommending that one treatment a week of a PDE5 inhibitor will be appropriate for most patients treated for ED. If the GP, in exercising his clinical judgement, considers that more than one treatment a week is appropriate, for example, the daily regimen of tadalafil for men having intercourse at least twice a week, he should prescribe that amount on the NHS (5, 6). Please note that this guidance relates to the treatment of ED and therefore would not apply to its off-license use for penile rehabilitation. Prescribing Issues Drug treatment for erectile dysfunction may only be prescribed on the NHS under certain circumstances i.e. to treat erectile dysfunction in men who (16): have diabetes, multiple sclerosis, Parkinson s disease, poliomyelitis, prostate cancer, severe pelvic injury, single gene neurological disease, spina bifida, or spinal cord injury; are receiving dialysis for renal failure; have had radical pelvic surgery, prostatectomy (including transurethral resection of the prostate), or kidney transplant; were receiving Caverject, Erecnos, MUSE, Viagra, or Viridal for erectile dysfunction, at the expense of the NHS, on 14 September 1998; are suffering severe distress as a result of impotence (prescribed in specialist centres only) *The prescription must be endorsed SLS. Evidence for use Radical prostatectomy is a well-established treatment option for organ-confined prostate cancer, which involves removal of the entire prostate and anastamosis of the bladder neck to the remaining urethra (7). Despite the introduction of the nerve-sparing technique and continued surgical advancement, ED remains a common complication that may take years to resolve, if at all (8). Regardless of the surgical technique used, prostate removal may result in a dormancy of the nerves that govern the functional aspects of erection. This may lead to a loss of daily and nocturnal erections associated with persistent failure of cavernous oxygenation and secondary erectile tissue damage, resulting from the reduction of pro-apoptotic (loss of smooth muscle) and pro-fibrotic factors (increase in collagen) within the corpora cavernosal (2). Page 2 of 11

3 The concept of penile rehabilitation was introduced in this is defined as the use of any drug or device at or after radical prostatectomy to prevent smooth muscle structural alterations and maximise erectile function recovery (9). This is different to, and should not be confused with, the treatment of ED following radical prostatectomy (8). Penile rehabilitation started with the use of intracavernous injections of alprostadil; studies utilising PDE5 inhibitors then followed, after promising results in animal research (9). To date there have been two published randomised, placebo-controlled trials of PDE5 inhibitors for penile rehabilitation; these are frequently cited in review articles on the subject. Padma-Nathan et al sought to evaluate the efficacy of a prophylactic, nightly regime of sildenafil in the prevention of long-term ED in men who had undergone nerve-sparing radical prostatectomy (10). Please note that the study was prematurely discontinued because the response rate at the interim analysis suggested a lack of response (the placebo response rate was much lower than expected) - the size of the trial was therefore smaller than planned. A total of 76 men (age range years) with normal pre-operative erectile function were randomised four weeks post-prostatectomy to double-blind treatment with sildenafil 50mg/day (n=23), sildenafil 100mg/day (n=28) or placebo (n=25) for 36 weeks. The primary endpoint was the percentage of patients who were responders after an 8-week washout period (during which no ED medications were taken). A responder was someone with a combined score of at least 8 on questions 3 and 4 of the International Index of Erectile Function (IIEF), who also answered yes to the question over the past 4 weeks have your erections been good enough for satisfactory sexual activity? The rate of responders was 26% (6/23) in the sildenafil 50mg group, 29% (8/28) in the sildenafil 100mg group and 4% (1/25) in the placebo group. The overall rate of response in the sildenafil groups was 27% (95% CI 16-42%; p=0.02 versus placebo). Of the 125 originally randomised to treatment, only 82 completed the 36-week doubleblind phase and the subsequent 8-week drug-free evaluation period was completed by 76 the latter constituted the population analysed for efficacy (as above). This low patient number (in addition to the low erection rates in both groups) weakens the strength of the result and the reliability of any conclusions made. In addition, the analysis was not intention-to-treat therefore withdrawal due to adverse events etc (which would happen in a real-life situation) has not been accounted for. The authors comment that follow-up studies are required to support these findings and to examine the effect of lower doses, earlier initiation of therapy and intermittent therapy, and to determine the optimal duration of treatment. Montsori et al compared nightly to on-demand vardenafil (versus placebo) following nerve sparing radical prostatectomy, in men who had normal pre-operative erectile function (11). This is the only located study that compared chronic PDE-5 inhibitor use to on-demand dosing in this patient group. In this multicentre, double-blind study, men were randomised within 14 days of surgery to receive vardenafil 10mg nightly with ondemand placebo (n=210), nightly placebo with on-demand vardenafil 10mg (n=208) or nightly placebo and on-demand placebo (n=210). Drop-out rates were 35%, 33% and 31%, respectively; the most common reasons were withdrawal of consent, protocol violation, adverse events, and lack of efficacy (latter predominantly in the placebo group). Treatment was for 9 months, after which there was a single-blind placebo washout for two months and an additional 2-month open-label vardenafil on-demand period. The primary endpoint was the percentage of patients IIEF-erectile function domain score of 22 (defined as mild ED) after the 2-month washout period (using the last-observationcarried-forward principle for those who did not complete the study). After the double-blind phase, the percentages of patients with IIEF-EF score 22 were 24.8%, 32.0% and 48.2% for the placebo, vardenafil nightly and vardenafil on-demand Page 3 of 11

4 groups, respectively (p= for vardenafil on-demand versus placebo, and p= vardenafil on-demand versus vardenafil nightly). The primary efficacy endpoint was however not met in this study there were no statistically significant differences among treatment groups in the percentage of patients with an IIEF-EF score 22 at the end of the washout period (28.9%, 24.1% and 29.1% of patients in placebo, vardenafil nightly and vardenafil on-demand groups, respectively). There were additionally no differences between the groups in various measures during the open-label on demand period including no advantage for vardenafil over placebo. The authors conclude that their findings support a paradigm shift towards on-demand dosing with PDE5 inhibitors for the treatment of ED in men in this patient group. Although this study raised many doubts about the concept of penile rehabilitation, suggesting that nightly dosing did not have any effect beyond that of on-demand use, the study received much criticism because of its design (12). Another prospective, randomised study compared the effectiveness of nightly intraurethral alprostadil and oral sildenafil (50mg) given following nerve sparing radical prostatectomy in men who had normal erectile function prior to surgery (13). The results found the two to be of a similar efficacy but they are difficult to interpret due to the lack of a placebo group (and the fact that there is no standard penile rehabilitation treatment that has demonstrated unequivocal efficacy, so there is no standard comparator). The results have therefore not been considered here. Other studies of PDE5 inhibitors (mainly sildenafil) have been published in the literature but these have not been discussed here as they are of a lower quality, with no randomisation and/or no placebo/control group. As vardenafil and sildenafil have short half-lives, it is possible that 24-hour PDE5 inhibition to extend the action of the drugs would obtain better results. Studies that could address this have however not yet been performed, and there are no published data for daily tadalafil, a long-lasting PDE5 inhibitor, for penile rehabilitation (9). The general data for tadalafil at any dose in this setting is very limited, with no randomised, placebocontrolled studies available (please see Appendix for the details of two retrospective studies supplied by the company; 14, 15). In summary, good-quality published evidence to support the use of PDE5 inhibitors (or any strategy) for penile rehabilitation is lacking. Prospective, randomised placebocontrolled studies are needed to firmly establish the efficacy of PDE5 inhibitors or other therapies in rehabilitation programmes to support the recovery of erectile function after radical prostatectomy. There is inconsistency between the currently available studies regarding the drug used, dose, frequency, and the possibility of selection bias and heterogeneity of treatments needs to be addressed in future research. Cost effectiveness (if available) Safety No relevant data on cost-effectiveness were located. As no studies of daily tadalafil in the proposed indication were located, safety data have been taken from the Cialis Summary of Product Characteristics (SPC). This is not a complete summary of side-effects/cautions/contra-indications and the SPC should be consulted for further information. The most commonly reported adverse reactions to tadalafil are headache and dyspepsia; other common ones include dizziness, flushing, nasal congestion, dyspepsia, back pain and myalgia. Uncommon side-effects include hypersensitivity reactions, blurred vision, sensations described as eye pain, swelling of eyelids, conjunctival hyperaemia, tachycardia (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, epistaxis, rash, urticaria, hyperhidrosis and chest pain. Other side effects are listed in SPC that occurred rarely or with an unknown frequency. Page 4 of 11

5 Tadalafil augments the hypotensive effects of nitrates and therefore it should not be given to anyone using any form of organic nitrate. For patients taking other antihypertensives, consideration should be given to a possible dose adjustment when daily tadalafil is started, as it may induce a blood pressure decrease. The combination of tadalafil and doxazosin is not recommended. Concurrent use of tadalafil and potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) may increase tadalafil exposure so caution is advised. Tadalafil should not be used in combination with other PDE5 inhibitors or other treatments for ED as the safety and efficacy of such a strategy has not been studied. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. The use of tadalafil in certain patients with cardiovascular disease who were excluded from clinical trials (e.g. MI within the previous 90 days) is contraindicated. Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in association with tadalafil and other PDE5 inhibitors. Patients should be advised to stop taking tadalafil and consult a physician immediately if they experience sudden visual defect. Costs Tariff status Activity costs Costs of alternatives Potential number of patients in Bedfordshire and Luton Impact per 100,000 population Affordability considerations Number Needed to Treat (NNT) Number Needed to Harm (NNH) Ethics Equity Once daily dosing of tadalafil is not recommended in patients with severe renal impairment and has not been evaluated in patients with hepatic insufficiency. If it is to be used in the latter patient group then a careful risk/benefit assessment must be made. Daily regimen: 28 x 2.5mg or 5mg tablets: (16) There is no standard treatment for penile rehabilitation due to the limitations of the currently available literature and therefore alternatives have not been considered. Prostate cancer is the most common cancer in men and makes up 24% of cancer diagnoses in men in the UK. It is predominantly a disease of older men but around 25% of cases occur in men younger than 65 years (4). In 2008, 34,335 men were diagnosed with prostate cancer and there were 9376 deaths from prostate cancer in England, Wales and Northern Ireland (4). No data on the number of radical prostatectomies, and therefore the eligible population for penile rehabilitation, were located from the sources searched. Not calculated due to insufficient data. Implementation Patient choice/ access considerations Page 5 of 11

6 Decisions from other bodies/ Nil located. Grey literature comments sought from Points for consideration/ Limitations of review Two randomised, placebo-controlled studies of PDE5 inhibitors for penile rehabilitation have been published one suggested benefit from sildenafil whereas the other suggested that regular vardenafil use post-prostatectomy is no better than on-demand use. Both of these studies have methodological issues. Although other data are available (mainly sildenafil), these studies are of a lower quality (e.g. uncontrolled, nonrandomised). The vardenafil study is the only one to have compared regular versus on-demand PDE5 inhibitor in the setting of penile rehabilitation, and further work comparing the two strategies is required to determine whether regular use has any advantages. There is inconsistency between the currently available studies regarding the drug used, dose, frequency, and the possibility of selection bias and heterogeneity of treatments needs to be addressed in future research. No published studies of daily tadalafil used post-prostatectomy as part of penile rehabilitation were located and the data in general for the efficacy of tadalafil for this indication at any dose are limited to retrospective studies, that have not been fully published. Although it has been postulated that daily tadalafil may be associated with superior outcomes to the other PDE5 inhibitors due to its longer half-life (allowing for 24-hour PDE5 inhibition), this remains to be seen until adequate trials are available. Can once daily tadalafil be prescribed on the NHS for penile rehabilitation following radical prostatectomy? References/ Sources of Review 1) Cialis SPC (last updated 21/2/2011). Accessed via on 16/8/2012 2) Salonia A et al (2012) Prevention and management of postprostatectomy sexual dysfunctions part 2: Recovery and preservation of erectile function, sexual desire, and orgasmic function. European Urology;62: ) NICE Clinical Guideline on prostate cancer (CG 58; 2008) 4) NICE Prostate Cancer guideline update (in progress) 5) Health Service Circular HSC 1999/148. Treatment for impotence. 30th June Accessed via ) London New Drugs Group Primary Care Briefing Daily tadalafil (May 2009) Daily-Tadalafil/?query=tadalafil&rank=100 7) Anon (2004) Management of localised prostate cancer. Drug and Therapeutics Bulletin;42: ) Hedges JC, Laborde E (2012) Penile rehabilitation after radical prostatectomy. The Journal of Urology; 187(1):15-17 Page 6 of 11

7 9) Glina S (2011) Erectile dysfunction after radical prostatectomy. Drugs Aging; 28(4): ) Padma-Nathan H et al (2008) Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Imp Res; 20: ) Montsori F et al (2008) Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. European Urology; 54: ) Mulhall JP (2009) Does on-demand vardenafil improve erectile function recovery after radical prostatectomy? Nature Clinical Practice Urology; 6(1): ) McCullough AR et al (2010) Recovery of erectile function after nerve sparing radical prostatectomy and penile rehabilitation with nightly intraurethral alprostadil versus sildenafil citrate. The Journal of Urology; 183: ) Stefaniak H et al (2005) Tadalafil therapy beginning postoperative day one preserves erectile function after radical prostatectomy preliminary results [abstract presented at the 69th Annual Southeast Section meeting of the American Urological Association: March 3-6, Charleston, SC]. J Am Coll Surg;201(3) (suppl 1):S94. 15) Mombet A et al (2006) Evaluation of sexual activity after laparoscopic radical prostatectomy. [Abstract also presented as a poster at the 21st Annual European Association of Urology meeting: April 5, Paris, France] Eur Urol Suppl 2006; 5(2):90. Abstract ) British National Formulary; volume 63, March 2012 Page 7 of 11

8 Appendix: Retrospective data supplied by company for tadalafil in penile rehabilitation G:\Prescribing Team\JPC\JPC\JPC-approved bulletins\sept 12\Bulletin 169 Tadalafil for treatment of penile rehabilitation following radical prostatectomy.doc Page 8 of 11

9 Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (date): Daily tadalafil (Cialis ) for penile rehabilitation following radical prostatectomy (September 2012) JPC Recommendation: The use of daily tadalafil for the treatment of penile rehabilitation following radical prostatectomy is not recommended. 1) Clinical Effectiveness No published studies of daily tadalafil used post-prostatectomy as part of penile rehabilitation were located from a literature search. No randomised, controlled studies of tadalafil at any dose in this setting were located; although lower quality data are available, their methodological limitations do not allow any conclusions to be made regarding the efficacy of tadalafil versus placebo or on-demand use (as treatment of ED) in this setting. In the absence of good quality data for tadalafil, the results of two randomised, placebocontrolled studies of other PDE5 inhibitors in the setting of penile rehabilitation have been discussed. Padma-Nathan et al found that sildenafil mg daily following prostatectomy was associated with a higher response rate than placebo (27% versus 4%; p=0.02); however the number of patients was small (only 76 of the original 125 randomised patients completed the full study), the analysis was not intention to treat, and erection rates were low these factors weaken the strength of the result and the reliability of any conclusions made. Conversely, Montsori et al found that regular nightly vardenafil 10mg was no better than ondemand use following prostatectomy in a randomised, placebo-controlled, double-blind study. Of note this is the only randomised study to have compared regular use of PDE5 inhibitors following prostatectomy to their on-demand use for the treatment of ED in this setting. Treatment was for nine months after which there was a 2-month single-blind wash-out; the primary endpoint was the percentage of patients who had an IIEF-erectile function domain score of 22 after this time. After the double-blind phase, more patients in the vardenafil ondemand group (48%) than the regular vardenafil group (32%) and the placebo group (25%) met this endpoint; there were however no statistically significant differences between groups after the washout phase. This study raised doubts about the concept of penile rehabilitation and suggested regular dosing has no advantages over on-demand use; however the study has been criticised because of its design. In summary, good-quality published evidence to support the use of PDE5 inhibitors (or any strategy) for penile rehabilitation is lacking, and prospective, randomised placebo-controlled studies are needed to firmly establish the efficacy of PDE5 inhibitors or other therapies in rehabilitation programmes to support the recovery of erectile function after radical prostatectomy. There is inconsistency between the currently available studies regarding the drug used, dose, frequency, and the possibility of selection bias and heterogeneity of treatments needs to be addressed in future research. 2) Cost Effectiveness No data located Page 9 of 11

10 3) Equity 4) Needs of the community Prostate cancer is the most common cancer in men and makes up 24% of cancer diagnoses in men in the UK. It is predominantly a disease of older men but around 25% of cases occur in men younger than 65 years (4). In 2008, 34,335 men were diagnosed with prostate cancer and there were 9376 deaths from prostate cancer in England, Wales and Northern Ireland (4). No data on the number of radical prostatectomies, and therefore the eligible population for penile rehabilitation, were located from the sources searched. 5) Need for healthcare (incorporates patient choice and exceptional need) There is no standard treatment for penile rehabilitation due to the limitations of the currently available literature. 6) Policy drivers None 7) Disinvestment The JPC agreed the following sections within the PCT Ethical and Commissioning Framework were not relevant to JPC discussions: Health Outcomes, Access, and Affordability. Page 10 of 11

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