Coverage Policy Manual
Policy #: 2014016
Category: Pharmacy
Initiated: July 2014
Last Review: July 2022
  Phosphodiesterase-5 (PDE-5) Inhibitors for Benign Prostatic Hypertrophy (e.g., Tadalafil)

Description:
Benign prostatic hypertrophy (BPH) is a histologic diagnosis consisting of the non-malignant proliferation of smooth muscle and epithelial cells of the prostate which is found in an increasing percentage of the male population beginning usually after age 50.   Nearly half of men with BPH develop prostatic enlargement with the concomitant bladder outlet obstruction.  A fraction of these individuals may develop lower urinary tract symptoms (LUTS).  Some individuals may present with obstructive LUTS but have no evidence of prostatic enlargement.  The symptoms—though not specific for BPH (frequency, nocturia, hesitancy, weak urinary stream, and urinary urgency)--appear gradually usually over a number of years.  A careful history, physical examination with rectal examination of the prostate, and several simple tests are generally sufficient to exclude other urological causes of LUTS.  The American Urological Association has a published (2010) set of guidelines regarding the diagnosis and optional evaluation of LUTS.
 
The AUA developed a symptom score to measure outcomes in studies of different treatments for BPH. The score is used to assess the severity of symptoms of BPH (not for differential diagnosis) It consists of seven questions: frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency, each of which is scored on a scale of 0 (not present) to 5 (almost always present). Symptoms are classified as mild (total score 0 to 7), moderate (total score 8 to 19) and severe (total score 20 to 35).
 
The International Prostate Symptom Score (IPSS) uses the same questions and scale as the AUA symptom score and adds a disease-specific quality of life question: "If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?"
 
In general, medical therapy of BPH is initiated for symptom (LUTS) relief affecting quality of life or in the circumstance of evidence of injury from BPH to the upper tract (hydronephrosis or renal insufficiency) or lower tract problems (recurrent UTI’s, significant urinary retention (> 25 % of bladder volume), or bladder decompensation).
 
Until recently, pharmacologic therapy has relied on two classes of drugs: alpha-adrenergic antagonists and 5-alpha-reductase inhibitors which have different mechanisms of action.  Alpha-adrenergic antagonists appear to be more effective than 5-alpha-reductase inhibitors for short-term and long-term treatment of BPH/LUTS. However, only 5-alpha-reductase inhibitors have demonstrated the potential for long-term reduction in prostate volume and need for prostate surgery. The use of agents from both classes in combination may be superior to using either class alone.  The five FDA-approved long-acting alpha-1-antagonists include terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin.  Alpha-1-adrenergic antagonists act against the dynamic component of bladder outlet obstruction by relaxing smooth muscle in the bladder neck, prostate capsule, and prostatic urethra.  Both tamsulosin (alpha-1A and alpha-1D) and silodosin (alpha-1A) have demonstrated selective receptor antagonism.  To date, there is a paucity of direct comparison studies involving alpha-1-antagonists, but a meta-analysis of trials involving alfuzosin, terazosin, tamsulosin, and doxazosin suggests comparable effects of symptom scores and urinary flow rates.  The most important adverse effects are orthostatic hypotension and dizziness.  The above-mentioned meta-analysis documented withdrawal rates of 4-10% for alfuzosin and tamsulosin while 8-20% withdrew for terazosin and doxazosin.  Tamsulosin had less documented orthostatic hypotension in elderly men. The hypotensive effects of alpha-1-antagonists may be increased by concurrent use of phosphodiesterase-5 inhibitors.
 
5-alpha-reductase inhibitors inhibit the conversion of testosterone with a resultant decrease in prostate size over 6-12 months.  Studies have demonstrated a reduction in obstructive symptom scores, an increase in urinary flow rates, and a reduction in prostate volume. Both finasteride and dutasteride are FDA-approved for use in BPH with comparable efficacy and safety.  Side effects are similar with some incidence of ejaculatory and erectile dysfunction.  However, in a long-term trial of finasteride versus placebo in men with BPH, adverse sexual effects were increased only during the first year of therapy.  These drugs can decrease PSA levels; the FDA recommends monitoring for prostate cancer with adjustments for the effect on PSA levels.  Short-term therapy with combined alpha adrenergic antagonist and 5-alpha-reductase inhibitor therapy appears to be superior to either agent alone in men with BPH/LUTS and larger prostate glands but not in men with only moderate BPH.  Long-term combination therapy is effective even in men with only moderate BPH.
 
Recent studies have demonstrated short-term effects of some PDE-5 inhibitors when used to treat LUTS related to BPH.  At present, only tadalafil (e.g., Cialis) has received FDA approval for use in mild to moderate symptomatic BPH.
 

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of phosphodiesterase-5 inhibitors (PDE-5 inhibitors) in the treatment of symptomatic benign prostatic hypertrophy (BPH) does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of phosphodiesterase-5 inhibitors (PDE-5 inhibitors) in the treatment of symptomatic benign prostatic hypertrophy (BPH) is considered not medically necessary.
 
 

Rationale:
A literature search conducted using the MEDLINE database through June 2014 identified the following controlled trials.
 
Three randomized, controlled trials assessing the safety and efficacy of tadalafil compared to standard treatment were identified and summarized below (Bechara, 2008; Madani, 2012; Oelke, 2012).
 
Bechara and colleagues reported on a small randomized, double-blind crossover pilot study assessing the safety and efficacy of tamsulosin versus tamsulosin plus tadalafil in the treatment of lower urinary tract symptoms suggestive of benign prostatic hypertrophy (LUTS/BPH) (Bechara, 2008). Thirty men, older than 50 years old, with a history of LUTS/BPH of at least 6 months, were randomized into two groups to receive tamsulosin 0.4 mg/day versus tamsulosin 0.4 mg/day plus tadalafil 20 mg/day for 45 days, and then switched to the other treatment mode for other 45 days. Twenty-seven patients completed the study. Improvements of IPSS score and IPSS-QOL were significant with both treatments but greater with the drug combination. Tamsulosin 0.4 mg/day plus tadalafil 20 mg/day was more effective than tamsulosin 0.4 mg/day alone to improve LUTS and erectile dysfunction and was also well tolerated. The authors report that large-scale, randomized, placebo-controlled studies are needed to further assess the long-term safety and effectiveness of these agents in treating LUTS/BPH with or without ED.
 
In 2012, Oelke and colleagues reported results of a larger study again assessing the use of tadalafil versus tamsulosin in the treatment of LUTS/BPH. In this study, men 45 years of age or older were randomized to receive either placebo (n=172), tadalafil 5 mg (n=171) or tamsulosin 0.4 mg (n=168) once daily for 12 weeks. International Prostate Symptom Score (IPSS) significantly improved versus placebo through 12 wk with tadalafil (-2.1; p=0.001; primary efficacy outcome) and tamsulosin (-1.5; p=0.023) and as early as 1 wk (tadalafil and tamsulosin both -1.5; p<0.01). BPH Impact Index significantly improved versus placebo at first assessment (week 4) with tadalafil (-0.8; p<0.001) and tamsulosin (-0.9; p<0.001) and through 12 wk (tadalafil -0.8, p=0.003; tamsulosin -0.6, p=0.026). Q(max) increased significantly versus placebo with both tadalafil (2.4ml/s; p=0.009) and tamsulosin (2.2ml/s; p=0.014). The authors report the study was limited in not being powered to directly compare tadalafil versus tamsulosin (Oelke, 2012). An editorial comment highlights the fact that this study was not designed to compare tadalafil and tamsulosin and to the author’s knowledge there is no definitive data to “conclude tadalafil works as well as an alpha blocker” (Kaplan, 2013).  
 
Also, in 2012, Madani published results of another randomized controlled trial assessing the safety and efficacy of tadalafil on LUTS/BPH (Madani, 2012). 132 patients with obstructive and irritative urinary tract symptoms due to BPH with no indication for surgical intervention and that reached plateau levels of response to treatment were selected. Two groups of 66 patients were randomly selected to receive either tadalafil 10mg or standard treatment. IPSS, maximum urinary flow rate (Qmax) and quality of life were assessed before and after a 3-month period of study. Before treatment, mean IPSS, Qmax and quality of life values in the treatment and placebo groups were 13.06 ± 4.37 and 13.66 ± 4.25, 8.92 ± 2.96 mL/s and 9.09 ± 2.91 mL/s, 2.93 ± 0.86 and 2.66 ± 0.78, respectively. After treatment, mean IPSS, Qmax, and quality of life values in treatment group were 7.66 ± 3.99, 9.99 ± 4.76 mL/s and 1.80 ± 0.98, respectively. These findings were compared to corresponding values of the placebo group (11.37 ± 3.64, 8.73 ± 2.22 mL/s and 2.19 ± 0.53, respectively): IPSS and quality of life were significantly different but Qmax didn't show a significant change.
 
Four studies assessing the safety and efficacy of the use of placebo compared with tadalafil in the treatment of LUTS/BPH (Brock, 2013; Porst, 2013; Porst, 2011; Broderick, 2010). These studies are small, short term and don’t assess the clinical utility of tadalafil compared to standard, accepted treatments for lower urinary tract symptoms of BPH.
 
In conclusion, while there is some evidence on the short-term efficacy of the use of tadalafil for the treatment of lower urinary tract symptoms suggestive of BPH, longer term studies assessing both the safety and efficacy of this use are needed. Additionally, the studies reviewed did not demonstrate superiority in either safety or efficacy comparable to standard treatments. Finally, treatment with tadalafil is less cost-effective than other effective treatments for this indication. Therefore, the use of tadalafil does not meet primary coverage criteria and is not medically necessary for the treatment of lower urinary tract symptoms suggestive of BPH.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new randomized controlled trials assessing the safety, efficacy and clinical utility. Several post hoc analysis were identified (Oelke, 2015; Roehrborn, 2015; Nickel, 2015) which do not prompt a change in the coverage statement.  
  
2016 Update
A literature search conducted through June 2016 did not reveal any new randomized controlled trials assessing the safety, efficacy and clinical utility.
 
2018 Update
A literature search conducted through June 2018 did not reveal any new randomized controlled trials assessing the safety, efficacy and clinical utility.
 
2019 Update
A literature search conducted through June 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement.

References: 5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer Accessed at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm

Bechara A, Romano S, Casabé A, et al.(2008) Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med. 2008 Sep;5(9):2170-8.

Brock G, Broderick G, Roehrborn CG, et al.(2013) Tadalafil once daily in the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) ion men without erectile dysfunction. BJU Int. 2013 Nov; 112(7):990-7.

Djavan B, Marberger M.(1999) A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36(1):1.

Madani AH, Afsharimoghaddam A, Roushani A., et al.(2012) Evaluation of tadalafil effect on lower urinary tract symptoms of benign prostatic hyperplasia in patients treated with standard medication. Int Braz J Urol. 2012;38:33-39.

Nickel JC, Brock GB, Herschorn S, et al.(2015) Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia – integrated data from 1,499 study participants. BJU Int. 2015 May;115(5):815-21.

Oelke M, Giuliano F, Mirone V, et al.(2012) Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomized, parallel, placebo-controlled clinical trial. Eur Urol. 2012 May;61(5):917-25.

Oelke M, Shinghal R, Sontag A, et al.(2015) Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from 4 pivotal, double-blind, placebo controlled studies. J Urol. 2015 May;193(5):1581-9

Porst H, Eim ED, Casabé AR, et al.(2011) Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011 Nov;60(5)”1105-13.

Porst H, Oelke M, Goldfischer ER.(2013) Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013 Sep;82(3):667-73.

Porst H., McVary KT, Montorsi F, et al.(2009) Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009 Oct;56(4):727-35.

Roehrborn CG, Casabé A, Glina S, et al.(2015) Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo. Int J Urol. 2015 Jun;22(6):582-7.

S. A. Kaplan(2012) Editorial comment on monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. J Urol 2013; 189: 1448-1449.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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