MEDICAL POLICY

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Tadalafil (Cialis) for Benign Prostatic Hyperplasia

Number 5.01.545*

Effective Date August 12, 2013

Revision Date(s) N/A

Replaces N/A

*This policy is managed through the Pharmacy benefit.

Policy

Tadalafil (Cialis®) may be considered medically necessary as second line treatment for symptoms of benign prostatic hyperplasia (BPH). (See Policy Guidelines below for detailed requirements.)

Use of tadalafil (Cialis®) to treat erectile dysfunction in patients without BPH is contractually excluded on most benefits. (See specific member contract information to determine coverage.)

Use of tadalafil (Cialis®) for all other indications is considered investigational.

Note: Tadalafil is available as Adcirca® in different strengths for the treatment of pulmonary arterial hypertension (PAH). For these patients, refer to the pulmonary arterial hypertension guidelines contained in a separate medical policy. (See Related Policies)

Related Policies

5.01.522

Advanced Therapies for Pharmacological Treatment of Pulmonary Arterial Hypertension

Policy Guidelines

Tadalafil (Cialis®) may be considered medically necessary when ALL of the following conditions are met:

  • Patient has a diagnosis of benign prostatic hyperplasia (BPH), AND
  • Patient has previously failed, had inadequate response to or failed to tolerate a generic alpha blocker (terazosin, tamsulosin, doxazosin or alfuzosin), finasteride or dutasteride, AND
  • Prescription is for either 2.5mg or 5mg taken once daily.

Note: Tadalafil (Cialis®) is also available in 10mg and 20mg tablets for use as needed. These are indicated ONLY for treatment of erectile dysfunction, not BPH.

Description

Benign prostatic hyperplasia (BPH) is a condition characterized by epithelial and stromal cell proliferation (enlargement) of the prostate gland. BPH and BPH-related lower urinary tract symptoms (LUTS) are age-dependent, with BPH being one of the top 10 most commonly diagnosed conditions in men over 50 years of age. The estimated prevalence of LUTS secondary to BPH in Caucasian Americans between the ages of 50 and 79 in 2000 was 42%. In a European cross sectional study of men >40 years of age attending urology clinics, the prevalence of LUTS secondary to BPH was 56% and erectile dysfunction was 40%. These conditions are also frequently comorbid in the same men. In BPH, as the prostate gland enlarges it may constrict the urethra and/or the bladder wall may thicken and become irritable resulting in lower urinary tract symptoms such as diminished urine stream, intermittency, straining, polyuria, nocturia, urinary urgency, and inability to empty the bladder.

Three classes of drugs are currently recommended by the AUA for the treatment of BPH: alpha adrenergic antagonists, 5-alpha reductase inhibitors, and anticholinergics. The approval of tadalafil for BPH occurred after the latest AUA management update; consequently its use for BPH is not addressed. The mechanism of action of alpha adrenergic antagonists is blockade of alpha-1 receptors in the prostate, bladder, and urethra which relaxes smooth muscle in these tissues and improves urine flow and symptoms associated with BPH. It is important to note that drugs in this class do not reduce prostate size. 5-Alpha reductase inhibitors interfere with testosterone’s stimulatory effect on prostate enlargement and therefore do reduce prostate size.

Alpha-1 adrenergic antagonists are generally considered a preferred first-line treatment option for patients with moderate to severe LUTS secondary to BPH. However, prazosin and phenoxybenzamine are not recommended due to a lack of evidence of effectiveness. Use of 5-alpha reductase inhibitors is recommended for patients with moderate to severe LUTS and demonstrated increased prostatic volume, prostate specific antigen (as a proxy for volume), and/or prostatic enlargement on digital rectal exam. These agents are not recommended for the treatment of LUTS in men without prostatic enlargement. Combination therapy with an alpha adrenergic antagonist and a 5-alpha reductase inhibitor has been shown to provide greater symptom relief and reduction in disease progression (prostate enlargement) compared with an agent from either class alone.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

This policy applies to all lines of business. Language pertaining specifically to contractual exclusion of tadalafil is applicable only to benefits that exclude coverage for treatment of erectile dysfunction.

Rationale

The clinical efficacy of tadalafil 5 mg once daily for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) was primarily established in 3 similarly designed multinational, 12-week, randomized, double-blind, placebo-controlled trials. Two of these studies were conducted in men with LUTS suggestive of BPH (Porst, 2011 and Roehrborn, 2008) and one was specific to men with comorbid BPH and erectile dysfunction (Egerdie, 2011). The primary efficacy endpoint in all 3 trials was change from baseline in total International Prostate Symptom Score (IPSS). The IPSS assesses severity of the spectrum of symptoms associated with BPH. The comorbid ED study had a co-primary endpoint that was change from baseline in the erectile function domain score of International Index of Erectile Function (IIEF-EF). All 3 trials consistently showed a statistically and clinically significant improvement in these surrogate outcomes after 12-weeks. While these studies were not specifically designed to evaluate the following endpoints, nocturia and objective urodynamic measures (peak urinary flow and postvoid residual volume) were consistently not improved.

A 1-year, open-label, safety extension of the registrational Roehrborn (2008) study suggests efficacy for LUTS secondary to BPH is maintained longer-term (Donatucci, 2011). Two other preliminary RCTs also consistently support the short-term (12-week) efficacy of tadalafil 5 mg once daily for LUTS secondary to BPH with or without comorbid ED.

Results from one unpublished, multinational, 12-week, randomized, double-blind, double dummy, placebo-controlled trial with a parallel tamsulosin (FLOMAX) 0.4 mg once daily arm were recently posted on clinical trials.gov (NCT00970632). While this study was not designed to compare the two active drugs, tadalafil 5 mg once daily appeared to provide similar improvements to that of tamsulosin (FLOMAX) 8in men with LUTS suggestive of BPH. As might be expected, tadalafil appeared superior to the apha-blocker for treatment of comorbid erectile dysfunction.

One prospective, open-label, uncontrolled study was identified on literature search that examined the efficacy and safety of add-on tadalafil at the approved 5 mg daily dose combined with an alpha-blocker (tamsulosin [FLOMAX] 0.2 mg or alfuzosin [UROXATRAL] 10 mg) for 12-weeks in 158 Korean men with concurrent LUTS-BPH and ED. Total IPSS and IIEF-5 were significantly (p<0.001) improved with combination therapy, but Qmax and PVR did not, compared to baseline low-dose alpha-blocker monotherapy.

The registrational RCTs show tadalafil 5 mg once daily to be well tolerated for the short-term treatment of LUTS suggestive of BPH with or without comorbid ED. Overall, adverse events were infrequent and the majority (>95%) were mild to moderate in severity. No unexpected adverse events occurred. No clinically significant changes in vitals or electrocardiogram were observed. Rates of myocardial infarction appeared similar to that of placebo in the same population, with the caveat that these trials were of short duration (12 weeks). In short-term (12-week) clinical trials, incidence of a positive orthostatic test was similar in tadalafil-treated and placebo-treated LUTS-BHP patients, about 20%. No priapism was reported.

A long-term (1-year) safety extension in the target population found no new or greater frequency of any adverse events, serious adverse events, or discontinuation for adverse events compared to double-blind short-term (12-week) treatment (Donatucci, 2011).

Two open-label safety extension trials of tadalafil 5 mg once daily in men with ED also showed the drug to be well tolerated for up to 2 years. No unexpected adverse events were observed. No deaths or serious adverse events, cardiovascular or otherwise, were attributed to study drug.

No sudden hearing or vision losses (non-arteritic anterior ischemic optic neuropathy [NAION]) were reported in short- or long-term clinical trials for LUTS secondary to BPH.

In the unpublished, multinational, 12-week, randomized, double-blind, double dummy, placebo-controlled trial with the parallel tamsulosin 0.4 mg once daily arm (NCT00970632), incidence of adverse events, serious adverse events, and discontinuation for adverse events appeared similar between tadalafil (CIALIS) 5 mg, tamsulosin (FLOMAX) 0.4 mg, and placebo once daily in men with LUTS-BPH with or without ED.

References

  1. Porst H, McVary KT< Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol 2009;56(4):727-735.
  2. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007;177:1401-1407.
  3. Lee JY, Park SY, Jeong TY, et al. Combined tadalafil and α-blocker therapy for benign prostatic hyperplasia in patients with erectile dysfunction: a multicenter prospective study. J Andrology 2012 Aug 25 [epub ahead of print].
  4. Porst H, Rajfer J, Casabe A, et al. Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J Sex Med 2008;5:2160-2169.
  5. Porst H, Kim ED, Casabe AR, et al. 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;60(5):1105-1113.
  6. Roehrborn CG, McVary KT, Elion-Mboussa A, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 2008;180:1228-1234.
  7. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJUI 2011;107:1110-1116.
  8. Roehrborn CG, Kaminetsky JC, Auerbach SM, et al. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil administration. BJUI 2009;105:502-507.
  9. Broderick GA, Brock GB, Roehrborn CG, et al. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology 2010;75:1452-1459.
  10. Egerdie RB, Auerbach S, Roehrborn CG, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med 2011 Oct 7 [epub ahead of print].
  11. National Kidney and Urological Diseases Information Clearinghouse. Prostate enlargement: benign prostatic hyperplasia. Available at http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement. Accessed July 31, 2013.
  12. National Kidney and Urological Diseases Information Clearinghouse. Kidney and urologic diseases statistics for the United States. Available at http://kidney.niddk.nih.gov/kudiseases/pubs/kustats. Accessed July 31, 2013.
  13. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003/updated 2010). Available at http://www.auanet.org/education/guidelines/benign-prostatic-hyperplasia.cfm. Last accessed July 31, 2013.
  14. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398.
  15. This policy was reviewed by the Premera Pharmacy and Therapeutics Committee, May 2013.

Coding

Codes

Number

Description

 

 

This policy is managed through the Pharmacy benefit.

Appendix

N/A

History

Date

Reason

08/12/13

New policy. Add to Prescription Drug section.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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