# Nonformulary Criteria for Use Checklist

# Clinically Uroselective Alpha~1~-Adrenergic Blockers

# in VA Patients with Benign Prostatic Hyperplasia

# VHA Pharmacy Benefits Management Services and Medical Advisory Panel

*The following recommendations are based on current medical evidence and
expert opinion from clinicians. The content of the document is dynamic
and will be revised as new clinical data becomes available. The purpose
of this document is to assist practitioners in clinical decision-making,
to standardize and improve the quality of patient care, and to promote
cost-effective drug prescribing. The clinician should utilize this
guidance and interpret it in the clinical context of the individual
patient. The manufacturer's labeling should be consulted for detailed
information when prescribing tamsulosin or alfuzosin.*

Of the available alpha~1~-adrenergic blockers, doxazosin, prazosin, and
terazosin are listed on the One VA National Formulary (VANF). Tamsulosin
and alfuzosin are considered clinically uroselective alpha~1~-blockers.
Tamsulosin and alfuzosin are not listed on the VANF but may be
considered for use in patients with benign prostatic hyperplasia (BPH)
under selected circumstances as defined in the criteria below.
**Tamsulosin is the preferred nonformulary clinically uroselective
alpha~1~-adrenergic blocker per VA national contract.**

All alpha~1~-blockers have been shown to improve lower urinary tract
symptoms (LUTS) associated with BPH (recommended doses for BPH are
doxazosin 4 to 8mg once daily, prazosin 2mg twice daily, terazosin 5 to
10mg once daily; lower doses have also been effective) although the
American Urological Association (AUA) guidelines state that there are
insufficient data to support the use of prazosin in BPH. There is no
evidence that tamsulosin or alfuzosin provide any benefit in patients
who have not responded to an adequate trial with a VANF
alpha~1~-blocker. It is unknown whether the clinically uroselective
alpha~1~-blockers offer an advantage in patients who are at risk for
falls. Based on meta-analyses by the AUA that found alfuzosin and
tamsulosin to have significantly less dizziness than terazosin but not
doxazosin, patients considered at risk for falls, but who do not have
evidence of postural hypotension, might preferentially be started on
doxazosin rather than terazosin; or a clinically uroselective
alpha~1~-blocker could be selected, at the discretion of the provider. 
Some patients experiencing side effects (especially syncope) from a
non-uroselective alpha~1~-blocker may not be good candidates to take a
uroselective agent as orthostasis and other class side effects may also
be seen with the clinically uroselective agents. Refer to comparison
table of adverse events reported with the alpha~1~-blockers.

+-----------------------------------------------------------------------+
| ######## INCLUSION CRITERIA FO                                        |
| R TAMSULOSIN (Must have at least ONE of the following to be eligible) |
+-----------------------------------------------------------------------+
| -   Significant symptomatic hypotension^a^, orthostatic^b^ or         |
|     postural hypotension, or syncope or near syncope^c^ while on a    |
|     VANF alpha~1~-blocker                                             |
|                                                                       |
| -   Significant adverse event attributed to a VANF alpha~1~-blocker   |
|     after consideration of ↓ dose or trial of alternate VANF          |
|     alpha~1~-blocker                                                  |
|                                                                       |
| -   Baseline^d^ significant orthostatic^a^ or postural hypotension    |
|     symptoms prior to treatment with a VANF alpha~1~-blocker          |
|                                                                       |
| -   Patients with concomitant hypertension (HTN) and BPH who are      |
|     being treated with antihypertensive therapy in addition to a VANF |
|     alpha~1~-blocker^e^, who develop symptomatic hypotension (despite |
|     adjustment of VANF alpha~1~-blocker or antihypertensive           |
|     therapy^f^) or who develop inadequate control of LUTS after       |
|     adjustment of VANF alpha~1~-blocker to avoid hypotension          |
|                                                                       |
| -   Conditions that do not allow adequate time for titration with an  |
|     alpha-blocker (e.g., urinary stone passage, acute urinary         |
|     retention, for bothersome LUTS immediately following              |
|     brachytherapy of prostate)                                        |
|                                                                       |
| ^a^ The change in blood pressure with terazosin has been found to be  |
| clinically insignificant in BPH patients who are either normotensive  |
| or have hypertension (HTN) that is well-controlled with pharmacologic |
| agents; patients with blood pressures in the lower range who are      |
| asymptomatic should receive a trial of a VANF alpha~1~-blocker,       |
| whenever possible (refer to table of BP lowering effects of terazosin |
| and doxazosin in patients who are normotensive, with or without       |
| treatment for HTN)                                                    |
|                                                                       |
| ^b^ Defined as a ↓ SBP [\>]{.underline} 20 mm Hg upon standing from   |
| the supine position, or a ↓ DBP \> 10 mm Hg upon standing with DBP \< |
| 65 mm Hg, or an ↑ pulse of [\>]{.underline} 20 bpm upon standing with |
| a standing pulse [\>]{.underline} 100 bpm                             |
|                                                                       |
| ^c^ Not related to inappropriate initiation of therapy                |
|                                                                       |
| ^d^ For patients with significant baseline hypotension (not receiving |
| antihypertensive medication), use of an alpha~1~-blocker should be at |
| the clinician's discretion                                            |
|                                                                       |
| ^e^ For additional information, refer to                              |
| <http://www.pbm.va.gov/criteria/allhatstatement.pdf> or               |
| <http://vaww.pbm.va.gov/criteria/allhatstatement.pdf>                 |
|                                                                       |
| ^f^ Antihypertensive agents being used for indications other than HTN |
| (e.g., heart failure, diabetic nephropathy, angina, cardiac           |
| arrhythmias, etc) may not be appropriate for modification             |
+-----------------------------------------------------------------------+
| **DOSING RECOMMENDATIONS**                                            |
+-----------------------------------------------------------------------+
| -   **Tamsulosin** is available as a 0.4mg capsule that is to be      |
|     administered 30 minutes after the same meal once daily; the       |
|     capsules should not be chewed, crushed, or opened                 |
|                                                                       |
| -   Since doses of tamsulosin greater than 0.4mg have not been found  |
|     to be consistently more effective and may result in increased     |
|     adverse effects (e.g., dizziness, orthostatic hypotension,        |
|     abnormal ejaculation), it is recommended that patients prescribed |
|     doses greater than 0.4mg daily be reevaluated for efficacy (e.g., |
|     per AUA/IPSS\*) and tolerability, and the dose lowered if         |
|     appropriate                                                       |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **MONITORING**                                                        |
+-----------------------------------------------------------------------+
| -   Due to the risk for symptomatic postural hypotension, dizziness,  |
|     or syncope, patients should be instructed to avoid situations     |
|     where injury may result if syncope occurs upon initiation of      |
|     therapy. In addition, patients should be queried as to whether    |
|     they experienced a fall while on treatment                        |
|                                                                       |
| -   Ejaculatory disorders have been reported with tamsulosin,         |
|     especially at higher doses                                        |
|                                                                       |
| -   Tamsulosin has rarely been associated with priapism and patients  |
|     should be informed as to the seriousness of this condition        |
|                                                                       |
| -   Due to the potential for significant hypotension with concomitant |
|     administration of an alpha~1~-blocker and PDE5 inhibitor (e.g.,   |
|     vardenafil), patients should be on a stable dose of their         |
|     alpha~1~-blocker or PDE5 inhibitor prior to administration of the |
|     other agent; start with the lowest recommended dose and titrate   |
|     based on response and tolerability. In addition, it is            |
|     recommended that simultaneous administration be avoided to reduce |
|     the potential for hypotension                                     |
|                                                                       |
| -   During cataract surgery, the occurrence of Intraoperative Floppy  |
|     Iris Syndrome (IFIS) has been observed in some patients receiving |
|     or previously treated with an alpha~1~-blocker. Product           |
|     information for tamsulosin includes a recommendation that         |
|     ophthalmologists should be aware of those patients receiving      |
|     treatment with an alpha~1~-blocker in order to prepare for        |
|     potential surgical modifications that may be required             |
+-----------------------------------------------------------------------+
| **RECOMMENDATIONS FOR DISCONTINUATION**                               |
+-----------------------------------------------------------------------+
| -   Patient does not experience an improvement in LUTS\*              |
|                                                                       |
| -   Patient experiences significant drug related adverse event; if an |
|     intolerable side effect occurs with tamsulosin, alfuzosin may be  |
|     considered (refer to the National PBM Drug Monograph for          |
|     Alfuzosin at <http://www.pbm.va.gov/monograph/Alfuzosin.pdf> or   |
|     <http://vaww.pbm.va.gov/drugmonograph/Alfuzosin.pdf> for          |
|     therapeutic considerations and recommendations for dosing and     |
|     monitoring)                                                       |
+-----------------------------------------------------------------------+

**\*AUA/IPSS:** The AUA Symptom Index/International Prostate Symptom
Score is a validated instrument that evaluates the patient's symptom
severity and frequency score. Seven questions that evaluate both
irritative and obstructive LUTS with a response rating from 0 to 5
(i.e., total score range 0 to 35) are included in the questionnaire.
Average 4 to 6 point improvement generally considered meaningful change
(refer to AUA Practice Guidelines Committee. AUA guideline on management
of benign prostatic hyperplasia (2003). Chapter 1: diagnosis and
treatment recommendations. J Urol 2003;170:530-47); reduction of
[\>]{.underline} 25% IPSS used as efficacy parameter in clinical trials

**Comparisons of Selected Adverse Events with the Alpha~1~-Blockers**

  -------------------------- --------------- --------------- ---------------- ---------------
  **Adverse Event (%)**      **Doxazosin**   **Terazosin**   **Tamsulosin**   **Alfuzosin**

  Dizziness                  13.3            15.4            11.5             5.1

  Syncope                    0.4             1.3             0.3              0.7

  Symptomatic Hypotension    2.7             NR              NR               0.7

  Asymptomatic Hypotension   5.4             7.5             6.7              NR

  Symptomatic Postural       4.0             6.3             2.5              NR
  Hypotension                                                                 

  Cardiovascular             1.9             2.2             7.8              1.2

  Asthenia                   15              11.5            6.6              4.3

  Headache                   7.7             7.2             11.5             5.2

  Acute Urinary Retention    0.1             3.5             3.5              NR

  Erectile Dysfunction       0.4             1.3             9.9              NR

  Ejaculatory Dysfunction    3.5             5.0             3.5              2.9
  -------------------------- --------------- --------------- ---------------- ---------------

Results of Meta-Analysis in AUA Guidelines. Management of BPH (2003).
Chapter 3: Results of the treatment outcome analyses. Available from
Internet. Accessed 2003 Nov 13. NR=not reported in meta-analysis

**Blood Pressure Changes in Normotensive Patients with BPH**

**Treated with a VANF Alpha~1~-Blocker**

  -------------------------- --------------------- -----------------------
  **Normotensive Patients**                        

  *Not on Treatment for HTN*                       

  Change in BP               Terazosin^a^          Doxazosin^b,c^

  SBP (mm Hg)                ↓ 3.1-3.5             ↓ 4.9-8

  DBP (mm Hg)                ↓ 1.7-2.4             ↓ 4.7-5

  *Receiving                                       
  Antihypertensive                                 
  Medication*                                      

  Change in BP               Terazosin^a^          Doxazosin^b,c^

  SBP (mm Hg)                ↓ 2.8-5.2             ↓ 2.3-6

  DBP (mm Hg)                ↓ 0.2-1.8             ↓ 2.7-3
  -------------------------- --------------------- -----------------------

^a^ Terazosin 5-10 mg (Lowe FC, et al., Urology 1999;54:81-5; Kirby RS,
Br J Urol 1998;82:373-9);

^b^ Doxazosin 1-16 mg, majority 4-8 mg (Guthrie RM, et al., Clin Ther
1999;21:1732-48);

^c^ Doxazosin 4-8 mg (Kaplan SA, et al., Urology 1995;46:512-7)

Contact person: Elaine M. Furmaga, PharmD, Clinical Pharmacy Specialist,
VACO PBM Services