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Diagnosis and management: The art of effective treatment for patients with lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS)

Dr Selvalingam Sothilingam
Consultant Urologist
Columbia Asia Cheras
Kuala Lumpur
Malaysia 
6 days ago
Case

· A 60-year-old teacher presented with lower urinary tract symptoms (LUTS)
· He was bothered by the following symptoms:
  - Incomplete voiding
  - Poor stream
  - Frequency
  - Nocturia (waking up 3 times nightly)
  - Occasional urgency
· The patient had no history of incontinence or haematuria, but had terminal dribbling
· He had tried herbal supplements, such as saw palmetto extract, for 6 months, but saw no improvement
· His International Prostate Symptom Score (IPSS) was 15 with a bothersome score of 3
· He had no history of sexual dysfunction, but a history of hypertension that was well controlled with antihypertensive monotherapy
· His prostate was mildly enlarged (23 g) with a smooth surface on digital rectal examination. It was not tender and his prostate-specific antigen (PSA) levels were 0.7 ng/mL (low)
· Uroflowmetry showed a maximum urinary flow rate (Qmax) of 12 mL/s and post void residual (PVR) volume of 100 mL
· Prescribed doxazosin 4 mg once daily at night and has not reported any adverse effects
· At follow-up after 2 months, the patient indicated that he was no longer experiencing urgency, his stream appeared better and he had less daytime frequency. He also had better sleep and only got up once on most nights
· Overall, the patient was satisfied with his treatment and a repeat uroflowmetry showed an improvement of  Qmax to 15 mL/sec and reduced PVR volume to 50 mL

  Patient presentation and management
  
  
1.    How common is BPH-LUTS and what are some important considerations for managing patients with BPH-LUTS?

LUTS are defined as storage (daytime urinary frequency, urgency and nocturia), voiding (straining, weak or intermittent stream, incomplete emptying) or postmicturition (dribbling) disturbances that affect the lower urinary tract.1-3 The prevalence of LUTS increases with age and is often associated with benign prostatic hyperplasia (BPH) in men.2,4 Many men consider symptoms of BPH to be a normal part of ageing, and generally, medical attention is sought only after symptoms become disruptive to a patient’s quality of life (QoL).2,3

A clinical diagnosis of BPH-LUTS requires ruling out prostate cancer by evaluating patient factors, including medical history, lifestyle and sexual history, as well as physiological measures. BPH-LUTS symptoms are usually assayed using several methods, which can include:2
· IPSS analyses
· Transrectal (internal) ultrasound of the prostate
· Uroflowmetry – to determine Qmax
· Urinalysis
· Ultrasound – to determine the prostate volume and PVR
· Prostate-specific antigen (PSA) – to assess the risk of prostate cancer

The aim of treatment for patients with BPH-LUTS is to alleviate bothersome symptoms, so it is important to determine whether a patient is storage or voiding symptom-predominant, and to consider prostate volume, when making a clinical diagnosis and deciding on a treatment plan.

2.    What treatment options are available for patients with BPH-LUTS?

Treatment is influenced by several factors, including the presence or absence of an obstruction, for example, due to an enlarged prostate.1 In general, drug treatments include a range of α-adrenergic antagonists (α-blockers), 5-α-reductase inhibitors (5ARIs), antimuscarinics (anticholinergics), and in some situations, a phosphodiesterase-5 inhibitor (PDE5i).1,2

When the prostate is not enlarged, (<40 g), an α-blocker monotherapy is often effective, otherwise a 5ARI is recommended alone or in combination with an α-blocker.1,2 Surgical intervention may also be appropriate for patients with BPH-LUTS, particularly for bothersome symptoms that cannot be alleviated with pharmacological therapy, and for patients with complications from BPH.1

3.    How efficacious and tolerable is doxazosin for patients with BPH-LUT

The American Urological Association (AUA) guidelines state that all α-blockers are similarly effective and well-tolerated for the management of BPH-LUTS.1-3,5 However, doxazosin, in particular, has a favourable efficacy and tolerability profile and can be used as a long-term treatment to lower the rate of clinical progression of BPH with fewer side effects compared with placebo.5,6 Doxazosin also improves Qmax versus other BPH-LUTS therapies (Figure 1).5,6 

HK-PFR-546a1-MY_figure 1

Doxazosin is also considered to be a well-tolerated treatment for BPH-LUTS and adverse events (AEs; eg, dizziness, headache) are generally mild.5 Some concerns have been expressed regarding doxazosin-related vasodilation in patients with vascular comorbidities, which may lead to potentially life-threatening events, particularly in older patients.3 Therefore, it is important to conduct a thorough patient history before prescribing an α-blocker and to continue to monitor a patient’s blood pressure throughout the course of therapy.

4.    Under what circumstances would you recommend combination therapy to a patient with BPH-LUTS?

Patients with an enlarged prostate (≥40 g) are candidates for combination therapy.
1 A combination of an α-blocker and a 5ARI is recommended for these patients because combination therapy has demonstrated efficacy in reducing BPH-LUTS progression and markedly improving symptoms, such as Qmax, relative to either therapy (Figure 1).1,6 While doxazosin and finasteride monotherapy both inhibit BPH-LUTS progression compared with placebo (39% and 34% risk reduction, respectively; p<0.001 and p=0.002, respectively), combination therapy is significantly more efficacious (66% risk reduction vs baseline;  p<0.001 vs placebo, doxazosin and finasteride).7,8 Furthermore, combination therapy offers significantly greater improvements in AUA symptom score compared with placebo and either monotherapy (p<0.001 for placebo and finasteride; p=0.006 for doxazosin).7,8 Several studies have since confirmed the superior efficacy of different combination therapies versus monotherapy in men with moderate-to-severe BPH-LUTS (Figure 2).1,8 

HK-PFR-546a1_Figure 2

While combination therapy is considered to be an effective treatment for patients with enlarged prostate BPH-LUTS,
1,8 it is associated with an increased risk of AEs compared with either drug as monotherapy. Doxazosin monotherapy is associated with dizziness, postural hypotension and asthenia, while finasteride is associated with erectile dysfunction, decreased libido and abnormal ejaculation.7 Combination therapy has an AE profile that is similar to the combined monotherapies with the addition of peripheral oedema and dyspnoea.7 In patients with an enlarged prostate, these additional AEs must be measured against QoL benefits. Surgical intervention may be considered as an alternative.

Summary

Patients experiencing bothersome symptoms suggestive of BPH-LUTS should seek medical attention because these symptoms are often mistakenly considered to be a normal part of the ageing process. Increased public awareness of symptoms related to BPH-LUTS would encourage patients to seek treatment and likely improve overall outcomes. Drug therapies are effective in alleviating symptoms of BPH-LUTS and can considerably improve patient QoL.1 Most therapies have manageable AE profiles,1 and doxazosin, in particular, is an effective and well-tolerated monotherapy for the long-term treatment of patients with small prostate BPH-LUTS.1-3,5 For patients with an enlarged prostate, combination therapy with a 5ARI can also provide symptomatic relief.7,8

CARDURA XL®

 Abbreviated Prescribing Information9
Composition: Doxazosin-Mesylate GITS
Indications: For the treatment of hypertension and can be used as the initial agent to control blood  pressure in the majority of patients. In patients not adequately controlled on a single antihypertensive agent, doxazosin may be used in combination with a thiazide diuretic, a beta-blocker, a calcium antagonist or an angiotensin- converting enzyme inhibitor. Indicated for the treatment of clinical symptoms in either hypertensive or normotensive patients with benign prostatic hyperplasia (BPH) and for reduced urinary flow associated with BPH.
Recommended dosage: Initial dose is 4mg once daily. The optimal effect of doxazosin may take up to 4  weeks. If necessary, dosage may be increased following this period to the maximum recommended dose of 8mg once daily.
Contraindications: Contraindicated in patients with a known hypersensitivity to quinazolines, doxazosin, or any of the inert ingredients.
Special warning and precautions for use: Postural Hypotension/Syncope: Patients should be advised how to avoid symptoms resulting from postural hypotension and what measures to take and be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of doxazosin therapy. Use with PDE-5 inhibitors: Doxazosin should be administered with caution in concomitant usage with PDE-5 inhibitors as it may lead to symptomatic hypotension. Impaired Hepatic Function and Gastrointestinal Disorders: Doxazosin should be administered with caution in patients with evidence of impaired hepatic function or in patients with pre-existing severe GI narrowing (pathologic or iatrogenic). Intraoperative Floppy Iris Syndrome (IFIS): Current or past use of alpha blockers should be made known to the ophthalmologic surgeon in advance of surgery. Priapism: In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical  assistance. Information to patients: Patients should be informed that doxazosin GITS should be swallowed whole. Patients should not chew,  divide or crush the tablets.
Drug interactions: Caution should be exercised when concomitantly administering  doxazosin  with  a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.
Common side effects: Hypertension: Palpitation, tachycardia, vertigo, abdominal pain, dry mouth, nausea, asthenia, chest pain, peripheral edema, back pain, myalgia, postural hypotension, dizziness, headache, bronchitis, coughing, pruritus, cystitis, and urinary incontinence. Benign Prostatic Hyperplasia: Vertigo, asthenia, peripheral edema, abdominal pain, dyspepsia, nausea, influenza-like symptoms, respiratory tract infection, urinary tract infection, back pain, myalgia, dizziness, headache, somnolence, bronchitis, dyspnea, rhinitis, hypotension, postural hypotension.
Formulation and preparation: 4mg tablets in pack of 100’s.
API-CARDURA XL-0716
Full   prescribing   information   is   available   upon   request.

CARDURA ®
Abbreviated Prescribing Information10
Composition: Doxazosin mesylate
Indications: For the treatment of hypertension and can be used as the initial agent to control blood pressure in the majority of patients. In patients not adequately controlled on a single antihypertensive agent, doxazosin may be used in combination with a thiazide diuretic, a beta-blocker, a calcium antagonist or an angiotensin-converting enzyme. Indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH)
Recommended dosage: Hypertension: The full dosage range is 1 mg to 16 mg daily. It is recommended that therapy be initiated at 1 mg once daily for 1 or 2 weeks to minimize the potential for postural hypotension and/or syncope. The dosage may be increased to 2 mg once daily for an additional 1 or 2 weeks. If necessary, the dosage may then be increased gradually at similar intervals to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. The usual dose is 2 mg to 4 mg once daily. Benign prostatic hyperplasia: The recommended  initial dosage is 1 mg  once daily to minimize the potential for postural hypotension and/or syncope. Depending on the patient, the dosage may be increased to 2 mg and thereafter to 4 mg and up to the maximum recommended dose of 8 mg. The recommended titration interval is 1 to 2 weeks. The usual recommended dose is 2 to 4 mg once daily.
Contraindications: Contraindicated for use in patients with a known hypersensitivity to quinazolines, doxazosin, or any of the inert ingredients.
Warning and precautions: Postural hypotension/syncope: Patients should be advised how to avoid symptoms resulting from postural hypotension and what measures to take and be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of doxazosin. Use with PDE-5 inhibitors: Doxazosin should be administered with caution in concomitant usage with PDE-5 inhibitors as it may lead to symptomatic hypotension. Impaired hepatic function: Doxazosin should be administered with caution in patients with evidence of impaired hepatic function. Intraoperative Floppy Iris Syndrome (IFIS): Current or past use of alpha blockers should be made known to the ophthalmologic surgeon in advance of surgery. Priapism: In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance.
Drug interactions: Caution should be exercised when concomitantly administering doxazosin with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.
Side effects: Vertigo, nausea, edema, asthenia, fatigue, malaise, dizziness, headache, postural dizziness, somnolence, syncope, rhinitis.
Formulation and preparation: 2 mg in pack of 100’s.
API-CARDURA-0716
Full   prescribing   information   is   available   upon   request.

References
1. American Urological Association. Management of Benign Prostatic Hyperplasia (BPH). Clinical Guidelines. Available at: http://www.auanet.org/guidelines/benign-prostatic-hyperplasia-(2010-reviewed-and-validity-confirmed-2014). Accessed 14 August 2017.
2. Park HJ, et al. World J Mens Health 2013;31:193–207.
3. Nickel JC, et al. Int J Clin Pract 2008;62:1547–1559.
4. Abolyosr A, et al. Urol Ann 2013;5:237–240.
5. Yuan JQ, et al. Medicine (Baltimore) 2015;94:e974.
6. Wilt TJ, MacDonald R. Clin Interv Aging 2006;1:389–401.
7. McConnell JD, et al. N Engl J Med 2003;349:2387–2398.
8. Roehrborn CG. BJU Int 2008;101(Suppl 3):17–21.
9. Pfizer (Malaysia) Cardura XL Prescribing Information: CARDURA XL-0716
10. Pfizer (Malaysia) Cardura Prescribing Information: CAR-SINMY-0716

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Most Read Articles
6 days ago
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04 Dec 2017
Later timing of puberty seems to correlate with lower areal bone mineral density in children and may affect the eventual risk of osteoporosis, a recent study suggests.
Jairia Dela Cruz, 6 days ago
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3 days ago
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