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Finasteride

Posted by admin on June 11th, 2010 No Comments

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Finasterid; Finasterida; Finasteridas; Finasteride; Finasteridi; Finastendum; Finasztend; MK-906; MK-0906; YM-152.

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Finasteride). A white or almost white crystalline powder. It exhibits polymorphism. Practically insoluble in water freely soluble in dehydrated alcohol and in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008 (Finasteride). A white to off-white crystalline solid. Very slightly soluble in water freely soluble in alcohol and in chloroform. Store in airtight containers.

Adverse Effects

The most commonly reported adverse effects of finasteride are decreased libido, erectile dysfunction, ejaculation disorders, and reduced volume of ejaculate. Breast tenderness and enlargement (gynaecomastia) may occur, and there have been reports of hypersensi-tivity reactions such as swelling of the lips and face, pruritus, urticaria, and rashes. Testicular pain has also been reported.

Incidence of adverse effects. In a study using prescription event monitoring data, the most commonly reported adverse effects of finasteride in 14 772 patients were impotence or ejacula-tory failure (2.1% of patients), reduced libido (1%), and breast disorders such as gynaecomastia (0.4%). Adverse effects reported in a single patient each, and verified on rechallenge, were ex-foliative dermatitis, perioral numbness, and swollen glands. Finasteride appeared to be associated with ataxia in 1 patient and wheeziness in another.

Effects on the breast. Gynaecomastia was the adverse effect of finasteride most frequently reported to the FDA between June 1992 and February 1995 (a total of 214 reports). The onset after therapy ranged from 14 days to 2.5 years, and the condition could be unilateral or bilateral. Mastectomy was performed in 12 men. Of the 86 men for whom follow-up information was available, partial or complete remission of gynaecomastia occurred in 80%, and no change occurred in 20%. In 2 of the cases, primary intra-ductal breast carcinoma was subsequently found, although 1 probably had breast cancer before finasteride therapy. Continued surveillance of the relationship between finasteride and breast cancer is required.

Effects on mental function. Depression has been reported in 20 patients given finasteride for the treatment of alopecia. In most cases the depression began about 3 to 4 months after starting finasteride, and resolved within a few weeks of stopping it. In 2 patients rechallenged with finasteride, depression recurred within 2 weeks of restarting the drug.

Precautions

Finasteride should be used with caution in hepatic impairment. When used for benign prostatic hyperplasia, finasteride should be used with caution in men at risk of obstructive uropathy. Patients should be evaluated for prostatic carcinoma before and during therapy. Use of finasteride decreases concentrations of serum markers of prostate cancer such as prostate specific antigen (PSA) by up to 50% even when cancer is present, and reference values should be adjusted accordingly the ratio of free to total PSA (percent free PSA) remains constant.

Studies in animals suggest finasteride could produce feminisation (hypospadia) of a male fetus if used in pregnant women therefore, its use is contra-indicated in women who are or may become pregnant. In addition, it is recommended that women in this category should not handle crushed or broken finasteride tablets. Finasteride has been detected in semen, therefore use of a condom is recommended if the patient’s sexual partner is, or may become, pregnant.

Pharmacokinetics

Finasteride is absorbed after oral doses, and peak plasma concentrations are achieved in 1 to 2 hours. The mean bioavailability has variously been reported as 63% and 80%. It is about 90% bound to plasma protein. Finasteride crosses the blood-brain barrier, and is distributed into semen. It is metabolised in the liver, primarily by the cytochrome P450 isoenzyme CYP3 A4, and excreted in urine and faeces as metabolites. The mean terminal half-life is about 6 hours in patients under 60 years of age but may be prolonged to about 8 hours in those 70 years of age or older.

Uses and Administration

Finasteride is an azasteroid that inhibits the type-2 iso-form of 5α-reductase, the enzyme responsible for conversion of testosterone to the more active dihydrotestos-terone, and therefore has anti-androgenic properties. It is given orally in a dose of 5 mg daily in the management of benign prostatic hyperplasia to cause regression of the enlarged prostate and to improve symptoms it may reduce the incidence of acute urinary retention and the need for surgery. Response may be delayed and treatment may be required for 6 months or more to assess whether benefit has been achieved.

In the treatment of male-pattern baldness (alopecia androgenetica) in men, finasteride is given orally in a dose of 1 mg daily. In general, use for 3 months or more is required before benefit is seen, and effects are reversed within 12 months of ceasing therapy.

Alopecia. In men with male-pattern baldness (alopecia), treatment with oral finasteride for 12 months resulted in an 11 % increase in vertex hair count, which was maintained in those who continued therapy. Extension of this study to 5 years found that long-term treatment with finasteride maintained beneficial effects, or at least slowed hair loss. The use of oral finasteride for this purpose has been reviewed. Some efficacy has also been found with topical finasteride.

Although finasteride is contra-indicated in women who are or may become pregnant (see Precautions, above), it has been investigated in the treatment of male-pattern baldness in postmeno-pausal women. However, a 1-year placebo-controlled study found no benefit from finasteride. There has been a report of benefit from finasteride in 4 women with hair loss due to hyper-androgenism.

Benign prostatic hyperplasia. Finasteride is used in the management of benign prostatic hyperplasia. It produces moderate reductions in prostate volume, although this takes a number of months and is not always associated with much symptomatic improvement therapy must be continued indefinitely for benefit to be maintained. A 4-year study found that finasteride reduced the probability of surgery and acute urinary retention in men with symptomatic benign prostate hyperplasia with prostatic enlargement. Although the need for prostatectomy was reduced by 55% it was pointed out that only 6% extra patients would benefit from treatment with finasteride. For every 100 men treated, 7 finasteride and 13 placebo recipients required surgery. A 2-year, open-label follow-up of this study reported that the reductions in probability of surgery and acute urinary retention were maintained. It was also found that in patients who switched from placebo to finasteride, these measures decreased to become similar to those recorded in men already receiving finasteride. A comparative 12-month study found the alpha blocker terazosin to be more effective than finasteride in relieving symptoms and improving peak urine flow rates the combination of finasteride plus terazosin was no more effective than terazosin alone. Moreover, although finasteride reduced prostatic volume, it was no more effective than placebo, a finding that is at odds with previous placebo-controlled studies. It has been suggested that the smaller median prostate size in this study may explain the negative findings, and that men with larger prostates do benefit from finasteride. Similar results were reported in a 12-month study using doxazosin. Later results from a large study showed that over a longer period of 4 or more years the combination of doxazosin and finasteride reduced the risk of clinical progression more than either drug alone. The combination of an alpha blocker and 5a-reductase inhibitor is therefore considered to be a suitable option for patients with urinary symptoms and demonstrable prostatic enlargement, and who are at significant risk of progression.

Hirsutism. Finasteride is reported to be effective for the treatment of hirsutism in women. It should be noted that finasteride should not be used in women who are or may become pregnant (see Precautions, above).

Malignant neoplasms of the prostate. Finasteride appears to have little effect in established prostate cancer,’ but is under investigation for its prevention. The results of 1 small study of its effects on the prostate found little evidence to support its use for prevention of malignancy in patients at high risk. In healthy men, a large controlled study, the Prostate Cancer Prevention Trial (PCPT), found that 7 years of finasteride prophylaxis reduced the incidence of prostate cancer by about 25% compared with placebo, but this benefit was offset by an increased risk of high-grade tumours associated with finasteride. The risk-benefit implications of these results have been debated, although some commentaries” suggest that preventive use would be justified, at least in selected patients. Further analysis of the PCPT data found that finasteride had introduced a detection bias for both prostate cancer and for high-grade prostate cancer. Finasteride increased the sensitivity of prostate specific antigen (PSA) testing, implying that the PCPT primary findings of increased risk of high-grade tumours were due, at least in part, to improved detection. The reported 25% decrease in prostate cancer incidence was also likely to be an underestimate. The European Association of Urology has endorsed a recommendation that prostate cancer management guidelines be updated to reflect these findings.

Preparations

British Pharmacopoeia 2008: Finasteride Tablets

The United States Pharmacopeia 31, 2008: Finasteride Tablets.

Proprietary Preparations

Argentina: Anatine † Andropel Avertex Conef † Daric Eutiz † Finasterin Fin-prostat Flutiamik Folcres HPB Nasteril Pelicrep † Propecia Proscar Pros-min Prostanil Prostanovag Prostene Renacidin Sutrico Tealep Tricofarma Urofin Urototal Vetiprost

Austral.: Propecia Proscar

Austria: Propecia Proscar

Belgium: Proscar

Brazil: Alfasin Capyla Finalop Finastec Finastil Flaxin Nasterid Nasterid A Pracap Prohair † Pronasteron Propecia Proscar Prostide Reduscarf

Canada: Propecia Proscar

Chile: Apeplus † Prohair Proscar Saniprostol Vastus

Czech Republic: Androfin Apo-Finas Duromeran Edufil Finajel † Finanorm Finard Finex Finpros Gefin Ibition Lekoprost Mostrafin Penester Propecia Proscar Radicut

Denmark: Propecia Proscar

Finland: Gefina Propecia Proscar

France: Chibro-Proscar Propecia

Germany: Propecia Proscar

Greece: Pervil Poruxin Propecia Proscar

Hong Kong: Propecia Proscar

Hungary: Finpros Proscar Prosterid

India: Fincar Finpecia Ultrafinaf

Indonesia: Finaxal Finpro Proscar Prostacom Reprostom

Ireland: Proscar

Israel: Pro-Cure Propecia

Italy: Finastid Genaprost Propecia Proscar Prostide

Malaysia: Propecia Proscar

Mexico: Propeshia Proscar

The Netherlands: Finaburg Propecia Proscar

Norway: Proscar

New Zealand: Propecia Proscar

Philippines: Propecia Proscar

Poland: Ambulase Finaride Finaster Lifin Penester Propecia Proscar Zasterid

Portugal: Propecia Proscar Prostacide Prostafin Zidoril Zylfina

Russia: Finast Penester Proscar Prosterid

South Africa: Propecia Proscar

Singapore Propecia Proscar

Spain: Eucoprost Propecia Proscar

Sweden: Propecia Proscar

Switzerland: Propecia Proscar

Thailand: Firide Harifin Propecia Proscar

Turkey: Dilaprost Finarid Propecia Proscar Prosterit

UK: Propecia Proscar

USA: Propecia Proscar

Venezuela: Finast † Nasterol Propecia Proscar Prosdina †

Multi-ingredient

Argentina: Tricoplus Conef †

India: Urimax F

Posted in Drugs

Common questions about Proscar

Posted by admin on April 17th, 2010 No Comments

What is symptomatic benign prostatic hyperplasia (BPH)?

In many men, after the age of 45, the prostate starts a process of enlargement called BPH. As the prostate enlarges, it gradually exerts pressure on the urethra. In many men, this results in urinary symptoms that can be bothersome and may interfere with daily life.

In some men, benign prostatic hyperplasia can lead to serious problems, including a sudden inability to pass urine (acute urinary retention), as well as the need for surgery. Acute urinary retention is an emergency condition that will require catheterization and may require surgery.

How does PROSCAR work?

PROSCAR helps shrink the prostate in many men. This can lead to improvement of symptoms. Therapy with PROSCAR may also reduce your risk for acute urinary retention (a sudden inability to pass urine) and the need for surgery.

Will PROSCAR reduce the risk of needing BPH-related (prostate) surgery?

PROSCAR is indicated to help reduce the risk of needing BPH-related surgery or suffering from acute urinary retention.

How long until PROSCAR starts to work—and for how long does it work?

PROSCAR works by shrinking the prostate gland. Even though the gland shrinks, it may take at least
6 months to see whether it improves your symptoms.

Six-year clinical studies have shown, if taken on a daily basis, PROSCAR shrinks the prostate and keeps it from growing in most men. As a result, for men who get symptom relief, it generally is maintained for the long term.

Posted in Drugs

What are the short and long-term side effects of finasteride (Proscar)?

Posted by admin on April 14th, 2010 No Comments

Question: What are the short and long-term side effects of finasteride (Proscar)?

Answer: The main side effect is impotence, but only in about 6% compared to 3% on placebo. That is to be expected with men of that age who are followed for a long time. Some men will for one cause or another will report impotence – that’s just the natural history of aging. No other significant side effects have been reported, either biochemical or subjectively perceived. This has been very thoroughly studied under the Good Clinical Practice international rules – any disorder that any subject has during the study period is registered, even if it’s unrelated to the drug. In our trial, 40% of the men already reported sexual dysfunction at the start of the trial, and we estimated that we might have had over-reporting of impotence because it was listed in the patient information as a possible side effect. When you alert the patients to anticipate a side effect, it is more frequently reported because they’re watching for it and they’re going to attribute it to the medication. We have data now for six years of treatment, which hasn’t altered the picture – the side effects have not increased or changed. The patients who have had a good response find that efficacy is maintained over that time – tolerance has not developed.

Posted in Questions & Answers

How many BPH sufferers could benefit from finasteride (Proscar)?

Posted by admin on April 13th, 2010 No Comments

Question: How many benign prostatic hyperplasia (BPH) sufferers could benefit from finasteride (Proscar)? Which factors determine who should receive it?

Answer: This comes down to the question of who is a good responder, and what is a good response. Is it complete abolition of symptoms or just a 50% improvement, enough to make the patient feel just like a normal elderly man? The degree of prostate gland enlargement is the key factor that predicts outcome of treatment. We performed a meta-analysis, pooling the results from similar trials, so we now have data from over 4,000 patients. This analysis clearly showed that men with more enlarged prostates, over 40 g, have a more significant benefit from the drug. The mean size of the prostates in our study was about 41 g, meaning half the men had prostates larger than that, and half smaller. In our estimation, about 40% of patients have the best effect from the drug, significantly better than reported in the trial. About 20% dropped out over the two years of the study, and the main reason was lack of expected efficacy. If you use the principle “intention to treat”, which means including results from every patient initially enrolled in a study, you get a true picture of what happens to the whole population you treat. It actually diminishes the end results, but it’s regarded as state of the art statistics. The intention is to see in a large group of patients what happens to the whole group, whether they stay in the trial or drop out.

Posted in Questions & Answers

Can finasteride (Proscar) reverse the progress of BPH?

Posted by admin on April 9th, 2010 No Comments

Benign prostatic hyperplasia (BPH) refers to a complex of symptoms that can include difficult, painful or frequent urination, interrupted stream, hesitancy in starting to urinate and a feeling of incomplete emptying after urination. These symptoms are caused by pressure exerted on the urethra as the prostate gland grows larger with age. Unless the urethra is so obstructed that urine cannot pass through, the condition is not dangerous, but it affects most men at some point in their advanced years and can significantly impair well-being.

The treatment of BPH has most commonly involved either surgery to cut out part of the prostate and thereby ease the pressure on the urethra, or watchful waiting, in which the patient is monitored closely but not actively treated. A number of drug therapies have recently been added to the treatment arsenal against benign prostatic hyperplasia. Finasteride works by inhibiting the production of the enzyme 5-alpha reductase, which converts testosterone into dihydrotestosterone. In this way it prevents further prostatic growth and can even reduce the volume of the prostate in many men.

Generic Name Drug: Finasteride

Trade Names Drug: Proscar, Propecia, Penester, Prosteride, Finasterid Alternova, Finasterid IVAX, Fincar, Finpecia, Finpros, Finax, Finast, Finara, Finalo, Gefina, Appecia, Hyplafin, Tectum, Prezepa

Finasteride has been proved safe and effective against BPH in three placebo-controlled studies of six months to one year’s duration. These studies also revealed the very pronounced effect of placebo against symptoms of BPH. Many men receiving placebo experience improvements in symptom scores and in urinary flow rates. This Scandinavian study wanted to see what results finasteride and placebo would have after two years of therapy, and particularly whether the benefits of placebo would persist over this longer time frame.

Seven hundred and seven men were enrolled at 59 Scandinavian centres in five countries. Men with severe intravesical obstruction, for which surgery is most often recommended, were not included in the study. All study subjects had mild to moderate symptoms of BPH, for which the primary aim of treatment is to relieve symptoms and prevent the need for invasive therapy. During a one-month lead-in period, all subjects received placebo in order to minimize the well-known placebo effect on BPH symptoms. Men were then randomly assigned to receive either 5 mg finasteride per day or placebo for the next 24 months.

A physical exam was accomplished at the start of the study and repeated after 12 and then 24 months of therapy. This included a digital rectal exam and laboratory tests such as PSA (prostate specific antigen) measurement. Urinary flow rates and residual urine volume after voiding were also tested on these three occasions. As well, all of the men completed a questionnaire every four months, rating the severity of nine urinary symptoms, five of them obstructive, on a scale of zero to six. The effectiveness of each regimen was judged by changes in symptom scores, maximum flow rate and prostate volume over the study period.

The beneficial effect of placebo noted in previous studies was evident in this study as well after 12 months of therapy, with many men showing mild improvements in total symptom scores and stable prostate volume. However, during the second year of therapy, those receiving placebo ceased to benefit, and symptom scores returned to levels seen at the start of the study. Men receiving finasteride, on the other hand, continued to improve on all markers of benign prostatic hyperplasia over the entire study period.

When changes over the course of the study were calculated for each group, the finasteride group had a mean decrease of 2.0 in total symptom score, dropping from 13.4 to 11.4 (out of a maximum possible score of 54), while those receiving placebo saw their symptom scores increase by 0.2. Obstructive symptom scores dropped by 1.5 ml/second in the finasteride group, but only by 0.2 ml/sec in the placebo group. The maximum urinary flow rate achieved by the finasteride group increased by 1.5, while falling by 0.3 in the placebo group. Prostate volume fell by 19.2 cm3 in men receiving finasteride while increasing by 11.5 cm3 in those receiving placebo.

In summary, after two years of therapy with finasteride (Proscar), BPH symptoms were markedly improved for men receiving finasteride, showing that the drug can, in fact, reverse the natural progression of benign prostatic hyperplasia. The benefits of placebo did not persist over the second year of therapy, eliminating the possibility that the benefits of finasteride could be due to the placebo effect.

Comment: The exciting thing is that this is the first drug (Proscar) that actually shrinks the prostate. The study data suggested the possibility that this drug could even save some patients from surgery by shrinking the prostate before urinary retention gets so severe that it becomes a medical emergency – we are now investigating that more thoroughly. Other treatments have only focused on symptoms, not on the underlying cause. Hopefully the future will bring drugs that are more selective. Our obligation as medical professionals is to select appropriate therapy for the patient and not subject them to treatment that won’t help them. You wouldn’t submit patients to major surgery if there was only a 50% chance that it would help, particularly for a benign condition. So the future must be to get tools to predict who will be a good responder from the outset.

Posted in Drugs

UroXatral: Drug for Treatment of BPH

Posted by admin on April 3rd, 2010 No Comments

Trade Name Drug: UroXatral

Generic Name Drug: Alfuzosin HCl

Company: Sanofi-Synthelabo

Indication / Use: Benign prostatic hyperplasia

Approval Date / FDA Class: 12 06 2003 / 1S

Development and Mechanism of Action:Benign prostatic hyperplasia (BPH) is defined histologically. Clinically, it is characterized by lower urinary tract symptoms (urinary frequency, urgency, a weak and intermittent stream, needing to strain, a sense of incomplete emptying, and nocturia) and can lead to complications, including acute urinary retention. The mechanisms by which BPH causes symptoms and complications are unclear, although obstruction of the bladder outlet is an important factor. The best documented risk factors are increasing age and functioning testes. Estimates of the prevalence of symptomatic BPH indicate that approximately 50% of men ages 51 to 60 have benign prostatic hyperplasia. Community- and practice-based studies suggest that men with lower urinary tract symptoms can expect slow progression of the symptoms. However, symptoms can wax and wane without treatment. In men with symptoms of BPH, rates of acute urinary retention range from 1% to 2% a year. The objective of drug therapy of BPH is to reduce or alleviate lower urinary tract symptoms, to prevent complications, and to minimize adverse effects of treatment.

Table 1. Pharmacokinetics of Alpha1-Blockers
Parameter Alfuzosin
(UroXatral)		 Prazosin
(Minipress)		 Terazosin
(Hytrin)		 Doxazosin
(Cardura)		 Tamsulosin
% Oral bioavailability 49% (fed) ND ND ~ 65 > 90 (fasting)
Tmax, h ~ 8 ~ 3 ~ 1 ~ 2 ­ – 3 4 – 5 (fasting)
6 – 7 (fed)
% Protein binding ~ 90 High 90 – 94 ~ 98 94 – 99
Metabolism CYP3A4 oxidation,
O-demethylation,
N-dealkylation		 Extensive via a demethylation
and conjugation		 ND Extensive via
O-demethylation
and hydroxylation		 CYP450
Elimination T /2, h 3 – 9 2 – 3 ~ 12 ~ 22 9 – 15
Excretion Urine (10%)
Feces (75 ­ 91%)		 Bile and feces Urine (~ 40%)
Feces (~ 60%)		 Urine (~ 9%)
Feces (~ 63%)		 Urine (76%)
Feces (21%)

Pharmacotherapy for benign prostatic hyperplasia includes the 5-alpha-reductase inhibitor finasteride (Proscar), and alpha1-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. Androgen receptor antagonists are of no value in BPH because of their adverse effects. Smooth muscle tone in the prostate and bladder neck is regulated by alpha1-adrenergic receptors. Blockade of these receptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of benign prostatic hyperplasia. Currently available alpha1-adrenoceptor antagonists appear to possess very similar clinical efficacy producing a 15% to 25% increase in maximum flow rate with a significant improvement in 30% to 40% of patients. The non­tissue selective alpha1-blockers (prazosin, terazosin, and doxazosin) can elicit postural symptoms related to orthostatic hypotension and they may cause episodes of dizziness and somnolence as a result of distribution to and action in the CNS. Uroselective alpha1-blockers dosed on a once-daily schedule, tamsulosin (Flomax) and, most recently, alfuzosin, have been developed to address the drawbacks of the nonselective agents.

Alfuzosin (UroXatral), a tetrahydroquinazoline derivative, differs from the non­tissue selective alpha1-blockers as a result of replacement of the piperazine heterocycle in the latter with a propylenediamine moiety in the structure of the new drug. Alfuzosin is not selective for any of the alpha1-adrenoceptor subtypes (A, B, or D) but has been shown to possess a high selectivity for receptors in the lower urinary tract. At doses three to 10 times higher than those required to induce significant urethral relaxation in animal models, alfuzosin shows the lowest and shortest-lasting hypotensive activity compared to doxazosin, tamsulosin, and terazosin. Pharmacokinetics: A comparison of selected pharmacokinetic parameters of the alpha1-adrenoceptor antagonists is provided in table 1. The oral absorption of alfuzosin is significantly aided by the presence of food. The drug is extensively cleared by hepatic metabolism primarily involving the 3A4 isoform. Excretion of the drug and metabolites occurs mainly in the feces.

While there is no relationship between peak plasma concentrations of alfuzosin and age, trough levels are positively correlated with age. The concentrations in subjects 75 and older are approximately 35% greater than in those below age 65. Relative to subjects with normal renal function, the mean Cmax and AUC values for alfuzosin are increased by approximately 50% in patients with mild, moderate, or severe renal impairment. Clearance of alfuzosin is reduced in patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), leading to threefold to fourfold higher plasma concentrations of the drug in these patients compared to healthy subjects. Therefore, alfuzosin is contraindicated in patients with moderate to severe hepatic impairment.

UroXatral: Clinical Profile

Alfuzosin (UroXatral) is officially indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. Clinical efficacy data for alfuzosin from placebo-controlled trials have demonstrated efficacy compared to placebo in urinary flow improvement and in improvement in urinary symptoms without the need for dose titration. A randomized controlled clinical trial in 256 men compared tamsulosin against alfuzosin while a second trial in 103 men compared alfuzosin against prazosin in the treatment of BPH. These trials found no significant difference in symptom score among a-blockers tested. A clinical trial in 1,051 men comparing alfuzosin against finasteride against both drugs combined over six months found that alfuzosin compared with finasteride significantly decreased the mean international prostate symptom score from baseline, and found no significant difference between alfuzosin alone and combination therapy.

Adverse Reactions

In the clinical trials, the most common adverse effects occurring more frequently than with placebo were dizziness, upper respiratory tract infection, headache, and fatigue. Withdrawals attributed to adverse events have been found to be similar for alfuzosin, tamsulosin (0.4-mg dose), and placebo. However, a higher withdrawal rate was found with doxazosin, terazosin, and tamsulosin (0.8-mg dose). There was little observable difference between the number of men experiencing dizziness with alfuzosin or tamsulosin compared with placebo. However, more men experienced dizziness after terazosin and doxazosin than placebo. Comparison of tamsulosin versus alfuzosin found similarities in the incidence of common adverse effects including dizziness (7%), asthenia (2%), and postural hypotension (2%).

As with other a-blockers, some patients may experience postural hypotension or syncope. If symptoms of angina pectoris should appear or worsen, the use of alfuzosin should be discontinued. Caution should be exercised when alfuzosin is administered in patients with severe renal insufficiency. Consideration should be given in deciding to prescribe alfuzosin for patients with a known QT prolongation or who are taking medications known to prolong QT, although there has been no signal of torsades de pointes in extensive postmarketing experience with alfuzosin outside the United States.

Drug Interactions

Clearance of alfuzosin (UroXatral) via CYP3A4 metabolic pathways results in interactions between the new drug and other drugs that either inhibit or induce this enzyme. Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax 2.3-fold and AUC increased 3.2-fold following a single 10-mg dose of alfuzosin. Therefore, alfuzosin should not be coadministered with potent inhibitors of CYP3A4, eg, ketoconazole, itraconazole, or ritonavir, because exposure is increased. Coadministration of alfuzosin with antihypertensive medications may enhance the effects of the latter on blood pressure.

Dosage and Administration

UroXatral (alfuzosin) hydrochloride is formulated as a 10-mg extended release tablet. The recommended dosage is one 10-mg extended-release tablet daily to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

Posted in Drugs: α-blockers

Selective and non-selective α-blockers for BPH

Posted by admin on March 28th, 2010 No Comments

Relevance to family physicians

Symptomatic benign prostatic hyperplasia (BPH) is a common condition encountered in about 50% of male patients older than 50. Prevalence increases with age. In the last few years, pharmacologic treatment and watchful waiting have played an increasing role in treating symptomatic BPH. Until recently, pharmacologic options were limited to non-selective α-blockers and finasteride (Proscar). Non-selective α-blockers are usually first-line agents because their onset of action is fast (4 to 6 weeks); their efficacy is maintained, especially in patients with smaller prostates; and they are not expensive. Non-selective α-blockers, initially developed to treat hypertension, can cause side effects, such as postural hypotension, dizziness, headache, palpitations, and syncope.

Tamsulosin (Flomax), a selective α-blocker, has been commercially available in Canada since June 1998. Because it is more urospecific than other α-blockers, it has less potential for causing symptomatic hypotension. The dose of tamsulosin does not need to be titrated and this might, therefore, decrease the frequency of follow-up visits and result in a faster onset of action. In this trial, tamsulosin is compared with alfuzosin (Uroxatral), which is roughly comparable to the terazosin (Hytrin) commonly prescribed in Canada.

Overview of study and outcomes

A total of 245 men at least 45 years old entered the study. Main inclusion criteria were a Boyarsky score >6 and a maximum urinary flow (Qmax) of <12mL/s and >4mL/s.

The Boyarsky system score is a symptom-assessment tool used to evaluate the severity of nocturia, frequency, hesitancy, intermittency, terminal dribbling, urgency, impairment of size and force of stream, dysuria, and sensation of incomplete voiding. The system allows 0 to 3 points for each of nine questions for a maximum of 27 points. Patients scoring < 7 points are considered mildly symptomatic; 8 to 19 points moderately symptomatic; and > 20 points severely symptomatic.

Main exclusion criteria for the trial were coexisting conditions affecting micturition, previous pelvic region surgery, and concomitant medications acting on the prostate (eg, anticholinergic drugs). After a 2-week placebo run-in period, patients were randomized to alfuzosin (n = 119) or tamsulosin groups (n = 126). Primary outcome variables, Qmax, and total Boyarsky score were measured at weeks 2, 6, and 12. Secondary outcome variables included irritative, obstructive, and individual symptom Boyarsky score; tolerability; and lifestyle issues. Intention-to-treat analysis was performed, and all statistical tests were two-sided.

Results

Tamsulosin (Flomax) and alfuzosin (Uroxatral) had similar strong effects on Qmax, which increased by 1.6 mL/s, and on total Boyarsky score, which decreased by 4.1 and 3.8 points, respectively. Maximum urinary flow was achieved within 2 weeks with tamsulosin and between 2 and 6 weeks with alfuzosin.

For the secondary end points, no difference was observed in the lifestyle questionnaire score or Boyarsky obstructive, irritative, and individual symptom scores between the two groups. Hypotensive effects, such as dizziness, headaches, palpitation or tachycardia, syncope, and postural hypotension, were experienced by 9.2% of patients in the tamsulosin group and 10.5% of patients in the alfuzosin group (P=.442). All other side effects, attributed to the drug or not, were not statistically significantly different between groups (53% vs 43%, P= .826).

At baseline in the tamsulosin group, mean supine blood pressure level was 143.9/85.7 mm Hg and mean standing blood pressure level was 141/88 mm Hg. At the end, there was no significant reduction of mean blood pressure levels in the tamsulosin group (-0.9 mmHg for supine and standing systolic blood pressure and +0.3 and -1.8 mmHg for supine and standing diastolic blood pressure). In the alfuzosin group, mean baseline supine blood pressure level was 146.1/88.5 mm Hg, and mean baseline standing blood pressure level was 142.9/88.6 mm Hg. A significant change from baseline in supine and standing systolic blood pressure level of-5.3 and -3.6 mm Hg, respectively, and in supine and standing diastolic blood pressure level of -3.6 and -4.5 mmHg, respectively, were observed. Differences between the groups were 4.4 mmHg for systolic and 2.7 to 3.9 mmHg for diastolic blood pressure level at end point (P≤.05). The authors did not explain whether these differences had an effect on symptoms.

Subgroup analysis showed that patients aged 65 or older (n=57) in the alfuzosin group experienced larger blood pressure level reductions than patients that age (n = 59) in the tamsulosin group. Changes of-0.1 to -1.0 in systolic and +0.6 to -0.8 in diastolic pressure levels were seen in the tamsulosin group; changes of -8.6 to -9.7 mmHg (systolic) and -5.4 and -6.2 mmHg (diastolic) were seen in the alfuzosin group. Differences in mean blood pressure levels from baseline to end point between the treatment groups were almost 9 mm Hg (systolic) and 5 mm Hg (diastolic) (P= .016). Normotensive patients in the alfuzosin group had greater supine blood pressure level reductions than those in the tamsulosin group (P=.029). Again, the authors did not elaborate whether these differences were in symptoms. No significant differences between the two treatment arms could be observed in patients younger than 65 years (n= 131) or in hypertensive patients (n=59).

Analysis of methodology

The study was well designed, but the omission of use ful information made it difficult to interpret and apply the results to a specific patient population. For example, patients’ baseline characteristics were not reported, and the lifestyle questionnaire was not described. Also, the exact onset of action of tamsulosin (Flomax) could not be determined because the first follow-up visit was 2 weeks after initiation of treatment. Finally, measuring patients’ and their partners’ satisfaction would have been helpful for using the results in the context of clinical practice.

Posted in Drugs: α-blockers

PSA Levels Predict Prostate Growth

Posted by admin on March 23rd, 2010 No Comments

When men over age 50 have their annual check-ups, the doctor often checks blood levels of prostate-specific antigen (PSA) to screen for prostate cancer. A new study suggests that PSA levels may also predict prostate growth in men with benign prostatic hyperplasia (BPH), or benign prostatic hypertrophy.

The Proscar Long-Term Efficacy and Safety Study enrolled more than 3,000 men over age 50 with a diagnosis of BPH and randomized them to receive either finasteride (Proscar) or placebo for four years. Participants came from 95 centers; at 13 of these centers, 10 percent of the men had MRIs to measure their prostate volume when the study began and each year after. In the current report, the researchers looked at information from the men who’d taken placebo to see what baseline measurements predict growth of the prostate.

The size of a man’s prostate is a good indicator of problems to come. For example, the larger a man’s prostate, the more likely it is that he will have an acute urinary retention problem. Men with large prostates also are less likely to respond to drug treatment and more likely to need prostate surgery.

Based on data from 164 patients, the researchers found that the prostate continued to grow steadily over the four years of the study, and the older a man, the more his prostate grew each year. Prostate-specific antigen levels also tended to rise with age.

What predicted prostate growth the best, however, was the amount of PSA in the blood when the study began. Almost one-third of the men with PSA levels less than 2.0 ng/ml had a decrease in their prostate size over the four years, compared to just one of those with a PSA level of more than 2.0 ng/ml.

Since men with large prostates are more likely to have problems, having a way to predict prostate growth would help doctors. And since many doctors use prostate-specific antigen tests to screen for prostate cancer anyway, they should be able to use the results to help manage prostate growth too.

Writing in the January issue of The Journal of Urology, the researchers explain that this simple idea may be harder to get across than you’d think. In the past, prostate size was considered unimportant, and doctors focused on treating urinary symptoms. Now that research has shown that PSA and prostate size do predict adverse outcomes, doctors will need to change their approach to thinking about management and future risk rather than just symptoms.

Posted in Prostate Specific Antigen

Terazosin (Hytrin), finasteride (Proscar), or both in BPH

Posted by admin on March 21st, 2010 No Comments

Glossary

Adrenergic: Relating to nerve cells of the autonomic nervous system. Alpha- and beta-adrenergic receptors receive chemical signals controlling autonomic functions. Adrenergic blockers prevent signals from being received by that class of receptor.

Androgen: Any male sex hormone, such as testosterone.

Prostatectomy: Surgery to reduce the size of the prostate gland.

Benign prostatic hyperplasia (BPH) most often manifests as obstructed urinary flow and irritative urinary symptoms. Treatments are aimed primarily at relieving such symptoms. Prostatectomy and watchful waiting are the long-accepted therapies. Two types of drug have recently been added to the therapeutic options for BPH and have been demonstrated to be safe and effective in previous studies. They have not, however, ever been compared against one another in a blinded study.

This study enrolled 1,229 men with symptoms of BPH who were attending outpatient clinics at participating Veterans’ Affairs medical centres in the United States between 1992 and 1994. They were between 45 and 80 years old, had symptom scores on the American Urological Association Symptom Index of at least eight, and a mean peak urinary flow rate of between 4 ml and 15 ml per second. After undergoing physical and laboratory exams and receiving placebo for four weeks, the men were assigned to one of four drug regimens. They received either placebo, terazosin (Hytrin) (10 mg/day), finasteride (Proscar) (5 mg/day) or a combination of the two drugs for 52 weeks.

Participants were examined at regular intervals over the course of the study, and pills were counted to assess compliance with the prescribed drug regimen. Men receiving terazosin (or its placebo) could have the dose reduced to 5 mg/day if they experienced ill effects at 10 mg. Side effects were inquired about at each follow-up visit. Patients receiving finasteride had significantly more problems with impotence and decreased sex drive, while those on terazosin reported dizziness more often and those receiving the combination reported more problems with ejaculation. In all, 18% of the patients discontinued their treatment before the end of the study for various reasons. However, only 4.8% of the finasteride group, 5.9% of the terazosin group and 7.8% of the combination group stopped taking their medication due to adverse effects — as well as 1.6% of those on placebo.

At the end of the study period, test results and symptom scores were compared to those recorded at the outset of the study, and the changes noted in each group were compared against each other. Mean symptom scores were decreased almost twice as much in the terazosin and combination groups as in the finasteride group, with the placebo group having an even smaller reduction. Mean increases in peak urinary flow rates were 1.4 ml/second for placebo, 1.6 ml/sec for finasteride, 2.7 ml/sec for terazosin and 3.2 ml/sec for the combination group. Prostate volume was found to increase by 0.6 cm3 in the placebo group and 0.5 cm3 in the terazosin group, while decreasing by 6.1 cm3 in the finasteride group and by 7.0 cm3 in the combination group. Prostate-specific antigen (PSA, a common measure of prostate health) levels were more improved in the terazosin and combination groups.

Given that the primary goal of treatment is to alleviate benign prostatic hyperplasia (BPH) symptoms, the authors concluded that the comparison of the two drugs clearly favoured terazosin. Terazosin produced significantly better improvements in symptom scores and urinary flow rates. As well, there appeared to be no advantage to taking finasteride and terazosin in combination, as results were not significantly better than in men receiving terazosin alone.

The finding that finasteride was no better than placebo contradicts other studies that looked at finasteride alone. The authors suggest that this may be due to the fact that different indexes of symptom scores were used, or that participants in the other studies had a higher degree of prostate enlargement at the outset. A longer study period may also have affected the outcome. As is so often the case with medical research, more studies need to be done so that all the possible variables can be accounted for before there are definitive answers.

Posted in Drugs

What is the best medical treatment for BPH?

Posted by admin on March 7th, 2010 No Comments

Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CU.
The efficacy of terazosin, finasteride or both in benign prostate hyperplasia.
 N Engl J Med 1996; 335:533-9.

Research question

There are two main types of medications for the treatment of benign prostate hyperplasia (BPH): the first are α-adrenergic-antagonist drugs (eg, terazosin) that relax the smooth muscle in the prostate and the second are 5-α-reductase inhibitors (eg, finasteride) that block formation of dihydrotestosterone and thereby shrink the prostate. Which works better? Does a combination of the two drugs work best?

Type of article and design

Randomized, controlled trial of therapy.

Relevance to family physicians

In the last few years you could hardly open a medical journal without being bombarded with information about finasteride (Proscar). Many of us were using terazosin (Hytrin) also to treat BPH patients who had symptoms or were tired of “watchful waiting.” Terazosin is cheaper, is covered on most provincial formularies, and works faster, but we often wondered which drug was more effective and whether a combination could be used for treatment-resistant cases to prevent surgery. In the United States in 1990, more than 329000 men had transurethral prostatectomies (TURPs). A TURP is very effective but patients are understandably concerned about the side effects of surgery. Benign prostatic hyperplasia is extremely common and becomes more common with age. It can have a deleterious effect on quality of life, especially in the context of such conditions as chronic disease and depression.

Overview of study and outcomes

This study recruited 1686 men, aged 45 to 80 years, who had symptomatic benign prostate hyperplasia and were seen at Veterans Affairs medical centres. During a 4-week lead-in time, the men received a placebo and were evaluated twice using the American Urological Association’s (AUA) symptom index; to be eligible, men had to score at least 8 points out of 35.

Uroflometry, residual volume after voiding, serum concentrations of prostate-specific antigen (PSA), urine culture and sensitivity, and transrectal ultrasound examinations were all performed. No threshold level of prostatic enlargement was required (which fits with current evidence that severity of BPH is not simply a function of size). Exclusion criteria were use of similar medications to those being tested, symptoms of severe coronary artery disease, orthostatic hypotension, prostate cancer, history of prostate surgery, and active urinary or kidney disease. This left 1229 men (73% of those recruited) who were mostly white, averaged approximately 65 years old, had prostatic volumes of 37 cm3, had PSAs of 2 to 3, and had AUA symptom scores of an average 16 out of 35.

Results

The men at each site, randomized to finasteride, terazosin, combination therapy, or placebo, were evaluated at 2, 4, and 8 weeks and then every 6 weeks for 1 year for AUA symptom scores and peak urinary flow rates. Symptom scores in each of the four groups had decreased at 1 year by 2.6 (placebo), 3.2 (finasteride), 6.1 (terazosin), and 6.2 (combination) points (P < 0.001). Peak urinary flow rates had increased by mean values of 1.4, 1.6, 2.7, and 3.2 mL/sec, respectively (P < 0.001). Adverse effects caused 1.9% of the placebo group, 6.2% of the finasteride group, 7% of the terazosin group, and 9.4% of the combination group to drop out. As expected, dizziness was significantly more frequent in the terazosin group. Impotence and decreased libido were significantly more frequent among finasteride subjects. Combination therapy had these side effects and significantly more ejaculatory abnormalities.

Analysis of methodology

This sophisticated, four-arm, randomized trial had good follow up and compliance. Groups were similar at the start of the trial and were treated equally with intention-to-treat analysis.

Application to clinical practice

This study is interesting in that it tells us that a drug that many physicians are prescribing is no better than placebo.

This conflicts with some previous data, and the editorial accompanying the study tells why: benign prostate hyperplasia is not a homogeneous process and size does not predict symptoms. This study had no threshold size of prostate whereas the previous two studies positive for finasteride were restricted to men with larger prostates (60 mL2 and 47 mL2, respectively). Given the mechanism of shrinking or debulking with finasteride, those with larger prostates might well do better than they did with placebo.

What is the clinical significance of a 3- to 4-point reduction out of 35 in an AUA symptom score? It might be worthwhile for patients with severe symptoms who are getting up at night repeatedly to urinate, but perhaps not for patients with milder symptoms who wish to avoid the adverse effects of terazosin. Including some patient-oriented outcomes might have been helpful to further assess the benefits of treatment against the adverse effects of medications. Quality-of-life measurements might have been helpful also to assess how lower scores and increased flow allowed better social functioning, especially for elderly or chronically ill men.

Bottom line

Terazosin is probably the first-line drug of choice for benign prostate hyperplasia given its effectiveness, low cost, and rapid action.

Finasteride did no better than placebo in this trial. Patients who are treatment resistant and have large prostates might choose finasteride as a final alternative if they wish to delay surgery. The mixed results of this trial indicate the heterogeneous nature of this disease process and dispel the myth that all symptoms of BPH are simply the result of an enlarging prostate.

Posted in Book review
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