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FDA Approves Finasteride Combined With Doxazosin To Reduce the Risk of Benign Prostatic Hyperplasia Symptoms

WHITEHOUSE STATION, N.J., April 20, 2004 - Merck & Co., Inc. today announced that the Food and Drug Administration (FDA) has approved changes to the prescribing information for PROSCAR® (finasteride) based on a landmark National Institutes of Health (NIH) study. Now, PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of the symptoms of benign prostatic hyperplasia (BPH), or benign enlargement of the prostate, from progressing over time (a confirmed rise of four or more points in AUA symptom score).

Benign prostatic hyperplasia is a common condition that occurs in more than 50 percent of men between the ages of 51 and 60 and up to 90 percent of men over the age of 90. Benign prostatic hyperplasia can block the flow of urine through the urethra and may cause symptoms, such as slow urinary stream, straining to urinate, frequent urination, nighttime urination and an urgency to urinate.

The new indication is based on the Medical Therapy of Prostatic Symptoms (MTOPS) study published in December 2003 in The New England Journal of Medicine. In this 3,047-patient study, PROSCAR combined with doxazosin significantly reduced the risk of BPH symptoms progressing when compared to placebo and to either PROSCAR or doxazosin alone.

“Before now, I commonly treated men first diagnosed with BPH with an alpha-blocker, such as doxazosin. Today, for the first time, the FDA has approved combination therapy with finasteride and doxazosin,” said Steven Kaplan, M.D, vice chairman, Department of Urology at Columbia University Medical Center, and MTOPS study investigator. “Finasteride when combined with doxazosin has been shown to reduce the risk of BPH symptoms getting worse. In my own practice, I plan to use more combination therapy to treat men with symptoms of BPH.”

Long-term NIH study conducted at 17 medical centers
MTOPS was a multi-center, double-blind, placebo-controlled study conducted and funded by the National Institute of Diabetes and Digestive and Kidney Diseases, a part of the NIH. In the four- to six-year study (average five years), 3,047 randomized men with moderate to severe BPH symptoms either took placebo (n=737), PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756) or a combination of the two active treatments (n=786).

The primary endpoint of the study was a composite measure of the first occurrence of any of the five following outcomes: a confirmed rise of four or more points from baseline in the American Urological Association (AUA) symptom score [the AUA symptom score scale ranges from 0 (no symptoms) to 35 (severe symptoms)], acute urinary retention, renal insufficiency due to BPH, recurrent urinary tract infections or incontinence. The most common event in the composite primary endpoint was an increase in AUA symptom score of four points or greater above baseline, referred to as symptom score progression. This accounted for 274 of the 351 events, or 78 percent, of the primary endpoint events.

Compared to placebo, treatment with combination therapy, PROSCAR alone and doxazosin alone significantly reduced the risk of experiencing one of the five outcome events. Combination therapy also resulted in a significant reduction in the risk of the composite primary endpoint compared to treatment with PROSCAR alone or doxazosin alone.

Combination therapy with PROSCAR and doxazosin significantly reduced the risk of the primary endpoint by 67 percent compared to placebo [from 17.4 percent with placebo (128 events) to 6.2 percent with combination therapy (49 events), for an absolute risk reduction of 11.2 percent]. Combination therapy also significantly reduced the risk by 49 percent compared to PROSCAR alone [from 11.6 percent with PROSCAR (89 events) to 6.2 percent with combination therapy (49 events), for an absolute risk reduction of 5.4 percent] and by 46 percent compared to doxazosin alone [from 11.2 percent with doxazosin (85 events) to 6.2 percent with combination therapy (49 events), for an absolute risk reduction of 5.0 percent].

PROSCAR with doxazosin reduced risk of symptom score progression by 64 percent
Combination therapy with PROSCAR and doxazosin significantly reduced the risk of symptom score progression by 64 percent compared to placebo [from 13.6 percent with placebo (100 events) to 5.2 percent with combination therapy (41 events), for an absolute risk reduction of 8.4 percent]. Combination therapy significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone (p MTOPS consistent with PLESS findings on acute urinary retention and BPH-related surgery
The results of the MTOPS study are consistent with the findings of the four-year, placebo-controlled study PLESS (PROSCAR Long-Term Efficacy and Safety Study) in that treatment with PROSCAR reduced the risk of acute urinary retention, a component of the MTOPS primary endpoint, and reduced the need for BPH-related surgery, another outcome in MTOPS.

In MTOPS, PROSCAR reduced the risk of developing acute urinary retention by 67 percent compared to placebo [from 2.4 percent with placebo (18 events) to 0.8 percent with PROSCAR (6 events), for an absolute risk reduction of 1.6 percent]. PROSCAR also reduced the risk of requiring BPH-related surgery by 64 percent compared to placebo [from 5.4 percent with placebo (40 events) to 2.0 percent with PROSCAR (15 events), for an absolute risk reduction of 3.4 percent].

Safety and tolerability findings in the MTOPS study
The individual adverse experiences which occurred more frequently in the combination group compared to either drug alone were asthenia (weakness) (16.8 percent in the combination group vs. 7.1 percent for placebo), postural hypotension (quick decrease in blood pressure) (17.8 vs. 8.0), peripheral edema (3.3 vs. 0.9), dizziness (23.2 vs. 8.1), decreased libido (11.6 vs. 5.7), rhinitis (2.4 vs. 0.5), abnormal ejaculation (14.1 vs. 2.3), impotence (22.6 vs. 12.2) and abnormal sexual function (3.1 vs. 0.9). Of these, the incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of this adverse experience reported for the two monotherapies (4.5 percent with doxazosin alone and 7.2 percent with PROSCAR alone). Combination therapy with PROSCAR and doxazosin was associated with no new clinical adverse experiences.

During the MTOPS study, there were four cases of breast cancer in men treated with PROSCAR but no cases in men not treated with PROSCAR. During the PLESS study that enrolled 3,040 men, there were two cases of breast cancer in placebo-treated men, but no cases were reported in men treated with PROSCAR. The relationship between long-term use of PROSCAR and male breast cancer is currently unknown.

About PROSCAR
PROSCAR is indicated for the treatment of symptomatic BPH in men with an enlarged prostate to: improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the need for surgery, including transurethral resection of the prostate (TURP) and prostatectomy. PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of BPH (a confirmed > 4 point increase in AUA symptom score).

PROSCAR is not indicated for use in children or women. PROSCAR is contraindicated in patients who are hypersensitive to any components of this medication and in women when they are or may potentially be pregnant. Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed.

Important information about PROSCAR
Side effects due to PROSCAR may include impotence (8.1 percent for PROSCAR vs. 3.7 percent for placebo) or less desire for sex (6.4 vs. 3.4). Some men taking PROSCAR may have changes (3.7 vs. 0.8) or problems (0.8 vs. 0.1) with ejaculation. In addition, some men may have breast swelling (0.5 vs. 0.1) and/or tenderness (0.4 vs. 0.1). Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Some men have reported allergic reactions such as rash, itching, hives and swelling of the lips and face. Rarely, testicular pain has been reported.

In a seven-year placebo controlled trial that enrolled 18,882 men, 9,060 had prostate needle biopsy data available for analysis. In the group taking PROSCAR, 280 (6.4 percent) men had prostate cancer with Gleason scores of seven to 10 detected on needled biopsy vs. 237 (5.1 percent) men in the placebo group. Of the total cases of prostate cancer diagnosed in this study, approximately 98 percent were classified as intracapsular (stage T1 or T2). The clinical significance of these findings is unknown.

Source: Merck

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