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Dutasteride, a second-generation 5
alpha-reductase inhibitor, is the first
and only medicine to inhibit both the
type 1 and type 2 enzymes responsible
for the conversion of testosterone to
DHT (dihydrotestosterone), the primary
cause of prostate growth. Dutasteride's
dual inhibition decreases levels of
DHT by 90 percent at two weeks and 93
percent at two years.
By reducing DHT levels, dutasteride
reduces the size of an enlarged prostate.
This reduction in prostate volume was
seen as early as one month with reductions
continuing through treatment. Shrinking
the enlarged prostate relieves urinary
obstruction and improves urinary flow.
Dutasteride also improves urinary symptoms
and reduces the risk of AUR (the sudden
complete inability to urinate) and BPH-related
surgery, two potential long-term serious
consequences of BPH. The pivotal phase
III study data were published in this
month's edition of the journal Urology.1
"With dutasteride, we now have
a medicine that reduces the production
of DHT by more than 90 percent, helping
to shrink the prostate," said Claus
Roehrborn, MD, a principal trial investigator
and professor and chairman of the Department
of Urology at the University of Texas
Southwestern Medical Center in Dallas,
Texas. "By taking dutasteride,
patients can improve urinary symptoms
and reduce their risk of suffering from
acute urinary retention - where you
suddenly can't urinate at all - or needing
BPH-related prostate surgery."
Dutasteride was approved by the Swedish
regulatory authority (MPA) on July 24th
2002. It will be marketed in Sweden
by the trade name AvolveÒ. The
MPA agreed to act as the Reference Member
State for the Mutual Recognition procedure
within Europe and GSK plan to market
the drug in all major European markets
once approvals are finalised during
2003. The European trade name (Avolve)
is to be confirmed.
Background on BPH
BPH is one of the most common health
problems in older men.2 BPH often begins
after age 50 and can progress and worsen
as men age. More than half of men over
age 60 experience BPH,3 and by age 80,
nearly 80 percent of men have the disease.3,4
In the United States alone, 375,000
hospital stays each year involve a diagnosis
of BPH.5
BPH is a progressive disease in which
the prostate gland surrounding the urethra
enlarges.6 As it grows, the prostate
obstructs the urethra, the tube through
which urine flows, causing urinary difficulties.
BPH symptoms interfere with normal activities
and reduce the sense of well being.7
Symptoms of BPH vary, but the most common
involve urinary problems, such as a
hesitant, interrupted weak stream; urgency
and leaking or dribbling; and more frequent
urination, especially at night.5 In
severe cases, the bladder and the kidney
may become damaged.5
An enlarged prostate can continue to
increase in size and may in severe cases
lead to AUR and the need for BPH-related
surgery.6 A 60-year-old man with a 20-year
life expectancy has a 23 percent risk
of developing acute urinary retention.8
Among men 60 years or older, with prostatic
enlargement and obstructive symptoms,
the 20-year probability of needing BPH-related
surgery is 39 percent.9
To diagnose BPH, a physician will discuss
urinary symptoms with a patient and
conduct a digital rectal exam. A physician
may also use a simple blood test that
measures a protein called "prostate-specific
antigen," or PSA. PSA is produced
by the prostate, and an increase in
levels is associated with prostate growth.6
While PSA is primarily used as a screening
tool for prostate cancer, it can also
be used to determine prostate enlargement.
CLINICAL TRIAL RESULTS
Dutasteride was investigated in three
large, well-controlled multi-center
studies involving 4,325 men aged 50
and above with a serum PSA level ³
1.5 ng/mL and < 10 ng/mL, and BPH
diagnosed by medical history and physical
examination, including enlarged prostate
(greater than or equal to 30 cc) and
BPH symptoms that were moderate to severe
according to the American Urological
Association Symptom Index.
Data from these two-year clinical trials
demonstrated that treatment with dutasteride
(0.5 mg once daily) reduced the risk
of both AUR and BPH-related surgical
intervention relative to placebo, improved
BPH-related symptoms, decreased prostate
volume, and increased maximum urinary
flow rates.
Dutasteride should not be used in women
and children. Women who are pregnant
or may become pregnant should not handle
dutasteride because of possibility of
absorption of dutasteride and subsequent
potential risk to a male foetus.
Men treated with dutasteride should
not donate blood until at least six
months after their final dose to prevent
giving dutasteride to a pregnant woman
through a blood transfusion. Men with
an allergic reaction to dutasteride
or its ingredients should not take it.
Men with liver disease should talk to
their doctor before taking dutasteride.
Clinical trials of dutasteride showed
that it was generally well tolerated.
Most side effects were mild or moderate
and generally went away while on treatment
in both the dutasteride and placebo
groups.
Drug-related side effects during the
first six months were as follows: impotence
(4.7 percent vs. 1.7 percent for placebo),
decreased libido (3 percent vs. 1.4
percent), breast tenderness and breast
enlargement (gynecomastia; 0.5 percent
vs. 0.2 percent) and ejaculation disorders
(1.4 percent vs. 0.5 percent).
The incidence of most drug-related
sexual adverse events decreased with
duration of treatment. The incidence
of drug-related breast tenderness and
breast enlargement remained constant
over the treatment period. Ejaculate
volume may be decreased in some patients
with continued treatment. This decrease
did not appear to interfere with normal
sexual function.
Dutasteride will reduce the amount
of PSA measured in the blood. A physician
will be aware of this effect and can
still use PSA to detect prostate cancer.
Although improvement in urinary symptoms
was seen in some patients by three months,
a therapeutic trial of at least six
months is usually necessary to assess
whether a beneficial response in symptom
relief is achieved with dutasteride.
Dutasteride was developed by GlaxoSmithKline
one of the world's leading research-based
pharmaceutical and health care companies.
GlaxoSmithKline is committed to improving
the quality of human life by enabling
people to do more, feel better and live
longer.
References
1 Roehrborn CG, Nickel C, Hoefner K,
Andriole G. Efficacy and safety of a
dual inhibitor of 5 alpha reductase
type 1 and 2 (dutasteride) in men with
benign prostatic hyperplasia. Urol.
2002;60:434-441
2 Meigs JB, Barry MJ, Giovannucci E,
Rimm EB, Stampfer MJ, Kawachi I. Incidence
rates and risk factors for acute urinary
retention: the health professionals
follow-up study. J Urol 1999; 162:376-382.
3 American Foundation for Urologic
Disease (AFUD). What is the Prostate
and What Does it Do? http://www.afud.org.
4 Marcelli M, Cunningham, GR. Hormonal
signaling in prostatic hyperplasia and
neuroplasia. J Clin Endocrin Metab 1999;
84(10):3463-3468.
5 National Institute for Diabetes and
Digestive and Kidney Diseases (NIDDK).
Prostate Enlargement: Benign Prostatic
Hyperplasia. June 2002. http://www.niddk.nih.gov/health/urology/pubs/prostate/index.htm.
6 Anderson JB, Roehrborn CG, Schalken
JA, Emberton M. The progression of benign
prostatic hyperplasia: examining the
evidence and determining the risk. Eur
Urol 2001; 39: 390-399.
7 Girman CJ, Epstein RS, Jacobsen SJ,
Guess HA, Panser LA, Oesterling JE,
Lieber MM. Natural history of prostatism:
impact of urinary symptoms on quality
of life in 2115 randomly selected community
men. Urol 1994; 44:825-831.
8 Jacobsen SJ, Jacobsen DJ, Girman
CJ et al. Natural history of prostatism:
risk factors for acute urinary retention.
J Urol 1997; 158: 481-487.
9 Arrighi HM, Metter EJ, Guess HA,
Fozzard JL. Natural history of benign
prostatic hyperplasia and risk of prostatectomy:
The Baltimore Longitudinal Study of
Aging. Urol (supplement) 1991; 38(1):4-8.
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