Proscar - Treatment for Prostate Enlargement & Hair Loss

DESCRIPTION

PROSCAR* (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5(alpha)-reductase, an intracellular enzyme that converts the androgen testosterone into 5(alpha)-dihydrotestosterone (DHT). Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5(alpha),17(beta))-. The empirical formula of finasteride is C₂₃H₃₆N₂O₂ and its molecular weight is 372.55. Its structural formula is:

Finasteride is a white crystalline powder with a melting point near 250C. It is freely soluble in chloroform and in lower alcohol solvents, but is practically insoluble in water.
PROSCAR (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of finasteride and the following inactive ingredients: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.

CLINICAL PHARMACOLOGY

The development and enlargement of the prostate gland is dependent on the potent androgen, 5(alpha)-dihydrotestosterone (DHT). Type II 5(alpha)-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.
Finasteride is a competitive and specific inhibitor of Type II 5(alpha)-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t - 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5(alpha)-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of PROSCAR at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but remained within the physiologic range.
Adult males with genetically inherited Type II 5(alpha)-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5(alpha)-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH. In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative to placebo. Intraprostatic content of prostate-specific antigen (PSA) was also decreased.
In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately three months of discontinuation of therapy.
Pharmacokinetics
Absorption
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63% (range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 and 54% higher than after the first dose in men 45-60 years old (n=12) and >70 years old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4-9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively, in the two age groups. Although steady state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a year of dosing.
Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF.
In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR 5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 g) that had no effect on circulating DHT levels in men (see also PRECAUTIONS, Pregnancy).
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5(alpha)-reductase inhibitory activity of finasteride.
Excretion
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral dose of ¹⁴C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces.
The mean terminal half-life of finasteride in subjects >70 years of age was approximately 8 hours (range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of age. As a result, mean AUC_{(0-24 hr)} after 17 days of dosing was 15% higher in subjects >70 years of age than in subjects 45-60 years of age (p=0.02).

PROSCAR* is for use by men only.

Please read this leaflet before you start taking PROSCAR. Also, read it each time you renew your prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss PROSCAR when you start taking your medication and at regular checkups.

Why your doctor has prescribed PROSCAR

Your doctor has prescribed PROSCAR because you have a medical condition called benign prostatic hyperplasia or BPH. This occurs only in men.

What is BPH?

BPH is an enlargement of the prostate gland. After age 50, most men develop enlarged prostates. The prostate is located below the bladder. As the prostate enlarges, it may slowly restrict the flow of urine. This can lead to symptoms such as:

• a weak or interrupted urinary stream
• a feeling that you cannot empty your bladder completely
• a feeling of delay or hesitation when you start to urinate
• a need to urinate often, especially at night
• a feeling that you must urinate right away.

In some men, BPH can lead to serious problems, including urinary tract infections, a sudden inability to pass urine (acute urinary retention), as well as the need for surgery.

Treatment options for BPH

There are three main treatment options for symptoms of BPH:

• Program of monitoring or "Watchful Waiting". If a man has an enlarged prostate gland and no symptoms or if his symptoms do not bother him, he and his doctor may decide on a program of monitoring which would include regular checkups, instead of medication or surgery.
• Medication. Your doctor may prescribe PROSCAR for BPH. See "What PROSCAR does" below.
• Surgery. Some patients may need surgery. Your doctor can suggest several different surgical procedures for BPH. Which procedure is best depends on your symptoms and medical condition.

There are two main treatment options to reduce the risk of serious problems due to BPH:

• Medication. Your doctor may prescribe PROSCAR for BPH. See "What PROSCAR does" below.
• Surgery. Some patients may need surgery. Your doctor can suggest several different surgical procedures for BPH. Which procedure is best depends on your symptoms and medical condition.

What PROSCAR does

PROSCAR lowers levels of a key hormone called DHT (dihydrotestosterone), which is a major cause of prostate growth. Lowering DHT leads to shrinkage of the enlarged prostate gland in most men. This can lead to gradual improvement in urine flow and symptoms over the next several months. PROSCAR will help reduce the risk of developing a sudden inability to pass urine and the need for surgery. However, since each case of BPH is different, you should know that:

• Even though the prostate shrinks, you may NOT notice an improvement in urine flow or symptoms.
• You may need to take PROSCAR for six (6) months or more to see whether it improves your symptoms.
• Therapy with PROSCAR may reduce your risk for a sudden inability to pass urine and the need for surgery.

What you need to know while taking PROSCAR

• You must see your doctor regularly. While taking PROSCAR, you must have regular checkups. Follow your doctor's advice about when to have these checkups.
• About side effects. Like all prescription drugs, PROSCAR may cause side effects. Side effects due to PROSCAR may include impotence (an inability to have an erection) or less desire for sex.

Some men taking PROSCAR may have changes or problems with ejaculation, such as a decrease in the amount of semen released during sex. This decrease in the amount of semen does not appear to interfere with normal sexual function. In some cases these side effects went away while the patient continued to take PROSCAR.

In addition, some men may have breast enlargement and/or tenderness. You should promptly report to your doctor any changes in your 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.

You should discuss side effects with your doctor before taking PROSCAR and anytime you think you are having a side effect.

• Checking for prostate cancer. Your doctor has prescribed PROSCAR for symptomatic BPH and not for cancer - but a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These checks should continue while you take PROSCAR. PROSCAR is not a treatment for prostate cancer.
• About Prostate-Specific Antigen (PSA). Your doctor may have done a blood test called PSA. PROSCAR can alter PSA values. For more information, talk to your doctor.
• A warning about PROSCAR and pregnancy. PROSCAR is for use by MEN only. Women who are or may potentially be pregnant must not use PROSCAR. They should also not handle crushed or broken tablets of PROSCAR.

If a woman who is pregnant with a male baby absorbs the active ingredient in PROSCAR after oral use or through the skin, it may cause the male baby to be born with abnormalities of the sex organs.

PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.