Proscar

Finasteride may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• inability to have or maintain an erection
• decreased sexual desire
• problems with ejaculation (including decreased volume of ejaculate)
• pain in the testicles
• depression

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• changes in the breasts such as increased size, lumps, pain, or nipple discharge
• rash
• itching
• hives
• swelling of the lips and face
• difficulty breathing or swallowing

Finasteride may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Taking finasteride may increase the risk that you will develop high-grade prostate cancer (a type of prostate cancer that spreads and grows more quickly than other types of prostate cancer). Talk to your doctor about the risks of taking finasteride.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

PROSCAR (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α- dihydrotestosterone (DHT).

Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17ß)-. 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 250°C. 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 Trials Experience

PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.

In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions.

Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo over the 4 years of the study. In years 2-4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.

Table 1: Drug-Related Adverse Experiences

The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open extensions, and PLESS were similar.

In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies.]

The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the MTOPS Study are listed in Table 2.

The individual adverse effects which occurred more frequently in the combination group compared to either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). 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.

Combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience.

Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on finasteride only and one was on combination therapy. [See Long-Term Data.]

The MTOPS Study was not specifically designed to make statistical comparisons between groups for reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study and previous studies of the single agents may not be appropriate based upon differences in patient population, dosage or dose regimen, and other procedural and study design elements.

Table 2: Incidence ≥2% in One or More Treatment Groups Drug-Related Clinical Adverse Experiences in MTOPS

High-Grade Prostate Cancer

The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received either PROSCAR (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%) [see INDICATIONS AND USAGE and WARNINGS AND PRECAUTIONS]. In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART), similar results for Gleason score 8-10 prostate cancer were observed (1% dutasteride vs 0.5% placebo).

No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR.

Breast Cancer

During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. During the 7- year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown.

Sexual Function

There is no evidence of increased sexual adverse experiences with increased duration of treatment with PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of therapy.

Postmarketing Experience

The following additional adverse events have been reported in postmarketing experience with PROSCAR. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• hypersensitivity reactions, such as pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face)
• testicular pain
• sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, decreased libido and ejaculation disorders (e.g. reduced ejaculate volume). These events were reported rarely in men taking PROSCAR for the treatment of BPH. Most men were older and were taking concomitant medications and/or had co-morbid conditions. The independent role of PROSCAR in these events is unknown.
• male infertility and/or poor seminal quality were reported rarely in men taking PROSCAR for the treatment of BPH. Normalization or improvement of poor seminal quality has been reported after discontinuation of finasteride. The independent role of PROSCAR in these events is unknown.
• depression
• male breast cancer

The following additional adverse event related to sexual dysfunction that continued after discontinuation of treatment has been reported in postmarketing experience with finasteride at lower doses used to treat male pattern baldness. Because the event is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure:

• orgasm disorders

Pregnancy category: X

Lactation: Excretion in milk unknown; contraindicated

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

If you take too much Proscar, call your local Poison Control Center or seek emergency medical attention right away.

5-mg blue, modified apple-shaped, film-coated tablets, with the code MSD 72 on one side and Proscar on the other.

Patients have received single doses of Proscar up to 400 mg and multiple doses of Proscar up to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific treatment for an overdose with Proscar can be recommended.

Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg), respectively.

Mechanism of Action

The development and enlargement of the prostate gland is dependent on the potent androgen, 5α-dihydrotestosterone (DHT). Type II 5α-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 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ~ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.

Pharmacodynamics

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. In a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range.

In patients receiving Proscar 5 mg/day, increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In healthy volunteers, treatment with Proscar did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.

In patients with BPH, Proscar has no effect on circulating levels of cortisol, prolactin, thyroid-stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density.

Adult males with genetically inherited Type II 5α-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 5α-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 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 μg) that had no effect on circulating DHT levels in men [see also Use in Specific Populations (8.1)].

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 5α-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).

Pediatric

Finasteride pharmacokinetics have not been investigated in patients <18 years of age.

Finasteride is not indicated for use in pediatric patients [see Warnings and Precautions (5.4), Use in Specific Populations (8.4)].

Gender

Finasteride is not indicated for use in women [see Contraindications (4), Warnings and Precautions (5.3 and 5.4), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2)].

Geriatric

No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance. [See Clinical Pharmacology (12.3) and Use in Specific Populations (8.5).]

Race

The effect of race on finasteride pharmacokinetics has not been studied.

Hepatic Impairment

The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of Proscar in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater.

Take Proscar exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medicine with a full glass of water.

Proscar can be taken with or without food. Take the medicine at the same time each day.

To be sure Proscar is helping your condition and not causing harmful effects, your blood may need to be tested often. Your doctor will also test your prostate specific antigen (PSA) to check for prostate cancer. Visit your doctor regularly.

Use Proscar regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store Proscar at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Get emergency medical help if you have any of these signs of an allergic reaction to Proscar: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you notice any breast lumps, pain, nipple discharge, or other breast changes. These may be signs of male breast cancer.

Less serious Proscar side effects may include:

• impotence, loss of interest in sex, or trouble having an orgasm;

• abnormal ejaculation;

• swelling in your hands or feet;

• swelling or tenderness in your breasts;

• dizziness, weakness;

• feeling like you might pass out;

• headache;

• runny nose; or

• skin rash.

The sexual side effects of Proscar (decreased libido, trouble having an erection, ejaculation problems) may continue after you stop taking this medication. Talk to your doctor if you have concerns about these side effects.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.