• PROSCAR (finasteride) as monotherapy is indicated for the treatment and control of benign prostatic hyperplasia (BPH) and for the prevention of urologic events to:

  • Reduce the risk of acute urinary retention;

    
    

  • Reduce the risk of surgery including transurethral resection of the prostate (TURP) and prostatectomy.

    
    

   

  
  

• PROSCAR causes regression of the enlarged prostate, improves urinary flow and improves the symptoms associated with BPH.

  
  

• 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).

  
  

 

Patients with an enlarged prostate are the appropriate candidates for therapy with PROSCAR. PROSCAR is not indicated to reduce the risk of developing prostate cancer in healthy men.

PROSCAR is not indicated for use in women or children.

PROSCAR is contraindicated in the following:

• Pregnant Women—Use in women when they are or may potentially be pregnant (see Warnings and Precautions, Exposure to Finasteride—Risk to Male Fetus);

  
  

• Hypersensitivity to any component of this product.

  
  

 

Patients with large residual urine volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy.

PROSCAR is not indicated for those patients who are candidates for immediate surgery.

No studies have been conducted to determine if PROSCAR can be used for the control of prostatic hyperplasia in asymptomatic patients.

The long term (>10 years) beneficial and adverse effects of PROSCAR have not yet been established.

Prior to treatment with PROSCAR, the patient should undergo a thorough urological evaluation to determine the severity of the condition, and to exclude the need for immediate surgery or the possibility of carcinoma of the prostate. Periodic follow-up evaluations should be performed to determine whether a clinical response has occurred.

No clinical benefit has yet been demonstrated in patients with prostate cancer treated with PROSCAR. Patients with BPH and elevated prostate-specific antigen (PSA) were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these studies, PROSCAR did not appear to alter the rate of prostate cancer detection. The overall incidence of prostate cancer was not significantly different in patients treated with PROSCAR or placebo.

Digital rectal examinations, as well as other evaluations for prostate cancer are recommended prior to initiating therapy with PROSCAR and periodically thereafter. Serum PSA is also used as one of the components of the screening process to detect prostate cancer. Generally, a baseline PSA >10 ng/mL (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 ng/mL, further evaluation is generally considered advisable. There is considerable overlap in PSA levels among men with and without prostate cancer. Therefore, in men with BPH, PSA values within the normal reference range do not rule out prostate cancer, regardless of treatment with PROSCAR. A baseline PSA <4 ng/mL does not exclude prostate cancer.

PROSCAR causes a decrease in serum PSA concentrations by approximately 50% in patients with BPH, even in the presence of prostate cancer (see Adverse Reactions, Laboratory Tests). This decrease in serum PSA levels in patients with BPH treated with PROSCAR should be considered when evaluating PSA data and does not rule out concomitant prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3000 patients in the 4-year, double-blind, placebo-controlled PROSCAR Long-Term Efficacy and Safety Study (PLESS) confirmed that in typical patients treated with PROSCAR for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.

Any sustained increases in PSA levels of patients treated with finasteride should be carefully evaluated, including consideration of non-compliance to therapy with PROSCAR.

Clinical experience with finasteride in men with prostate cancer (n=72) suggests that the reduction in PSA from malignant prostate disease appears to be no greater than the percentage reduction of PSA from benign prostate disease.

Pregnant Women and Nursing Women: PROSCAR is contraindicated for use in women when they are or may potentially be pregnant (see Contraindications). Because of the ability of Type II 5 alpha-reductase inhibitors such as finasteride to inhibit conversion of testosterone to dihydrotestosterone, PROSCAR may cause abnormalities of the external genitalia of a male fetus when administered to a pregnant woman. It is not known whether finasteride is excreted in human milk. In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring. Therefore, if this drug is used during pregnancy or if pregnancy occurs while taking or exposed to this drug, the pregnant woman should be apprised of the potential hazard to the male fetus.

See Pregnant Women.

Women should not handle crushed or broken tablets of PROSCAR when they are or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus (see Warnings and Precautions, Pregnant Women). 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.

PROSCAR is not indicated for use in children. Safety and effectiveness in children have not been established.

Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels decrease in patients treated with PROSCAR.

PROSCAR is well tolerated.

In PLESS, 1524 patients treated with PROSCAR 5 mg daily and 1516 patients treated with placebo were evaluated for safety over a period of 4 years. 4.9% (74 patients) were discontinued from treatment due to side effects associated with PROSCAR compared with 3.3% (50 patients) treated with placebo. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with placebo discontinued therapy as a result of side effects related to sexual function, which were the most frequently reported side effects.

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: PROSCAR

Drug-related Adverse Experiences

	Treatment	Year 1 (%)	Years 2, 3 and 4a (%)
Impotence	Placebo Finasteride	3.7 8.1	5.1 5.1
Decreased Libido	Placebo Finasteride	3.4 6.4	2.6 2.6
Decreased Volume of Ejaculate	Placebo Finasteride	0.8 3.7	0.5 1.5
Ejaculation Disorder	Placebo Finasteride	0.1 0.8	0.1 0.2
Breast Enlargement	Placebo Finasteride	0.1 0.5	1.1 1.8
Breast Tenderness	Placebo Finasteride	0.1 0.4	0.3 0.7
Rash	Placebo Finasteride	0.2 0.5	0.1 0.5

^a. Combined years 2–4.

The adverse experience profile in the one-year, placebo-controlled, Phase III studies and the five-year extensions, including 853 patients treated for 5 to 6 years, was similar to that reported in years 2-4 in PLESS. There is no evidence of increased adverse experiences with increased duration of treatment with PROSCAR. The incidence of new drug related sexual adverse experiences decreased with duration of treatment.

The following additional adverse reactions have been reported in post-marketing experience:

• hypersensitivity reactions, including pruritus, urticaria and swelling of the lips and face;

  
  

• and testicular pain

  
  

 

The MTOPS study compared finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), combination therapy of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), and placebo (n=737). In this study, the safety and tolerability profile of the combination therapy was generally consistent with the profiles of the individual components. The incidence of ejaculation disorder in patients receiving combination therapy was comparable to the sum of incidences of this adverse experience for the two monotherapies. The individual adverse effects that 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).

Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on finasteride only and one was on the combination therapy. During the four year, placebo-controlled PLESS study, which enrolled 3040 men, there were 2 cases of breast cancer in the placebo treated men, but no cases were reported in men treated with finasteride. The relationship between the long-term use of finasteride and male breast cancer is currently unknown.

Table 2: PROSCAR

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

Adverse Experience	Placebo (N=737) (%)	Doxazosin 4 mg or 8 mga (N=756) (%)	Finasteride (N=768) (%)	Combination (N=786) (%)
Body as a Whole
Asthenia	7.1	15.7	5.3	16.8
Headache	2.3	4.1	2.0	2.3
Cardiovascular
Hypotension	0.7	3.4	1.2	1.5
Postural Hypotension	8.0	16.7	9.1	17.8
Metabolic and Nutritional
Peripheral Edema	0.9	2.6	1.3	3.3
Nervous
Dizziness	8.1	17.7	7.4	23.2
Libido Decreased	5.7	7.0	10.0	11.6
Somnolence	1.5	3.7	1.7	3.1
Respiratory
Dyspnea	0.7	2.1	0.7	1.9
Rhinitis	0.5	1.3	1.0	2.4
Urogenital
Abnormal Ejaculation	2.3	4.5	7.2	14.1
Gynecomastia	0.7	1.1	2.2	1.5
Impotence	12.2	14.4	18.5	22.6
Sexual Function Abnormal	0.9	2.0	2.5	3.1

^a. Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4. Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the study.

In a 7-year placebo-controlled trial that enrolled 18 882 healthy men, of whom 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving PROSCAR and 1147 (24.4%) men receiving placebo. The clinical significance of this observation on the occurrence of prostate cancer in men treated with PROSCAR is unknown. In the PROSCAR group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in the placebo group. The mechanism of an increased occurrence of high-grade prostate cancers in men treated with PROSCAR in this study is unknown. Additional analyses have indicated that the observation of an increase in high-grade prostate tumors in men treated with PROSCAR may be due to a detection bias that could be mediated through an effect on the volume of the prostate induced by long term PROSCAR treatment. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (clinical stage T1 or T2) at diagnosis. The clinical significance of the Gleason 7-10 data is unknown. PROSCAR is not indicated to reduce the risk of developing prostate cancer in healthy men.

When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels are decreased in patients treated with PROSCAR (see Warnings and Precautions, Effects on PSA and Prostate Cancer Detection).

In most patients, a rapid decrease in PSA is seen within the first months of therapy, after which time PSA levels stabilize to a new baseline. The post-treatment baseline approximates half of the pre-treatment value. Therefore, in typical patients treated with PROSCAR for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men. For clinical interpretation, see Warnings and Precautions, Effects on PSA and Prostate Cancer Detection.

No other difference in standard laboratory parameters was observed between patients treated with placebo or PROSCAR.

No drug interactions of clinical importance have been identified. PROSCAR, at prescribed doses, does not appear to affect significantly the cytochrome P450-linked drug metabolizing enzyme system. Compounds which have been tested in man have included propranolol, digoxin, glyburide, warfarin, theophylline and antipyrine and no clinically meaningful interactions were found. However, patients on medications with narrow therapeutic indices, such as phenytoin, should be carefully monitored when treatment with PROSCAR is initiated.

Although specific interaction studies were not performed, in clinical studies PROSCAR was used concomitantly with ACE-inhibitors, acetaminophen, acetylsalicylic acid, alpha-blockers, beta-blockers, calcium channel blockers, cardiac nitrates, diuretics, H₂ antagonists, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), quinolones and benzodiazepines without evidence of clinically significant adverse interactions.

• PROSCAR as monotherapy is indicated for the treatment and control of benign prostatic hyperplasia (BPH) and for the prevention of urologic events to:

  • Reduce the risk of acute urinary retention;

    
    

  • Reduce the risk of surgery including transurethral resection of the prostate (TURP) and prostatectomy.

    
    

   

  
  

• PROSCAR causes regression of the enlarged prostate, improves urinary flow and improves the symptoms associated with BPH.

  
  

• 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).

  
  

The recommended dosage of PROSCAR is one 5 mg tablet daily with or without food (for information on doxazosin, see a doxazosin Product Monograph).

No adjustment in dosage is required in patients with varying degrees of renal insufficiency (creatinine clearances as low as 0.15 mL/s [9 mL/min]) as pharmacokinetic studies did not indicate any change in the disposition of finasteride.

No adjustment in dosage is required although pharmacokinetic studies indicated the elimination of finasteride is decreased in patients more than 70 years of age.

If a tablet is missed at its usual time, an extra dose should not be taken. The next dose should be taken as usual.

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.

No specific treatment of overdosage with PROSCAR is recommended

PROSCAR a synthetic 4-azasteroid compound, is an inhibitor of Type II 5 alpha-reductase, an intracellular enzyme which metabolizes testosterone into the more potent androgen dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), enlargement of the prostate gland is dependent upon the conversion of testosterone to DHT within the prostate. PROSCAR is highly effective in reducing circulating and intraprostatic DHT. Finasteride has very low affinity for the androgen receptor.

In the PROSCAR Long-Term Efficacy and Safety Study (PLESS), the effect of therapy with PROSCAR on BPH-related urologic events (surgical intervention [e.g., transurethral resection of the prostate and prostatectomy] or acute urinary retention requiring catheterization) was assessed over a 4-year period in 3016 patients with moderate to severe symptoms of BPH. In this double-blind, randomized, placebo-controlled multicenter study, treatment with PROSCAR reduced the risk of total urologic events by 51% and was also associated with a marked and sustained regression in prostate volume, and a sustained increase in maximum urinary flow rate and improvement in symptoms.

In a study in 15 healthy male subjects, the mean bioavailability of a 5 mg PROSCAR tablet was 63% (range, 34-108%), based on the ratio of the area under the curve (AUC) relative to a 5 mg intravenous dose infused over 60 minutes. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1 to 2 hours postdose. The mean plasma half-life of elimination was 6 hours (range, 3-16 hours). Following the intravenous infusion, mean plasma clearance was 2.75 mL/s (range, 1.17-4.65 mL/s) (165 mL/min, range, 70-279 mL/min) and mean steady-state volume of distribution was 76 L (range, 44-96 L). In a separate study, the bioavailability of finasteride was not affected by food.

Approximately 90% of circulating finasteride is bound to plasma proteins. Finasteride has been found to cross the blood-brain barrier.

No dosage adjustment is necessary for the elderly or patients with renal insufficiency.

Store at room temperature (15-30°C) and protect from light to prevent discoloration.

Women should not handle crushed or broken tablets of PROSCAR when they are or may potentially be pregnant (see Warnings and Precautions, Special Populations, Exposure to Finasteride—Risk to Male Fetus)