Proscar (Finasteride)




5 Alpha-reductase Inhibitor

Action And Clinical Pharmacology: Finasteride is a synthetic 4-azasteroid compound which is a competitive and specific inhibitor of 5 alpha-reductase, an intracellular enzyme which metabolizes testosterone into the more potent androgen dihydrotestosterone (DHT). Finasteride has very low affinity for the androgen receptor.

Benign prostatic hyperplasia (BPH) is a common finding in men over the age of 50 and its prevalence increases with age. The development of the prostate gland and subsequent BPH are partially dependent upon the conversion of testosterone to DHT within the prostate. As with other androgen mediated processes, BPH is a slowly progressing disorder and therefore, reversal of the clinical manifestations of BPH may require several months of treatment.

Within 24 hours after oral administration of a single 5 mg dose of finasteride, circulating DHT levels are reduced by approximately 60%. In patients with BPH, finasteride, given for 12 months at a dose of 5 mg/day, was shown to reduce circulating DHT concentrations by approximately 70%.

In one year clinical trials, patients treated with 5 mg daily dose of finasteride demonstrated a suppression of DHT associated with an approximate 20% mean decrease in prostate volume, an increase of ³ 3 mL/s in maximum urinary flow rate in about 35% of patients, and an improvement in total, as well as obstructive symptoms. This control of BPH was maintained throughout the long-term open extensions of these trials for up to 36 months. However, the effects of finasteride are reversible if treatment is stopped.

Compared to baseline values, patients showed an improvement in all three primary efficacy parameters at first evaluation – month 3 for prostate volume and week 2 for urinary flow and symptoms. Compared to placebo, a statistically significant difference in the decrease in prostate volume and prostate specific antigen (PSA) occurred after 3 months. Statistically significant differences in favor of finasteride compared to placebo were also seen in maximum urinary flow rates by 4 months and in both total and obstructive symptoms scores by 7 months. However, not all patients responded.

In a study in 15 healthy male subjects, the mean bioavailability of a 5 mg finasteride tablet was 63% (range, 34 to 108%), based on the ratio of the area under the curve (AUC) relative to a 5 mg i.v. dose infused over 60 minutes. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27 to 49 ng/mL) and was reached 1 to 2 hours postdose. The mean plasma half-life of elimination was 6 hours (range, 3 to 16 hours). Following the i.v. infusion, mean plasma clearance was 165 mL/min (range, 70 to 279 mL/min) and mean steady-state volume of distribution was 76 L (range, 44 to 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.

Indications And Clinical Uses: For the treatment of symptomatic benign prostatic hyperplasia (BPH), to cause regression of the enlarged prostate, improve urinary flow and improve the symptoms associated with BPH.

There is a regression of the enlarged prostate gland in most patients treated with finasteride. Approximately 50 to 60% of patients experienced a significant increase in urinary flow (greater than 10%) and improvement in symptoms of benign prostate enlargement when treated with finasteride. Although some patients may respond sooner, a minimum of 6 months of treatment may be necessary to determine whether an individual will respond to finasteride. Eighty-five to 90% of those patients who do respond to finasteride, do so during the first 12 months of treatment. It is not possible to identify prospectively those patients who will respond (see Dosage).

Prior to initiating therapy with finasteride, thorough evaluation should be performed to identify other conditions, such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic disorders, that might mimic BPH.

Contra-Indications: Finasteride is not indicated for use in women or children.

Finasteride is contraindicated in the following: Hypersensitivity to any component of this product.

Pregnancy: Use in women when they are or may potentially become pregnant (see Precautions, Exposure to Finasteride – Risk to Male Fetus).

Manufacturers’ Warnings In Clinical States: Pregnancy and Lactation: Finasteride is contraindicated for use in women when they are or may potentially become pregnant (see Contraindications). Because of the ability of 5 alpha-reductase inhibitors such as finasteride to inhibit conversion of testosterone to dihydrotestosterone, finasteride may cause abnormalities of the external male genitalia when administered to a woman carrying a male fetus. It is not known whether finasteride is excreted in human milk.

Precautions: General: Since the beneficial response to finasteride may not be manifested immediately, patients with large residual urine volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for this therapy.

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

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

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

Prior to treatment with finasteride, 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.

Prostate Cancer: Digital rectal examinations, as well as other evaluations for prostate cancer are recommended prior to initiating therapy with finasteride and periodically thereafter. Serum PSA is being increasingly 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. The physician should be aware that a baseline PSA
Finasteride causes a decrease in serum PSA levels in patients with BPH even in the presence of prostate cancer. This reduction of PSA levels should be considered when evaluating PSA laboratory data and does not suggest a beneficial effect of finasteride on prostate cancer. In controlled clinical trials finasteride did not appear to alter the rate of prostate cancer detection.

Any sustained increases in PSA levels while on finasteride should be carefully evaluated, including consideration of noncompliance to therapy with finasteride.

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.

Exposure to Finasteride – Risk to Male Fetus: Crushed or broken Proscar tablets should not be handled by women when they are or may become pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus (see Warnings).

Children: Finasteride is not indicated for use in children.

Safety and effectiveness in children have not been established.

Drug Interactions: No drug interactions of clinical importance have been identified. Finasteride, 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. However, patients on medications with narrow therapeutic indices, such as phenytoin, should be carefully monitored when treatment with finasteride is initiated.

Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies finasteride was used concomitantly with ACE-inhibitors, 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.

Adverse Reactions: Based on experience in a total of over 1 950 patients, of whom 1 645 patients were treated for 1 year and over 360 for more than 1 year, finasteride is well tolerated. In these clinical studies, 1.4% of patients were withdrawn due to adverse reactions attributable to finasteride.

In controlled clinical studies of 12 months duration involving 543 patients treated with finasteride 5 mg, adverse reactions considered by the investigators as possibly, probably or definitely drug-related, occurring with a frequency greater than 1% and greater than with placebo were: impotence (3.7% on finasteride, 1.1% on placebo), decreased libido (3.3%, 1.6%) and decreased volume of ejaculate (2.8%, 0.9%).

The adverse experience profile for approximately 1 100 patients treated with 5 mg/day finasteride for 24 months, 400 patients treated for 36 months and 50 patients treated for 48 months was similar to that observed in the 12-month studies. There is no evidence of increased adverse experiences with increased duration of treatment with finasteride. The incidence of new drug related sexual adverse experiences decreases with duration of treatment and, in over 60% of patients who develop sexual adverse experiences, they resolve with continued treatment.

The following additional adverse reactions have been reported in postmarketing experience: breast tenderness and enlargement; hypersensitivity reactions, including lip swelling and skin rash.

Laboratory Tests: When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels are decreased in patients treated with finasteride (see Precautions, Prostate Cancer).

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 pretreatment value. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Therefore, in typical patients treated with finasteride for 6 months or more, PSA values should be doubled for comparison to normal ranges in untreated men. 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 finasteride treatment.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Patients have received single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for 3 months without adverse effects.

No specific treatment of overdosage with finasteride is known.

Dosage And Administration: The recommended dosage is one 5 mg tablet daily with or without food.

Although early improvement may be seen, a therapeutic trial of at least 6 months but not exceeding 1 year may be necessary, in some patients, to assess whether a beneficial response has been achieved. If no clinical benefit is evident within this period, patients should be re-evaluated and the decision for continuation or discontinuation of finasteride therapy should be based upon assessment of their disease status.

Renal Insufficiency: Adjustments in dosage are not necessary 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.

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

Availability And Storage: Each blue, apple-shaped, film-coated tablet, with the code MSD 72 on one side and PROSCAR on the other, contains: finasteride 5 mg. Nonmedicinal ingredients: cellulose and cellulose derivatives, docusate sodium, FD&C Blue 2/aluminum lake, lactose, magnesium stearate, sodium starch glycolate, starch, talc, titanium dioxide and yellow ferric oxide. Blister packages of 30. Store at room temperature (15 to 30°C) and protect from light to prevent discoloration.

Crushed or broken tablets should not be handled by women when they are or may potentially become pregnant (see Contraindications and Warnings).

PROSCAR® MSD Finasteride 5 Alpha-reductase Inhibitor

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