Finasteride

American Health Packaging

HIGHLIGHTS OF PRESCRIBING INFORMATIONFINASTERIDE Tablets USPThese highlights do not include all the information needed to use Finasteride safely and effectively. See full prescribing information for Finasteride. Finasteride (Finasteride) TABLET, FILM COATED for ORAL use.Initial U.S. Approval: 1992RECENT MAJOR CHANGES Indications and Usage, Limitations of Use (1.3) 06/2011 Warnings and Precautions,      Increased Risk of High-Grade Prostate Cancer (5.2) 06/2011INDICATIONS AND USAGE Finasteride, is a 5α-reductase inhibitor, indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to (1.1): • Improve symptoms • Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. Finasteride 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 American Urological Association (AUA) symptom score) (1.2). Limitations of Use: Finasteride is not approved for the prevention of prostate cancer (1.3).DOSAGE AND ADMINISTRATION Finasteride tablets may be administered with or without meals (2). Monotherapy: One tablet (5 mg) taken once a day (2.1). Combination with Doxazosin: One tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin (2.2). DOSAGE FORMS AND STRENGTHS 5 mg film-coated tablets (3). CONTRAINDICATIONS Hypersensitivity to any components of this product (4). Women who are or may potentially be pregnant (4, 5.4, 8.1, 16).WARNINGS AND PRECAUTIONS •Finasteride reduces serum prostate specific antigen (PSA) levels by approximately 50%. However, any confirmed increase in PSA while on finasteride may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor 5.1). • Finasteride may increase the risk of high-grade prostate cancer (5.2, 6.1). • Women should not handle crushed or broken finasteride tablets when they are pregnant or may potentially be pregnant due to potential risk to a male fetus (5.3, 8.1, 16). • Finasteride is not indicated for use in pediatric patients or women 5.4, 8.1, 8.4, 12.3). • Prior to initiating treatment with finasteride for BPH, consideration should be given to other urological conditions that may cause similar symptoms (5.6). Side Effects The drug-related adverse reactions, reported in ≥1% in patients treated with finasteride and greater than in patients treated with placebo over a 4-year study are: impotence, decreased libido, decreased volume of ejaculate, breast enlargement, breast tenderness and rash (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1  INDICATIONS & USAGE
  • 1.1 Monotherapy
  • 1.2 Combination with Alpha-Blocker
  • 1.3 Limitations of Use
• 2  DOSAGE & ADMINISTRATION
  • 2.1 Monotherapy
  • 2.2 Combination with Alpha-Blocker
• 3  DOSAGE FORMS & STRENGTHS
• 4  FINASTERIDE CONTRAINDICATIONS
• 5  WARNINGS AND PRECAUTIONS
  • 5.1 Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection
  • 5.2 Increased Risk of High-Grade Prostate Cancer
  • 5.3 Exposure of Women — Risk to Male Fetus
  • 5.4 Pediatric Patients and Women
  • 5.5 Effect on Semen Characteristics
  • 5.6  Consideration of Other Urological Conditions
• 6  FINASTERIDE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7  DRUG INTERACTIONS
  • 7.1 Cytochrome P450-Linked Drug Metabolizing Enzyme System
  • 7.2 Other Concomitant Therapy
• 8  USE IN SPECIFIC POPULATIONS
  • 8.1  Pregnancy
  • 8.3  Nursing Mothers
  • 8.4  Pediatric Use
  • 8.5  Geriatric Use
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 10  OVERDOSAGE
• 11  FINASTERIDE DESCRIPTION
• 12  CLINICAL PHARMACOLOGY
  • 12.1  Mechanism of Action
  • 12.2  Pharmacodynamics
  • 12.3  Pharmacokinetics
• 13  NONCLINICAL TOXICOLOGY
  • 13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14  CLINICAL STUDIES
  • 14.1 Monotherapy
  • 14.2 Combination with Alpha-Blocker Therapy
  • 14.3 Summary of Clinical Studies
• 16  HOW SUPPLIED
• STORAGE AND HANDLING
• 17  PATIENT COUNSELING INFORMATION
  • 17.1 Increased Risk of High-Grade Prostate Cancer
  • 17.2 Exposure of Women – Risk to Male Fetus
  • 17.3 Additional Instructions
• PATIENT INFORMATION ABOUT
• Package/Label Display Panel

FULL PRESCRIBING INFORMATION

1  INDICATIONS & USAGE

1.1 Monotherapy

Finasteride tablets, USP are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

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

1.2 Combination with Alpha-Blocker

Finasteride 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 American Urological Association (AUA) symptom score).

1.3 Limitations of Use

Finasteride is not approved for the prevention of prostate cancer.

2  DOSAGE & ADMINISTRATION

Finasteride tablets may be administered with or without meals.

2.1 Monotherapy

The recommended dose of finasteride is one tablet (5 mg) taken once a day [see Clinical Studies (14.1)].

2.2 Combination with Alpha-Blocker

The recommended dose of finasteride is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin [see Clinical Studies (14.2)].

3  DOSAGE FORMS & STRENGTHS

Finasteride tablets, USP 5 mg are blue, round, biconvex film-coated tablets, with “F5” on one side and “” on the other.

4  CONTRAINDICATIONS

Finasteride is contraindicated in the following:

• •Hypersensitivity to any component of this medication.
• •Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. [See also Warnings and Precautions (5.3), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2).] In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.

5  WARNINGS AND PRECAUTIONS

5.1 Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

In clinical studies, finasteride reduced serum PSA concentration by approximately 50% within six months of treatment. This decrease is predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals.

For interpretation of serial PSAs in men taking finasteride, a new PSA baseline should be established at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on finasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor. Non-compliance with finasteride therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with finasteride for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the utility of PSA to detect prostate cancer in men treated with finasteride.

Finasteride may also cause decreases in serum PSA in the presence of prostate cancer.

The ratio of free to total PSA (percent free PSA) remains constant even under the influence of finasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value appears necessary.

5.2 Increased Risk of High-Grade Prostate Cancer

Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8 to 10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See Indications and Usage 1.3) and Adverse Reactions (6.1).] Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established.

5.3 Exposure of Women — Risk to Male Fetus

Women should not handle crushed or broken finasteride tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. Finasteride tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. [See Contraindications (4), Use in Specific Populations (8.1), Clinical Pharmacology (12.3), How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2).]

5.4 Pediatric Patients and Women

Finasteride is not indicated for use in pediatric patients [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)] or women [see also Warnings and Precautions (5.3), Use in Specific Populations (8.1), Clinical Pharmacology (12.3), How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2)].

5.5 Effect on Semen Characteristics

Treatment with finasteride for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate was observed. These parameters remained within the normal range and were reversible upon discontinuation of therapy with an average time to return to baseline of 84 weeks.

5.6  Consideration of Other Urological Conditions

Prior to initiating treatment with finasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.

6  ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

4-Year Placebo-Controlled Study (Long-term Efficacy and Safety Study)

In a long-term efficacy and safety study, 1524 patients treated with finasteride 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 finasteride 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 finasteride was ≥1% and greater than placebo over the 4 years of the study. In years 2 to 4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.

Phase III Studies and 5-Year Open Extensions

The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open extensions, and the long-term efficacy and safety study were similar.

Medical Therapy of Prostatic Symptoms (MTOPS) Study

In the Medical Therapy of Prostatic Symptoms (MTOPS) study, 3047 men with symptomatic BPH were randomized to receive finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies (14.2).]

The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the MTOPS 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 was not specifically designed to make statistical comparisons between groups for reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS 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.

Long-Term Data

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 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 to 10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%) [see Indications and Usage (1.3) and Warnings and Precautions (5.2)]. In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART), similar results for Gleason score 8 to 10 prostate cancer were observed (1% dutasteride vs 0.5% placebo).

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

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 long-term efficacy and safety 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 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 finasteride. New reports of drug-related sexual adverse experiences decreased with duration of therapy.

6.2 Postmarketing Experience

The following additional adverse events have been reported in post-marketing experience with finasteride. 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, including pruritus, urticaria, and swelling of the lips 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 finasteride for the treatment of BPH. Most men were older and were taking concomitant medications and/or had co-morbid conditions with a known association to ED. The independent role of finasteride in these events is unknown.
• •male infertility and/or poor seminal quality were reported rarely in men taking finasteride for the treatment of BPH. Normalization or improvement of seminal quality has been reported after discontinuation of finasteride. The independent role of finasteride 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:

• 1.orgasm disorders

7  DRUG INTERACTIONS

7.1 Cytochrome P450-Linked Drug Metabolizing Enzyme System

No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found.

7.2 Other Concomitant Therapy

Although specific interaction studies were not performed, finasteride was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, H₂ antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions.

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

Pregnancy Category X. [See Contraindications (4).]

Finasteride is contraindicated for use in women who are or may become pregnant. Finasteride is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus.

Abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or broken finasteride tablets or semen from a male partner taking finasteride. With regard to finasteride exposure through the skin, finasteride tablets are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. Women who are pregnant or may become pregnant should not handle crushed or broken finasteride tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken finasteride tablets, the contact area should be washed immediately with soap and water. With regard to potential finasteride exposure through semen, two studies have been conducted in men receiving finasteride 5 mg/day that measured finasteride concentrations in semen [see Clinical Pharmacology (12.3)].

In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 days of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride.

No developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions.

No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6 to 18) at maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit.

The fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose.

8.3  Nursing Mothers

Finasteride is not indicated for use in women. It is not known whether finasteride is excreted in human milk.

8.4  Pediatric Use

Finasteride is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.

8.5  Geriatric Use

Of the total number of subjects included in the long-term efficacy and safety study, 1480 and 105 subjects were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.6 Hepatic Impairment

Caution should be exercised in the administration of finasteride in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)].

10  OVERDOSAGE

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

11  DESCRIPTION

Finasteride, USP, 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,17β)-. The empirical formula of finasteride is C₂₃H₃₆N₂O₂ and its molecular weight is 372.55. Its structural formula is: