FIN5C 5 MG Oral Tablet
DRUG INTERACTIONS
7 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 tablets USP 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, H 2 antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions.
OVERDOSAGE
10 Patients have received single doses of finasteride tablets USP up to 400 mg and multiple doses of finasteride tablets USP up to 80 mg/day for three months without adverse effects.
Until further experience is obtained, no specific treatment for an overdose with finasteride tablets USP can be recommended.
Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m 2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m 2 (400 mg/kg) and 5900 mg/m 2 (1000 mg/kg), respectively.
DESCRIPTION
11 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 C 23 H 36 N 2 O 2 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.
Finasteride tablets USP for oral administration are film-coated tablets that contain 5 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, docusate sodium, magnesium stearate, opadry blue (FD&C blue #2 aluminium lake, hypromellose, talc, titanium dioxide, yellow iron oxide).
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CLINICAL STUDIES
14 14.1 Monotherapy Finasteride tablets USP, 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their 5-year open extensions.
Finasteride tablets USP was further evaluated in a long-term efficacy and safety study, a double-blind, randomized, placebo-controlled, 4-year, multicenter study.
3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for efficacy.
1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group).
Effect on Symptom Score Symptoms were quantified using a score similar to the American Urological Association Symptom Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one symptom, for a total possible score of 34.
Patients in a long-term efficacy and safety study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0 to 34 point scale).
Patients randomized to finasteride tablets USP who remained on therapy for 4 years had a mean (± 1 SD) decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the placebo group.
(See Figure 1.) A statistically significant improvement in symptom score was evident at 1 year in patients treated with finasteride tablets USP vs placebo (–2.3 vs –1.6), and this improvement continued through Year 4.
Figure 1 Symptom Score in A Long-Term Efficacy and Safety Study Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study.
Although an early improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to assess whether a beneficial response in symptom relief had been achieved.
The improvement in BPH symptoms was seen during the first year and maintained throughout an additional 5 years of open extension studies.
Effect on the Need for Surgery In a long-term efficacy and safety study, efficacy was also assessed by evaluating treatment failures.
Treatment failure was prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for alternative therapy.
BPH-related urological events were defined as urological surgical intervention and acute urinary retention requiring catheterization.
Complete event information was available for 92% of the patients.
The following table summarizes the results.
Table 4 All Treatment Failures in A Long-Term Efficacy and Safety Study Patients (%)* Event Placebo N=1503 Finasteride N=1513 Relative Risk † 95% CI PValue † All Treatment Failures 37.1 26.2 0.68 (0.57 to 0.79) <0.001 Surgical Interventions for BPH 10.1 4.6 0.45 (0.32 to 0.63) 20 9.2 6.7 Bladder Stone 0.4 0.5 Incontinence 2.1 1.7 Renal Failure 0.5 0.6 UTI 5.7 4.9 Discontinuation due to worsening of BPH, lack of improvement, or to receive other medical treatment 21.8 13.3 *patients with multiple events may be counted more than once for each type of event †Hazard ratio based on log rank test Compared with placebo, finasteride tablets USP was associated with a significantly lower need for BPH-related surgery.
Compared with placebo, finasteride tablets USP was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for finasteride tablets USP; 55% reduction in risk, 95% CI: (37% to 68%)]; see Figure 2.
Effect on Maximum Urinary Flow Rate In the patients in long-term efficacy and safety study who remained on therapy for the duration of the study and had evaluable urinary flow data, finasteride tablets USP increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the placebo group.
There was a clear difference between treatment groups in maximum urinary flow rate in favor of finasteride tablets USP by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study.
In the earlier 1-year studies, increase in maximum urinary flow rate was comparable to long-term efficacy and safety study and was maintained through the first year and throughout an additional 5 years of open extension studies.
Effect on Prostate Volume In long-term efficacy and safety study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients.
In patients treated with finasteride tablets USP who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study.
Finasteride tablets USP decreased prostate volume by 17.9% (from 55.9 ml at baseline to 45.8 ml at 4 years) compared with an increase of 14.1% (from 51.3 ml to 58.5 ml) in the placebo group (p<0.001).
(See Figure 3.) Results seen in earlier studies were comparable to those seen in long-term efficacy and safety study.
Mean prostate volume at baseline ranged between 40 to 50 ml.
The reduction in prostate volume was seen during the first year and maintained throughout an additional five years of open extension studies.
Figure 3 Prostate Volume in A Long-Term Efficacy and Safety Study Prostate Volume as a Predictor of Therapeutic Response A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with finasteride tablets USP, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline.
figure1.jpg figure2.jpg figure3 14.3 Summary of Clinical Studies The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume, suggest that finasteride tablets USP arrests the disease process of BPH in men with an enlarged prostate.
HOW SUPPLIED
16 /STORAGE AND HANDLING Finasteride tablets USP, 5 mg are blue color, round film coated tablets, debossed with ‘H’ on one side ‘37’ on other side.
They are supplied as follows: NDC 65977-5025-0 bottles of 30 NDC 65977-5025-1 bottles of 100 NDC 65977-5025-2 bottles of 1000 NDC 65977-5025-3 bottles of 90 NDC 65977-5025-4 bottles of 500 Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light and keep container tightly closed.
Women should not handle crushed or broken finasteride tablets USP 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 [ see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) and Patient Counseling Information (17.2) ].
RECENT MAJOR CHANGES
Indications and Usage, Limitations of Use ( 1.3 ) 06/2011 Warnings and Precautions, Increased Risk of High-Grade Prostate Cancer ( 5.2 ) 06/2011
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects included in a 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) ].
DOSAGE FORMS AND STRENGTHS
3 DOSAGE FORMS & STRENGTHS Finasteride tablets USP, 5 mg are blue color, round film coated tablets, debossed with ‘H’ on one side ‘37’ on other side.
5 mg film-coated tablets ( 3 ).
MECHANISM OF ACTION
12.1 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 (t ½ ∼ 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.
INDICATIONS AND USAGE
1 INDICATIONS & USAGE Finasteride tablets USP, 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.
Limitations of Use: Finasteride tablets USP is not approved for the prevention of prostate cancer ( 1.3 ).
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.
1.3 Limitations of Use Finasteride tablets USP are not approved for the prevention of prostate cancer.
PEDIATRIC USE
8.4 Pediatric Use Finasteride tablets USP is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category X.
[See Contraindications (4) .] Finasteride tablets USP are contraindicated for use in women who are or may become pregnant.
Finasteride tablets USP 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 USP or semen from a male partner taking finasteride tablets USP.
With regard to finasteride exposure through the skin, finasteride tablets USP 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 USP because of possible exposure of a male fetus.
If a pregnant woman comes in contact with crushed or broken finasteride tablets USP, 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 tablets USP, 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.
NUSRING MOTHERS
8.3 Nursing Mothers Finasteride tablets USP is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Finasteride tablets USP reduces serum prostate specific antigen (PSA) levels by approximately 50%.
However, any confirmed increase in PSA while on finasteride tablets USP 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 tablets USP may increase the risk of high-grade prostate cancer ( 5.2 , 6.1 ).
• Prior to initiating therapy with finasteride tablets USP, appropriate evaluation should be performed to rule out other urological conditions, including prostate cancer, that might mimic BPH ( 5.3 , 12.3 ).
• Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant due to potential risk to a male fetus ( 5.4 , 8.1 , 16 ).
• Finasteride tablets USP are not indicated for use in pediatric patients or women ( 5.5 , 8.1 , 8.3 , 8.4 , 12.3 ).
5.1 Effects on Prostate Specific Antigen (PSA)and the Use of PSA in Prostate Cancer Detection In clinical studies, finasteride tablets USP 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 tablets USP, 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 tablets USP 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 tablets USP therapy may also affect PSA test results.
To interpret an isolated PSA value in patients treated with finasteride tablets USP 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 tablets USP.
Finasteride tablets USP 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 tablets USP.
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).
5αreductase 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 Evaluation for Other Urological Conditions Prior to initiating therapy with finasteride tablets USP, appropriate 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.
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.
5.4 Exposure of Women — Risk to Male Fetus Women should not handle crushed or broken finasteride tablets USP 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 USP 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) .] 5.5 Pediatric Patients and Women Finasteride tablets USP 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 (5.4) , Use in Specific Populations (8.1) , Clinical Pharmacology (12.3) , How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2) ].
5.6 Effect on Semen Characteristics Treatment with finasteride tablets USP 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling.] 17.1 Increased Risk of High-Grade Prostate Cancer Patients should be informed that there was an increase in high-grade prostate cancer in men treated with 5α-reductase inhibitors indicated for BPH treatment, including finasteride tablets USP, compared to those treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see Indications and Usage (1.3) , Warnings and Precautions (5.2) , and Adverse Reactions (6.1) ].
17.2 Exposure of Women — Risk to Male Fetus Physicians should inform patients that women who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets USP because of the possibility of absorption of finasteride and the subsequent potential risk to the male fetus.
Finasteride tablets USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed.
If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or broken finasteride tablets USP, the contact area should be washed immediately with soap and water [see Contraindications (4) , Warnings and Precautions (5.4) , Use in Specific Populations (8.1) and How Supplied/Storage and Handling (16) ].
17.3 Additional Instructions Physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with finasteride tablets USP.
This decrease does not appear to interfere with normal sexual function.
However, impotence and decreased libido may occur in patients treated with finasteride tablets USP [see Adverse Reactions (6.1) ].
Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge.
Breast changes including breast enlargement, tenderness and neoplasm have been reported [see Adverse Reactions (6.1) ].
Physicians should instruct their patients to read the patient package insert before starting therapy with finasteride tablets USP and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding finasteride tablets USP.
Revised: November 2011 address.jpg
DOSAGE AND ADMINISTRATION
2 DOSAGE & ADMINISTRATION Finasteride tablets USP may be administered with or without meals.
Finasteride tablets USP may be administered with or without meals ( 2 ).
Monotherapy: One tablet (5 mg) taken once a day ( 2.1 ).
2.1 Monotherapy The recommended dose of finasteride tablet USP are one tablet (5 mg) taken once a day [see Clinical Studies (14.1) ].