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Effective Treatments & Why They Work

Although Minoxidil and Finasteride are the two hair loss treatments that have been FDA-approved, they’re not the only treatments available.

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The Toronto Hair Transplant Centre is internationally known for our pioneering work in hair transplantation.

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DUTASTERIDE (AVODART®) FIGHTS HAIR LOSS

Although Minoxidil and Finasteride are the two hair loss treatments that have been FDA-approved, they’re not the only treatments available. Dutasteride (Avodart) is another treatment many men have found to help in their battle against hair loss

Description

AVODART (dutasteride) is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT).

Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula: Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.

AVODART Soft Gelatin Capsules for oral administration contain 0.5 mg of the active ingredient dutasteride in yellow capsules with red print. Each capsule contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are gelatin (from certified BSE-free bovine sources), glycerin, and ferric oxide (yellow). The soft gelatin capsules are printed with edible red ink.

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The Toronto Hair Transplant Centre is internationally known for our pioneering work in hair transplantation.

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Our Results

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The Toronto Hair Transplant Centre is internationally known for our pioneering work in hair transplantation.

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Clinical Pharmacology

Pharmacodynamics

Mechanism of Action: Dutasteride inhibits the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5α-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.

Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

Effect on 5α-Dihydrotestosterone and Testosterone

The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with benign prostatic hyperplasia (BPH) treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.

In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, p<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, p<0.001).

Adult males with genetically inherited type 2 5α-reductase deficiency also have decreased DHT levels. These 5α-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5α-reductase deficiency have been observed in these individuals.

Our Results

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The Toronto Hair Transplant Centre is internationally known for our pioneering work in hair transplantation.

Our huge archive is here to help you see what we can do for you. Use the link below to view some sample cases.

View All Case Studies

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Other Effects

Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry (DEXA) compared with either placebo or baseline.

In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer study.

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Pharmacokinetics

Absorption

Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in 5 healthy subjects is approximately 60% (range, 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance.

Distribution

Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).

In a study of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range, 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.

Special Populations: Pediatric

Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years.

Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24- and 87-years following administration of a single 5-mg dose of dutasteride. In this single-dose study, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal studies, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender: AVODART is not indicated for use in women (see WARNINGS and PRECAUTIONS). The pharmacokinetics of dutasteride in women have not been studied.

Race: The effect of race on dutasteride pharmacokinetics has not been studied.

Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients (see PRECAUTIONS: Use in Hepatic Impairment).

Drug Interactions

In vitro drug metabolism studies reveal that dutasteride is metabolized by the human cytochrome P450 isoenzymes CYP3A4 and CYP3A5. In a human mass balance analysis (n = 8), dutasteride was extensively metabolized. Less than 20% of the dose was excreted unchanged in the feces. No clinical drug interaction studies have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics.

However, based on the in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin, terazosin, warfarin, digoxin, and cholestyramine (see PRECAUTIONS: Drug Interactions).

Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.

Clinical Studies

Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind studies, each with 2-year open-label extensions (n = 2,340). More than 90% of the study population was Caucasian. Subjects were at least 50 years of age with a serum prostate-specific antigen (PSA) ≤1.5 ng/mL.

Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35. The baseline AUA-SI score across the 3 studies was approximately 17 units in both treatment groups.

Summary of Clinical Studies

Data from 3 large, well-controlled efficacy studies demonstrate that treatment with AVODART (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume, and increases maximum urinary flow rates. These data suggest that AVODART arrests the disease process of BPH in men with an enlarged prostate.

Indications and Usage

AVODART is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

  • Improve symptoms
  • Reduce the risk of acute urinary retention
  • Reduce the risk of the need for BPH-related surgery

CONTRADICTIONS

AVODART is contraindicated for use in women and children.

AVODART is contraindicated for patients with known hypersensitivity to dutasteride, other 5α-reductase inhibitors, or any component of the preparation.

WARNINGS

Exposure of Women—Risk to Male Fetus: Dutasteride is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle AVODART Soft Gelatin Capsules because of the possibility of absorption of dutasteride and the potential risk of a fetal anomaly to a male fetus (see CONTRAINDICATIONS). In addition, women should use caution whenever handling AVODART Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

PRECAUTIONS

General: Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with AVODART. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5α-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy.

Blood Donation: Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

Use in Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized and has a half-life of approximately 5 weeks at steady state, caution should be used in the administration of dutasteride to patients with liver disease.

Use with Potent CYP3A4 Inhibitors: Although dutasteride is extensively metabolized, no metabolically based drug interaction studies have been conducted. The effect of potent CYP3A4 inhibitors has not been studied. Because of the potential for drug-drug interactions, care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir).

Effects on Prostate-Specific Antigen and Prostate Cancer Detection: Digital rectal examinations, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with AVODART and periodically thereafter.

Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients.

Therefore, for interpretation of serial PSAs in a man taking AVODART, a new baseline PSA concentration should be established after 3 to 6 months of treatment, and this new value should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with AVODART for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men.

The free-to-total PSA ratio (percent free PSA) remains constant at Month 12, even under the influence of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary.

Information for Patients

Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with AVODART and to reread it upon prescription renewal for new information regarding the use of AVODART.

AVODART Soft Gelatin Capsules should not be handled by a woman who is pregnant or who may become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus (see CONTRAINDICATIONS and WARNINGS: Exposure of Women—Risk to Male Fetus).

Physicians should inform patients that ejaculate volume might be decreased in some patients during treatment with AVODART. This decrease does not appear to interfere with normal sexual function. In clinical trials, impotence and decreased libido, considered by the investigator to be drug-related, occurred in a small number of patients treated with AVODART or placebo (see ADVERSE REACTIONS: Table 1).

Men treated with dutasteride should not donate blood until at least 6 months have passed following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion (see PRECAUTIONS: Blood Donation).

Drug Interactions

Care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors (see PRECAUTIONS: Use with Potent CYP3A4 Inhibitors).

Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans. In vitro studies demonstrate that dutasteride does not displace warfarin, diazepam, or phenytoin from plasma protein binding sites, nor do these model compounds displace dutasteride.

Digoxin: In a study of 20 healthy volunteers, AVODART did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.

Warfarin: In a study of 23 healthy volunteers, 3 weeks of treatment with AVODART 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin.

Alpha-Adrenergic Blocking Agents: In a single sequence, crossover study in healthy volunteers, the administration of tamsulosin or terazosin in combination with AVODART had no effect on the steady-state pharmacokinetics of either alpha-adrenergic blocker. The percent change in DHT concentrations was similar for AVODART alone compared with the combination treatment.

A clinical trial was conducted in which dutasteride and tamsulosin were administered concomitantly for 24 weeks followed by 12 weeks of treatment with either the dutasteride and tamsulosin combination or dutasteride monotherapy. Results from the second phase of the trial revealed no excess of serious adverse events or discontinuations due to adverse events in the combination group compared to the dutasteride monotherapy group.

Calcium Channel Antagonists: In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when co-administered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was co-administered with dutasteride (+7%, n = 4).

The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended.

Cholestyramine: Administration of a single 5-mg dose of AVODART followed 1 hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.

Other Concomitant Therapy

Although specific interaction studies were not performed with other compounds, approximately 90% of the subjects in the 3 Phase III pivotal efficacy studies receiving AVODART were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of AVODART and concurrent therapy when AVODART was co-administered with anti-hyperlipidemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.

Drug/Laboratory Test Interactions: Effects on Prostate-Specific Antigen: PSA levels generally decrease in patients treated with AVODART as the prostate volume decreases. In approximately one-half of the subjects, a 20% decrease in PSA is seen within the first month of therapy. After 6 months of therapy, PSA levels stabilize to a new baseline that is approximately 50% of the pre-treatment value. Results of subjects treated with AVODART for up to 2 years indicate this 50% reduction in PSA is maintained. Therefore, a new baseline PSA concentration should be established after 3 to 6 months of treatment with AVODART (see PRECAUTIONS: Effects on PSA and Prostate Cancer Detection).

Reproductive Function: The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group.

Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.

Central Nervous System Toxicity: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally mediated toxicity without associated histopathological changes at exposure 425- and 315-fold the expected clinical exposure (of parent drug), respectively.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the expected clinical exposure to a 0.5 mg daily dose) in females only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.

In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day for males and 0.8, 6.3, and 15 mg/kg/day for females, there was an increase in Leydig cell adenomas in the testes at 53 mg/kg/day (135-fold the expected clinical exposure). An increased incidence of Leydig cell hyperplasia was present at 7.5 mg/kg/day (52-fold the expected clinical exposure) and 53 mg/kg/day in male rats.

A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5α;-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5α;-reductase inhibition. At tumorigenic doses in rats, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure.

Mutagenesis: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.

Impairment of Fertility: Treatment of sexually mature male rats with dutasteride at doses of 0.05, 10, 50, and 500 mg/kg/day (0.1- to 110-fold the expected clinical exposure of parent drug) for up to 31 weeks resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs.

The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5α;-reductase–related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles.

The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500 mg/kg/ day for 29 to 30 weeks.

Pregnancy: Pregnancy Category X (see CONTRAINDICATIONS). AVODART is contraindicated for use in women. AVODART has not been studied in women because preclinical data suggest that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs in a male fetus carried by a woman exposed to dutasteride.

In an intravenous embryo-fetal development study in the rhesus monkey (12/group), administration of dutasteride at 400, 780, 1,325, or 2,010 ng/day on gestation days 20 to 100 did not adversely affect development of male external genitalia. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed in monkeys treated with the highest dose.

Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times based on blood levels of parent drug (32 to 186 times based on a ng/kg daily dose) the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. Dutasteride is highly bound to proteins in human semen (>96%), potentially reducing the amount of dutasteride available for vaginal absorption.

In an embryo-fetal development study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in feminization of male fetuses (decreased anogenital distance) and male offspring (nipple development, hypospadias, and distended preputial glands) at all doses (0.07- to 111-fold the expected male clinical exposure). An increase in stillborn pups was observed at 30 mg/kg/day and reduced fetal body weight was observed at doses ≥2.5 mg/kg/day (15- to 111-fold the expected clinical exposure). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses of 12.5 and 30 mg/kg/day (56- to 111-fold the expected clinical exposure).

In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of F1 generation male offspring occurred at doses ≥2.5 mg/kg/day (14- to 90-fold the expected clinical exposure in men).

At a daily dose of 0.05 mg/kg/day (0.05-fold the expected clinical exposure), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and decrease prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day.

Feminization of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5α;-reductase inhibitors. These results are similar to observations in male infants with genetic 5α;-reductase deficiency.

In the rabbit, embryo-fetal study doses of 30, 100, and 200 mg/kg (28- to 93-fold the expected clinical exposure in men) were administered orally on days 7 to 29 of pregnancy to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses.

A second embryo-fetal study in rabbits at doses of 0.05, 0.4, 3.0, and 30 mg/kg/day (0.3- to 53-fold the expected clinical exposure) also produced evidence of feminization of the genitalia in male fetuses at all doses. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

Nursing Mothers: AVODART is not indicated for use in women. It is not known whether dutasteride is excreted in human breast milk.

Pediatric Use: AVODART is not indicated for use in the pediatric population. Safety and effectiveness in the pediatric population have not been established.

Geriatric Use: Of 2,167 male subjects treated with AVODART in 3 clinical studies, 60% were 65 and over and 15% were 75 and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Most adverse reactions were mild or moderate and generally resolved while on treatment in both the AVODART and placebo groups. The most common adverse events leading to withdrawal in both treatment groups were associated with the reproductive system.

Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of AVODART in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment studies, each with 2-year open-label extensions. During the double-blind treatment period, 2,167 male subjects were exposed to AVODART, including 1,772 exposed for 1 year and 1,510 exposed for 2 years.

When including the open-label extensions, 1,009 male subjects were exposed to AVODART for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age, 66 years) and greater than 90% Caucasian. Over the 2-year double-blind treatment period, 376 subjects (9% of each treatment group) were withdrawn from the studies due to adverse experiences, most commonly associated with the reproductive system, with similar findings during the 2-year open-label extensions.

Withdrawals due to adverse events considered by the investigator to have a reasonable possibility of being caused by the study medication occurred in 4% of the subjects receiving AVODART and in 3% of the subjects receiving placebo. Table 1 summarizes clinical adverse reactions that were reported by the investigator as drug-related in at least 1% of subjects receiving AVODART and at a higher incidence than subjects receiving placebo.

* A drug-related adverse event is one considered by the investigator to have a reasonable possibility of being caused by the study medication. In assessing causality, investigators were asked to select from 1 of 2 options: reasonably related to study medication or unrelated to study medication.

† Includes breast tenderness and breast enlargement.

Long-Term Treatment (Up to 4 Years): There is no evidence of increased drug-related sexual adverse events (impotence, decreased libido and ejaculation disorder) or gynecomastia with increased duration of treatment. The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.

Post marketing Experience: The following adverse reactions have been identified during post approval use of AVODART. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) potential causal connection to AVODART.

• allergic reactions, including rash, pruritus, urticaria, and localized edema.

OVERDOSAGE

In volunteer studies, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical study, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg.

There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.

DOSAGE AND ADMINISTRATION

The recommended dose of AVODART is 1 capsule (0.5 mg) taken orally once a day. The capsules should be swallowed whole. AVODART may be administered with or without food.

No dosage adjustment is necessary for subjects with renal impairment or for the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Geriatric and Renal Impairment). Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made (see PRECAUTIONS: General).

HOW SUPPLIED

AVODART Soft Gelatin Capsules 0.5 mg are oblong, opaque, dull yellow, gelatin capsules imprinted with “GX CE2” in red ink on one side packaged in bottles of 30 (NDC 0173-0712-15) and 90 (NDC 0173-0712-04) with child-resistant closures.

Storage and Handling: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Dutasteride is absorbed through the skin. AVODART Soft Gelatin capsules should not be handled by women who are pregnant or who may become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus (see CLINICAL PHARMACOLOGY: Pharmacokinetics, WARNINGS: Exposure of Women—Risk to Male Fetus, and PRECAUTIONS: Information for Patients and Pregnancy).

Manufactured by Cardinal Health
Beinheim, France for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2005, GlaxoSmithKline. All rights reserved.
May 2005 RL-2188

FINASTERIDE (PROPECIA) PREVENTS HAIR LOSS

Finasteride is a hair loss treatment that has been FDA-approved to treat hair loss. Finasteride (Propecia) is a synthetic 4 azasteroid compound, is a specific inhibitor of steroid Type II 5α reductase, an intracellular enzyme.

Finasteride (Propecia) is 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:

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.

PROPECIA tablets for oral administration are film-coated tablets that contain 1 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl cellulose LF, titanium dioxide, magnesium stearate, talc, docusate sodium, yellow ferric oxide, and red ferric oxide.

Clinical Pharmacology

Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into DHT. Two distinct isozymes are found in mice, rats, monkeys, and humans: Type I and II. Each of these isozymes is differentially expressed in tissues and developmental stages. In humans, Type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5α-reductase is responsible for approximately one-third of circulating DHT. The Type II 5α-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT.

In humans, the mechanism of action of finasteride is based on its preferential inhibition of the Type II isozyme. Using native tissues (scalp and prostate), in vitro binding studies examining the potential of finasteride to inhibit either isozyme revealed a 100-fold selectivity for the human Type II 5α-reductase over Type I isozyme (IC50=500 and 4.2 nM for Type I and II, respectively).

For both isozymes, the inhibition by finasteride is accompanied by reduction of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex).

Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a 1-mg tablet. Mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range.

In men with male pattern hair loss (androgenetic alopecia), the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Administration of finasteride decreases scalp and serum DHT concentrations in these men. The relative contributions of these reductions to the treatment effect of finasteride have not been defined. By this mechanism, finasteride appears to interrupt a key factor in the development of androgenetic alopecia in those patients genetically predisposed.

A 48-week, placebo-controlled study designed to assess by phototrichogram the effect of PROPECIA on total and actively growing (anagen) scalp hairs in vertex baldness enrolled 212 men with androgenetic alopecia. At baseline and 48 weeks, total and anagen hair counts were obtained in a 1-cm2 target area of the scalp. Men treated with PROPECIA showed increases from baseline in total and anagen hair counts of 7 hairs and 18 hairs, respectively, whereas men treated with placebo had decreases of 10 hairs and 9 hairs, respectively.

These changes in hair counts resulted in a between-group difference of 17 hairs in total hair count (p<0.001) and 27 hairs in anagen hair count (p<0.001), and an improvement in the proportion of anagen hairs from 62% at baseline to 68% for men treated with PROPECIA.

Pharmacokinetics Absorption

In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26-170%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. At steady state following dosing with 1 mg/day (n=12), maximum finasteride plasma concentration averaged 9.2 ng/mL (range, 4.9-13.7 ng/mL) and was reached 1 to 2 hours post dose; AUC(0-24 hr.) was 53 ng•hr/mL (range, 20-154 ng•hr/mL). Bioavailability of finasteride was not affected by food.

Distribution

Mean steady-state volume of distribution was 76 liters (range, 44-96 liters; n=15). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing.

Finasteride has been found to cross the blood-brain barrier.

Semen levels have been measured in 35 men taking finasteride 1 mg/day for 6 weeks. In 60% (21 of 35) of the samples, finasteride levels were undetectable.

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

Following intravenous infusion in healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279 mL/min). Mean terminal half-life in plasma was 4.5 hours (range, 3.3-13.4 hours; n=12). 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.

Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age.

Special Populations

Pediatric: Finasteride pharmacokinetics have not been investigated in patients.

Gender: PROPECIA is not indicated for use in women.

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 also Pharmacokinetics, Excretion, and PRECAUTIONS, Geriatric Use sections.

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

Renal Insufficiency: No dosage adjustment is necessary in patients with renal insufficiency. 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 those 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 men 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.

Hepatic Insufficiency

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

Drug Interactions (also see PRECAUTIONS, Drug Interactions)

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 include antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found.

Clinical Studies in Men

The efficacy of PROPECIA was demonstrated in men (88% Caucasian) with mild to moderate androgenetic alopecia (male pattern hair loss) between 18 and 41 years of age. In order to prevent seborrheic dermatitis which might confound the assessment of hair growth in these studies, all men, whether treated with finasteride or placebo, were instructed to use a specified, medicated, tar-based shampoo (Neutrogena T/Gel®** Shampoo) during the first 2 years of the studies.

There were three double-blind, randomized, placebo-controlled studies of 12-month duration. The two primary endpoints were hair count and patient self-assessment; the two secondary endpoints were investigator assessment and ratings of photographs. In addition, information was collected regarding sexual function (based on a self-administered questionnaire) and non-scalp body hair growth. The three studies were conducted in 1879 men with mild to moderate, but not complete, hair loss. Two of the studies enrolled men with predominantly mild to moderate vertex hair loss (n=1553). The third enrolled men having mild to moderate hair loss in the anterior mid-scalp area with or without vertex balding (n=326). Studies in Men with Vertex Baldness

Of the men who completed the first 12 months of the two vertex baldness trials, 1215 elected to continue in double-blind, placebo-controlled, 12-month extension studies. There were 547 men receiving PROPECIA for both the initial study and first extension periods (up to 2 years of treatment) and 60 men receiving placebo for the same periods. The extension studies were continued for 3 additional years, with 323 men on PROPECIA and 23 on placebo entering the fifth year of the study.

In order to evaluate the effect of discontinuation of therapy, there were 65 men who received PROPECIA for the initial 12 months followed by placebo in the first 12-month extension period. Some of these men continued in additional extension studies and were switched back to treatment with PROPECIA, with 32 men entering the fifth year of the study. Lastly, there were 543 men who received placebo for the initial 12 months followed by PROPECIA in the first 12-month extension period. Some of these men continued in additional extension studies receiving PROPECIA, with 290 men entering the fifth year of the study (see Figure below).

Patients who switched from placebo to PROPECIA (n=425) had a decrease in hair count at the end of the initial 12-month placebo period, followed by an increase in hair count after 1 year of treatment with PROPECIA. This increase in hair count was less (56 hairs above original baseline) than the increase (91 hairs above original baseline) observed after 1 year of treatment in men initially randomized to PROPECIA. Although the increase in hair count, relative to when therapy was initiated, was comparable between these two groups, a higher absolute hair count was achieved in patients who were started on treatment with PROPECIA in the initial study. This advantage was maintained through the remaining 3 years of the studies. A change of treatment from PROPECIA to placebo (n=48) at the end of the initial 12 months resulted in reversal of the increase in hair count 12 months later, at 24 months (see Figure below).

At 12 months, 58% of men in the placebo group had further hair loss (defined as any decrease in hair count from baseline), compared with 14% of men treated with PROPECIA. In men treated for up to 2 years, 72% of men in the placebo group demonstrated hair loss, compared with 17% of men treated with PROPECIA. At 5 years, 100% of men in the placebo group demonstrated hair loss, compared with 35% of men treated with PROPECIA.

Patient self-assessment was obtained at each clinic visit from a self-administered questionnaire, which included questions on their perception of hair growth, hair loss, and appearance. This self-assessment demonstrated an increase in amount of hair, a decrease in hair loss, and improvement in appearance in men treated with PROPECIA. Overall improvement compared with placebo was seen as early as 3 months (p<0.05), with improvement maintained over 5 years.

Investigator assessment was based on a 7-point scale evaluating increases or decreases in scalp hair at each patient visit. This assessment showed significantly greater increases in hair growth in men treated with PROPECIA compared with placebo as early as 3 months (p<0.001). At 12 months, the investigators rated 65% of men treated with PROPECIA as having increased hair growth compared with 37% in the placebo group.

At 2 years, the investigators rated 80% of men treated with PROPECIA as having increased hair growth compared with 47% of men treated with placebo. At 5 years, the investigators rated 77% of men treated with PROPECIA as having increased hair growth, compared with 15% of men treated with placebo.

An independent panel rated standardized photographs of the head in a blinded fashion based on increases or decreases in scalp hair using the same 7-point scale as the investigator assessment. At 12 months, 48% of men treated with PROPECIA had an increase as compared with 7% of men treated with placebo. At 2 years, an increase in hair growth was demonstrated in 66% of men treated with PROPECIA, compared with 7% of men treated with placebo. At 5 years, 48% of men treated with PROPECIA demonstrated an increase in hair growth, 42% were rated as having no change (no further visible progression of hair loss from baseline) and 10% were rated as having lost hair when compared to baseline.

In comparison, 6% of men treated with placebo demonstrated an increase in hair growth, 19% were rated as having no change and 75% were rated as having lost hair when compared to baseline.

Other Results in Vertex Baldness Studies

A sexual function questionnaire was self-administered by patients participating in the two vertex baldness trials to detect more subtle changes in sexual function. At Month 12, statistically significant differences in favor of placebo were found in 3 of 4 domains (sexual interest, erections, and perception of sexual problems). However, no significant difference was seen in the question on overall satisfaction with sex life.

In one of the two vertex baldness studies, patients were questioned on non-scalp body hair growth. PROPECIA did not appear to affect non-scalp body hair.

Study in Men with Hair Loss in the Anterior Mid-Scalp Area

A study of 12-month duration, designed to assess the efficacy of PROPECIA in men with hair loss in the anterior mid-scalp area, also demonstrated significant increases in hair count compared with placebo. Increases in hair count were accompanied by improvements in patient self-assessment, investigator assessment, and ratings based on standardized photographs. Hair counts were obtained in the anterior mid-scalp area and did not include the area of bitemporal recession or the anterior hairline.

Summary of Clinical Studies in Men

Clinical studies were conducted in men aged 18 to 41 with mild to moderate degrees of androgenetic alopecia. All men treated with PROPECIA or placebo received a tar-based shampoo (Neutrogena T/Gel®** Shampoo) during the first 2 years of the studies. Clinical improvement was seen as early as 3 months in the patients treated with PROPECIA and led to a net increase in scalp hair count and hair regrowth. In clinical studies for up to 5 years, treatment with PROPECIA slowed the further progression of hair loss observed in the placebo group. In general, the difference between treatment groups continued to increase throughout the 5 years of the studies.

Ethnic Analysis of Clinical Data from Men

In a combined analysis of the two studies on vertex baldness, mean hair count changes from baseline were 91 vs -19 hairs (PROPECIA vs placebo) among Caucasians (n=1185), 49 vs -27 hairs among Blacks (n=84), 53 vs -38 hairs among Asians (n=17), 67 vs 5 hairs among Hispanics (n=45) and 67 vs -15 hairs among other ethnic groups (n=20). Patient self-assessment showed improvement across racial groups with PROPECIA treatment, except for satisfaction of the frontal hairline and vertex in Black men, who were satisfied overall.

Study in Women

In a study involving 137 postmenopausal women with androgenetic alopecia who were treated with PROPECIA (n=67) or placebo (n=70) for 12 months, effectiveness could not be demonstrated. There was no improvement in hair counts, patient self-assessment, investigator assessment, or ratings of standardized photographs in the women treated with PROPECIA when compared with the placebo group (see INDICATIONS AND USAGE).

Indications and Usage

PROPECIA is indicated for the treatment of male pattern hair loss (androgenetic alopecia) in MEN ONLY. Safety and efficacy were demonstrated in men between 18 to 41 years of age with mild to moderate hair loss of the vertex and anterior mid-scalp area (see CLINICAL PHARMACOLOGY, Clinical Studies).

Efficacy in bitemporal recession has not been established.

PROPECIA is not indicated in women (see CLINICAL PHARMACOLOGY, Clinical Studies and CONTRAINDICATIONS).

PROPECIA is not indicated in children (see PRECAUTIONS, Pediatric Use).

Contradictions

PROPECIA is contraindicated in the following:

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 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, EXPOSURE OF WOMEN – RISK TO MALE FETUS; and PRECAUTIONS, Information for Patients and Pregnancy.) In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.

Hypersensitivity to any component of this medication.

WARNINGS

PROPECIA is not indicated for use in pediatric patients (see INDICATIONS AND USAGE; and PRECAUTIONS, Pediatric Use) or women (see also WARNINGS, EXPOSURE OF WOMEN – RISK TO MALE FETUS; PRECAUTIONS, Information for Patients and Pregnancy; and HOW SUPPLIED, Storage and Handling).

EXPOSURE OF WOMEN – RISK TO MALE FETUS

Women should not handle crushed or broken PROPECIA 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. PROPECIA 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 also CONTRAINDICATIONS; PRECAUTIONS, Information for Patients and Pregnancy; and HOW SUPPLIED, Storage and Handling.)

PRECAUTIONS

General caution should be used in the administration of PROPECIA in patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Information for Patients

Women should not handle crushed or broken PROPECIA 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. PROPECIA 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 also CONTRAINDICATIONS; WARNINGS, EXPOSURE OF WOMEN – RISK TO MALE FETUS; PRECAUTIONS, Pregnancy; and HOW SUPPLIED, Storage and Handling.)

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).

See also Patient Package Insert.

Physicians should instruct their patients to read the patient package insert before starting therapy with PROPECIA and to read it again each time the prescription is renewed so that they are aware of current information for patients regarding PROPECIA.

Drug/Laboratory Test Interactions

Finasteride had no effect on circulating levels of cortisol, thyroid-stimulating hormone, or thyroxine, nor did it affect the plasma lipid profile (e.g., total cholesterol, low-density lipoproteins, high-density lipoproteins and triglycerides) or bone mineral density. In studies with finasteride, no clinically meaningful changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH) or prolactin were detected. In healthy volunteers, treatment with finasteride did not alter the response of LH and FSH to gonadotropin releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.

In clinical studies with PROPECIA (finasteride, 1 mg) in men 18-41 years of age, the mean value of serum prostate-specific antigen (PSA) decreased from 0.7 ng/mL at baseline to 0.5 ng/mL at Month 12. Further, in clinical studies with PROSCAR (finasteride, 5 mg) when used in older men who have benign prostatic hyperplasia (BPH), PSA levels are decreased by approximately 50%. These findings should be taken into account for proper interpretation of serum PSA when evaluating men treated with finasteride.

Drug Interactions

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 include antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found.

Other concomitant therapy: Although specific interaction studies were not performed, finasteride doses of 1 mg or more were concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α- blockers, analgesics, angiotensin-converting enzyme (ACE) inhibitors, anticonvulsants, benzodiazepines, beta blockers, calcium-channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMG-CoA reductase inhibitors, prostaglandin synthetase inhibitors (also referred to as NSAIDs), and quinolone anti-infectives without evidence of clinically significant adverse interactions.

No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (1824 times the human exposure) as determined in the carcinogenicity studies.

In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (4344 times the human exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 80 mg/kg/day of finasteride (488 times the human exposure), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity, and an associated significant decrease in the weights of the seminal vesicles and prostate.

All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats but is not relevant in man.

Pregnancy

Teratogenic Effects: Pregnancy Category X

See CONTRAINDICATIONS.

PROPECIA is not indicated for use in women.

No developmental abnormalities have been observed in first filial generation (F1) male or female offspring resulting from mating finasteride-treated male rats (80 mg/kg/day; 488 times the human exposure) with untreated females. Administration of finasteride at 3 mg/kg/day (20 times the human exposure, estimated) during the late gestation and lactation period resulted in slightly decreased fertility in F1 male offspring. No effects were seen in female offspring.

No evidence of malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6-18 of gestation at doses up to 100 mg/kg/day (1908 times the recommended human dose of 1 mg/day, based on body surface area comparison). However, effects on male genitalia would not be expected since the rabbits were not exposed during the critical period of genital system development.

The in-utero effects of finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20-100), a species more predictive of human development than rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses up to 800 ng/day (at least 250 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 1 mg/day, based on body surface area comparison) resulted in no abnormalities in male fetuses.

In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a 2 mg/kg/day dose of finasteride 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.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

Clinical efficacy studies with PROPECIA did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the elderly for PROPECIA (see CLINICAL PHARMACOLOGY, Pharmacokinetics). However, the efficacy of PROPECIA in the elderly has not been established.

Adverse Reactions

Clinical Studies for PROPECIA (finasteride 1 mg) in the Treatment of Male Pattern Hair Loss

In three controlled clinical trials for PROPECIA of 12-month duration, 1.4% of patients taking PROPECIA (n=945) were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related (1.6% for placebo; n=934).

In a study of finasteride 1 mg daily in healthy men, a median decrease in ejaculate volume of 0.3 mL (-11%) compared with 0.2 mL (–8%) for placebo was observed after 48 weeks of treatment. Two other studies showed that finasteride at 5 times the dosage of PROPECIA (5 mg daily) produced significant median decreases of approximately 0.5 mL (-25%) compared to placebo in ejaculate volume, but this was reversible after discontinuation of treatment.

In the clinical studies with PROPECIA, the incidences for breast tenderness and enlargement, hypersensitivity reactions, and testicular pain in finasteride-treated patients were not different from those in patients treated with placebo.

Post marketing Experience for PROPECIA (finasteride 1 mg)

Breast tenderness and enlargement; hypersensitivity reactions including rash, pruritus, urticaria, and swelling of the lips and face; and testicular pain. See Controlled Clinical Trials and Long-Term Open Extension Studies for PROSCAR* (finasteride 5 mg) in the Treatment of Benign Prostatic Hyperplasia. Controlled Clinical Trials and Long-Term Open Extension Studies for PROSCAR* (finasteride 5 mg) in the Treatment of Benign Prostatic Hyperplasia

In the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a 4-year controlled clinical study, 3040 patients between the ages of 45 and 78 with symptomatic BPH and an enlarged prostate were evaluated for safety over a period of 4 years (1524 on PROSCAR 5 mg/day and 1516 on placebo). 3.7% (57 patients) treated with PROSCAR 5 mg 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.

The adverse experience profiles in the 1-year, placebo-controlled, Phase III BPH studies and the 5- year open extensions with PROSCAR 5 mg and PLESS were similar.

There is no evidence of increased adverse experiences with increased duration of treatment with PROSCAR 5 mg. New reports of drug-related sexual adverse experiences decreased with duration of therapy.

The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. During a 4- to 6-year placebo- and comparator-controlled study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with PROSCAR but no cases in men not treated with PROSCAR. In another 4-year, placebo-controlled study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-treated men, but no cases were reported in men treated with PROSCAR.

In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, 9060 had prostate needle biopsy data available for analysis. 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. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The clinical significance of these findings is unknown. This information from the literature (Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:213-22) is provided for consideration by physicians when PROSCAR is used as indicated. PROSCAR is not approved to reduce the risk of developing prostate cancer.

Overdosage

In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions. 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.

Dosage and Administration

The recommended dosage is 1 mg orally once a day.

PROPECIA may be administered with or without meals.

In general, daily use for three months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit, which should be re-evaluated periodically. Withdrawal of treatment leads to reversal of effect within 12 months.

How Supplied

No. 6642 — PROPECIA tablets, 1 mg, are tan, octagonal, film-coated convex tablets with “stylized P” logo on one side and PROPECIA on the other. They are supplied as follows:

NDC 0006-0071-31 unit of use bottles of 30 (with desiccant)
NDC 0006-0071-61 PROPAK®*** – carton of 3 unit of use bottles of 30 (with desiccant)
NDC 0006-0071-54 PROPAK – carton of 1 unit of use bottle of 90 (with desiccant).

Storage and Handling

Store at room temperature, 15-30°C (59-86°F). Keep container closed and protect from moisture. Women should not handle crushed or broken PROPECIA 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. PROPECIA tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed. (See WARNINGS, EXPOSURE OF WOMEN – RISK TO MALE FETUS; and PRECAUTIONS, Information for Patients and Pregnancy.)

Issued October 2004
*** Registered trademark of MERCK & CO., Inc.

PRESCRIBING MINOXIDIL (ROGAINE) FOR HAIR LOSS

Action and Clinical Pharmacology of Minoxidil (Rogaine)

When applied topically, minoxidil topical solution has been shown to stimulate hair growth in individuals with alopecia androgenetic (male pattern baldness). Although the exact mechanism of action of minoxidil in the treatment of alopecia androgenetic is not known, there may be more than one mechanism by which minoxidil stimulates hair growth; they include: vasodilation of the microcirculation around the hair follicles which may stimulate hair growth; direct stimulation of the hair follicle cells to enter into a proliferative phase: resting phase (telogen) follicles being stimulated to pass into active phase (anagen) follicles; alteration of the effect of androgens on genetically predetermined hair follicles: minoxidil may affect the androgen metabolism in the scalp by inhibiting the capacity of androgens to affect the hair follicles.

Following topical application of minoxidil topical solution, minoxidil is poorly absorbed from normal intact skin, with an average of 1.4% (range 0.3 to 4.5%) of the total applied dose reaching the systemic circulation. The effects of concomitant dermal diseases or occlusion on absorption are unknown. Serum minoxidil levels resulting from topical administration are governed by the drug’s percutaneous absorption rate; increases in surface area of application do not result in proportionate increases in the serum minoxidil level. Steady state is achieved by the end of the third dosing interval (36 hours) when the drug is administered twice daily.

Approximately 95% of the systemically absorbed minoxidil from topical dosing is eliminated within 4 days. The metabolic biotransformation of minoxidil absorbed following topical application has not been fully determined.

Absorption from the gastrointestinal tract following oral administration of minoxidil tablets is essentially complete (at least 95%). Approximately 90% of orally administered minoxidil is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring and by conversion to more polar products.

Known metabolites exert much less pharmacologic effect than minoxidil itself and all are excreted principally in the urine. Minoxidil does not bind to plasma proteins; its renal clearance corresponds to glomerular filtration rate and it does not cross the blood brain barrier. Minoxidil and its metabolites are hemodialyzable, although this does not rapidly reverse its pharmacological effect.

Increased hair growth has not been associated with increased systemic absorption of topical minoxidil. The onset of hair growth stimulation requires twice daily applications of minoxidil topical solution for 4 or more months and is variable among patients. Upon discontinuation of topically applied minoxidil, new hair growth has been anecdotally reported to stop and restoration of pretreatment appearance to occur within 3 to 4 months.

Indications and Clinical Uses of Minoxidil (Rogaine)

The treatment of alopecia androgenetic (male pattern baldness).

Contra-Indications

Hypersensitivity to minoxidil, propylene glycol or ethanol.

Pregnancy and Lactation

Minoxidil topical solution should not be used by pregnant or nursing women.

Manufacturers’ Warnings in Clinical States

Although the following systemic effects have not been associated with the topical use of minoxidil topical solution, there is some absorption of minoxidil from the skin and the potential exists for systemic effects such as tachycardia, angina, edema or potentiation of the orthostatic hypotension produced by guanethidine. Patients should be observed periodically for any suggestion of systemic effects of minoxidil. In the event of systemic side effects discontinue administration of the drug.

If necessary, fluid retention and edema can be managed with diuretic treatment. Tachycardia and angina can be controlled by administration of beta-adrenergic blocking drugs or other sympathetic nervous system suppressants. Patients should discontinue use of minoxidil topical solution and contact their physician in the event of systemic effects and/or severe dermatologic reactions.

Pregnancy and Lactation

The safety for use of minoxidil topical solution in pregnancy has not been established. Orally administered minoxidil has been shown to reduce the conception rate in rats and to show evidence of increased fetal resorption in rabbits when administered at 5 times the human oral dose. There was no evidence of teratogenic effects in rats and rabbits.

Systemically absorbed minoxidil is secreted in human milk.

Children

Safety and effectiveness of minoxidil topical solution in patients under 18 years of age has not been established.

Patients with Underlying Cardiovascular Disease

Patients should not use minoxidil topical solution if they have a history of underlying coronary artery disease, cardiac dysrhythmias, congestive heart failure, or valvular heart disease. Patients with hypertension, including those under treatment with anti-hypertensive agents, should be monitored closely and their medication adjusted if necessary. Minoxidil topical solution should be used with caution in patients with any other cardiovascular disease present.

Precautions

Before prescribing minoxidil topical solution, ensure that the patient reads and understands the contents of the patient-package insert including the application instructions.

Minoxidil topical solution will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin, mucous membranes), the area should be bathed with copious amounts of cool tap water.

Inhalation of the spray mist should be avoided.

Accidental ingestion of minoxidil topical solution could lead to serious adverse effects.
The effects of minoxidil topical solution in patients with concomitant dermal diseases, or in those using topical corticosteroids or other dermatologic preparations are unknown. It has not been clearly determined whether occlusion will increase the absorption of minoxidil after administration of the topical solution. As is the case with other topically applied drugs, decreased integrity of the epidermal barrier caused by inflammation or disease processes in the skin, may increase percutaneous absorption of minoxidil.

Geriatrics

Studies involving subjects over the age of 65 years have not been performed hence the safety and effectiveness of minoxidil topical solution in these patients has not been established.

Drug Interactions

There are currently no known drug interactions associated with the use of minoxidil topical solution. Although it has not been clinically demonstrated, there exists the possibility of potentiating orthostatic hypotension in patients concurrently taking guanethidine.

Adverse Reactions

The most frequently encountered adverse effects in clinical trials with minoxidil topical solution were minor dermatologic reactions. In light of the findings that systemic levels of minoxidil from topical application are low in relation to systemic levels from oral dosing, this distribution of encountered adverse effects is to be expected. Local irritation was the most common adverse reaction reported, including scaling, erythema/flushing, dermatitis, dry skin, hypertrichosis (in areas other than where minoxidil topical solution was applied), burning sensation and rash.

Infrequent adverse reactions including allergic reactions (sensitivity, hives, generalized erythema and facial swelling); dizziness; tingling sensation; headache; weakness; neuritis; edema; eye irritation; altered taste; ear infection (otitis externa); and visual disturbances have been reported. Rarely reported adverse reactions included alopecia, hair abnormalities, chest pain, blood pressure changes, pulse changes, hepatitis, and kidney stones.

The occurrence rates for adverse reactions derived from the total adverse reactions of all patients (placebo [one-third of these patients received placebo treatment for 4 months] 2% minoxidil and 3% minoxidil treated) enrolled in 2 pivotal efficacy/safety studies (2 326 patients), are as follows: Dermatological: itching (3%); scaling, erythema, dermatitis, dry skin (1 to 2%); hypertrichosis, burning sensation, rash, folliculitis, desquamation, alopecia (hair loss), skin abscess, acne, eczema, eruptions, excoriation, flaking scalp, hair abnormalities, nail disorders, seborrhea, other skin irritations (0.1 to 1.0%).

Cardiovascular: flushing (1 to 2%); chest pain, changes in blood pressure, changes in pulse rate, fainting (0.1 to 1.0%).
CNS: headache, dizziness (1 to 2%).
Allergic: fever (1 to 2%); allergic reaction, non-specific allergic reaction, hives, allergic rhinitis, facial swelling and sensitivity, chills (0.1 to 1.0%).
Renal: edema (1 to 2%); kidney stones (0.1 to 1.0%).
Respiratory: shortness of breath (0.1 to 1.0%).
Neurological: neuritis (1 to 2%); weakness (0.1 to 1.0%).
Hepatic: hepatitis (0.1 to 1.0%).
Special senses: eye irritations, bitter taste, ear infection (otitis externa), taste alteration, visual disturbance (0.1 to 1.0%).

Symptoms and Treatment of Overdose

Symptoms and Treatment: Accidental ingestion of minoxidil topical solution may produce systemic effects related to the vasodilatory action of minoxidil (5 mL of the 2% topical solution contains 100 mg minoxidil, the maximum recommended adult oral dose for the treatment of hypertension). There have been only a few instances of deliberate or accidental overdosage with oral minoxidil (Loniten tablets).

In a reported case of accidental ingestion, a 3-year-old male swallowed 1 to 2 mL of a 3% concentration of topical minoxidil solution. After vomiting he was treated in an emergency room. The child was found to be alert and active with no obvious signs of distress. His temperature was 37°C, pulse 152, respiration 32, and systolic blood pressure 110 by palpation. Cardiovascular, chest, lungs, abdomen, head, skin and neurological examinations were normal. Blood levels taken indicated a total minoxidil level (glucuronide and unchanged) of 320.6 ng/mL. The child was discharged without sequelae.

Signs and symptoms of drug overdosage would most likely include cardiovascular effects associated with fluid retention, lowered blood pressure and tachycardia. Fluid retention can be managed with appropriate diuretic therapy. Tachycardia can be controlled by administration of a beta-adrenergic blocking agent.

If exaggerated hypotension is encountered, it is most likely to occur in association with residual sympathetic nervous system blockade from previous therapy (guanethidine-like effects or alpha-adrenergic blockade). The recommended treatment is i.v. administration of normal saline.

Sympathomimetic drugs, such as norepinephrine or epinephrine, should be avoided because of their excessive cardiac-stimulating action. Phenylephrine, angiotensin II, vasopressin and dopamine, which reverse the effects of orally administered minoxidil, should only be used if inadequate perfusion of a vital organ is evident.

Oral LD50 in rats has ranged from 1 321 to 3 492 mg/kg; in mice 2 457 to 2 648 mg/kg. Minoxidil and its metabolites are hemodialyzable, although this does not rapidly reverse its pharmacological effect.

Dosage and Administration

For external use only. Use only as directed.

A total dose of 1 mL minoxidil topical solution should be applied twice per day to the scalp, beginning at the center of the affected area. This dose should be used regardless of the size of the affected area. The total daily dose should not exceed 2 mL. The method of application varies according to the disposable applicator used, as indicated below. After applying minoxidil topical solution, wash hands thoroughly. Do not apply the topical solution to any other area of the body.

Apply minoxidil topical solution when the hair and scalp are thoroughly dry. Do not use a hairdryer to speed the drying of the topical solution, because blowing air on the scalp may decrease the effectiveness of the drug.

Pump-Spray Applicator: (Works best for applying minoxidil topical solution to large areas): (1) Remove large outer cap and keep it. (2) Remove small inner cap and discard it. (3) Insert the pump spray applicator into bottle and screw on firmly. (4) After aiming the pump toward the center of the bald area of the scalp, press the pump once and spread minoxidil topical solution with fingertips to cover all of the bald area. Repeat for a total of 6 times, to apply a dose of 1 mL. Avoid breathing spray mist. (5) Replace large outer cap over the pump spray applicator when not in use.

Rub-On Applicator: Works best for applying minoxidil topical solution to small areas of the scalp. (1) Remove large outer cap and keep it. (2) Remove small inner cap and discard it. (3) Insert the rub-on applicator into bottle and screw on firmly. (4) Hold the bottle upright and squeeze it once to fill the upper chamber to the black line. The chamber now contains 1 full dose (1 mL). (5) Hold the bottle upside down, then rub applicator on the scalp to apply minoxidil topical solution over the entire bald area – until the chamber is completely empty. (6) Replace large outer cap over the rub-on applicator when not in use.

Extended Spray-Tip Applicator: Works best for applying minoxidil topical solution to small areas of the scalp, or under hair. (1) Remove large outer cap and discard it. (2) Remove small inner cap and discard it. (3) Insert the pump spray applicator into the bottle and screw on firmly. (4) Remove small spray head from top of pump spray applicator. (5) Fit the extended spray tip applicator onto the spray shaft and push down firmly. (6) Remove the small cap on the end of the extended tip and keep it. (7) After aiming the applicator toward the center of the bald area of the scalp, press the pump once and spread the minoxidil topical solution with fingertips to cover all of the bald area. Repeat for a total of 6 times, to apply a dose of 1 mL. Avoid breathing spray mist. (8) If desired, replace the small cap onto the end of extended tip when not in use.

Clinical experience with minoxidil topical solution indicates that twice daily application for 4 or more months may be required before evidence of hair growth stimulation can be expected. Onset and degree may be variable among patients. Relapse to pretreatment appearance following discontinuation of medication has been anecdotally reported to occur within 3 to 4 months.

Availability and Storage

Each mL of clear, colorless to slightly yellow solution contains: minoxidil 20 mg (2%) in alcohol (63%), propylene glycol and water. Bottles containing 60 mL of solution with the following metered disposable applicators: pump spray, extended tip and rub-on assemblies.

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