Propecia (Finasteride) - Hair Loss Treatment

DESCRIPTION

PROPECIA* (finasteride), 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 C₂₃H₃₆N_2O2 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, docusate sodium, magnesium stearate, hydroxypropyl methylcellulose 2910, hydroxypropyl cellulose, titanium dioxide, talc, 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 5a-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

PROPECIA^® (Finasteride) Tablets, 1 mg

concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a 1-mg tablet.
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.
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) or follicle-stimulating hormone (FSH) 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. Mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline in the first year of treatment, but these levels were within the physiologic range.
Pharmacokinetics
Following an oral dose of ¹⁴C-finasteride in man, 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. The major compound isolated from urine was the monocarboxylic acid metabolite; virtually no unchanged drug was recovered. The t-butyl side chain monohydroxylated metabolite has been isolated from plasma. These metabolites possessed no more than 20% of the 5a-reductase inhibitory activity of finasteride. In a study in 15 healthy male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26-170%), based on the ratio of AUC relative to a 5-mg intravenous dose infused over 60 minutes. Following intravenous infusion, mean plasma clearance was 165 mL/min (range, 70-279 mL/min) and mean steady-state volume of distribution was 76 liters (range, 44-96 liters). In a separate study, the bioavailability of finasteride was not affected by food.
Approximately 90% of circulating finasteride is bound to plasma proteins. Finasteride has been found to cross the blood-brain barrier.
There is a slow accumulation phase for finasteride after multiple dosing. At steady state following dosing with 1 mg/day, maximum finasteride plasma concentration averaged 9.2 ng/mL (range, 4.9- 13.7 ng/mL) and was reached 1 to 2 hours postdose; AUC_{(0-24 hr)} was 53 ng•hr/mL (range, 20- 154 ng•hr/mL) and mean terminal half-life of elimination was 4.8 hours (range, 3.3-13.4 hours). Semen levels have been measured in 35 men taking finasteride 1 mg daily for 6 weeks. In 60% (21 of 35) of the samples, finasteride levels were undetectable. The mean finasteride level was 0.26 ng/mL and the highest level measured was 1.52 ng/mL. Using this highest semen level measured and assuming 100% absorption from a 5-mL ejaculate per day, human exposure through vaginal absorption would be up to 7.6 ng per day, which is 750 times lower than the exposure from the no-effect dose for developmental abnormalities in Rhesus monkeys (see PRECAUTIONS, Pregnancy).
The elimination rate of finasteride decreases somewhat with age. 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. These findings are of no clinical significance, and a reduction in dosage in the elderly is not warranted. No dosage adjustment is necessary in patients with renal insufficiency. In patients with chronic renal impairment (creatinine clearance ranging from 9.0 to 55 mL/min), the values for 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). Furthermore, 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.

PROPECIA** is for use by MEN ONLY.

Please read this leaflet before you start taking PROPECIA. Also, read the information included with PROPECIA each time you renew your prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss PROPECIA when you start taking your medication and at regular checkups.

What is PROPECIA used for?

PROPECIA is used for the treatment of male pattern hair loss on the vertex and the anterior mid-scalp area.

PROPECIA is for use by MEN ONLY and should NOT be used by women or children.

What is male pattern hair loss?

Male pattern hair loss is a common condition in which men experience thinning of the hair on the scalp. Often, this results in a receding hairline and/or balding on the top of the head. These changes typically begin gradually in men in their 20s.

Doctors believe male pattern hair loss is due to heredity and is dependent on hormonal effects. Doctors refer to this type of hair loss as androgenetic alopecia.

Results of clinical studies:

For 12 months, doctors studied over 1800 men aged 18 to 41 with mild to moderate amounts of ongoing hair loss. Of these men, approximately 1200 with hair loss at the top of the head participated in additional extension studies, resulting in a total study time of up to five years. In general, men who took PROPECIA maintained or increased the number of visible scalp hairs and noticed improvement in their hair in the first year. Improvement, compared to the start of the study, was maintained through the remaining years of treatment. Hair counts in men who did not take PROPECIA continued to decrease.

In one study, patients were questioned on the growth of body hair. PROPECIA did not appear to affect hair in places other than the scalp.

Will PROPECIA work for me?

For most men, PROPECIA increases the number of scalp hairs in the first year of treatment, helping to fill in thin or balding areas of the scalp. In addition, men taking PROPECIA may note a slowing of hair loss. Although results will vary, generally you will not be able to grow back all of the hair you have lost. There is not sufficient evidence that PROPECIA works in the treatment of receding hairline in the temporal area on both sides of the head.

Male pattern hair loss occurs gradually over time. On average, healthy hair grows only about half an inch each month. Therefore, it will take time to see any effect.

PROPECIA^® Finasteride) Tablets

You may need to take PROPECIA daily for three months or more before you see a benefit from taking PROPECIA. PROPECIA can only work over the long term if you continue taking it. If the drug has not worked for you in twelve months, further treatment is unlikely to be of benefit. If you stop taking PROPECIA, you will likely lose the hair you have gained within 12 months of stopping treatment. You should discuss this with your doctor.

PROPECIA is not effective in the treatment of hair loss due to androgenetic alopecia in postmenopausal women. PROPECIA should not be taken by women.

How should I take PROPECIA?

Follow your doctor's instructions.

• Take one tablet by mouth each day.
• You may take PROPECIA with or without food.
• If you forget to take PROPECIA, do not take an extra tablet. Just take the next tablet as usual.

PROPECIA will not work faster or better if you take it more than once a day.

Who should NOT take PROPECIA?

• PROPECIA is for the treatment of male pattern hair loss in MEN ONLY and should not be taken by women (see A warning about PROPECIA and pregnancy).
• PROPECIA should not be taken by children.
• Anyone allergic to any of the ingredients.

A warning about PROPECIA and pregnancy.

Women who are or may potentially be pregnant:

• must not use PROPECIA
• should not handle crushed or broken tablets of PROPECIA.

If a woman who is pregnant with a male baby absorbs the active ingredient in PROPECIA, either by swallowing or through the skin, it may cause abnormalities of a male baby's sex organs. If a woman who is pregnant comes into contact with the active ingredient in PROPECIA, a doctor should be consulted. PROPECIA tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.

What are the possible side effects of PROPECIA?

Like all prescription products, PROPECIA may cause side effects. In clinical studies, side effects fromPROPECIA were uncommon and did not affect most men. A small number of men experienced certain sexual side effects. These men reported one or more of the following: less desire for sex; difficulty in achieving an erection; and, a decrease in the amount of semen. Each of these side effects occurred in less than 2% of men. These side effects went away in men who stopped taking PROPECIA. They also disappeared in most men who continued taking PROPECIA.