No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced respective systemic exposure in rats of 888 and 2192 times those observed in man receiving the recommended human dose of 1 mg/day. All exposure calculations were based on calculated AUC (0 to 24 hr) for animals and mean AUC(0 to 24 hr) for man (0.05 mcg•hr/mL).
In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenomas was observed at 1824 times the human exposure (250 mg/kg/day). In mice at 184 times the human exposure, estimated (25 mg/kg/day) and in rats at 312 times the human exposure (≥40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for 1 year at 240 and 2800 times (20 mg/kg/day and 45 mg/kg/day, respectively), or in mice treated for 19 months at 18.4 times the human exposure, estimated (2.5 mg/kg/day).
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 4344 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 488 times the human exposure (80 mg/kg/day), 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.
The efficacy of finasteride tablets USP 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 finasteride tablets USP, 1 mg 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 finasteride tablets USP, 1 mg 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 finasteride tablets USP 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 finasteride tablets USP, 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 finasteride tablets USP in the first 12-month extension period. Some of these men continued in additional extension studies receiving finasteride tablets USP, with 290 men entering the fifth year of the study (see Figure 1 below).
Hair counts were assessed by photographic enlargements of a representative area of active hair loss. In these two studies in men with vertex baldness, significant increases in hair count were demonstrated at 6 and 12 months in men treated with finasteride tablets USP, while significant hair loss from baseline was demonstrated in those treated with placebo. At 12 months there was a 107-hair difference from placebo (p<0.001, finasteride tablets USP [n=679] vs placebo [n=672]) within a 1-inch diameter circle (5.1 cm2). Hair count was maintained in those men taking finasteride tablets USP for up to 2 years, resulting in a 138-hair difference between treatment groups (p<0.001, finasteride tablets USP [n=433] vs placebo [n=47]) within the same area. In men treated with finasteride tablets USP, the maximum improvement in hair count compared to baseline was achieved during the first 2 years. Although the initial improvement was followed by a slow decline, hair count was maintained above baseline throughout the 5 years of the studies. Furthermore, because the decline in the placebo group was more rapid, the difference between treatment groups also continued to increase throughout the studies, resulting in a 277-hair difference (p<0.001, finasteride tablets USP [n=219] vs placebo [n=15]) at 5 years (see Figure 1 below).
Patients who switched from placebo to finasteride tablets USP (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 finasteride tablets USP. 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 finasteride tablets USP. 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 finasteride tablets USP in the initial study. This advantage was maintained through the remaining 3 years of the studies. A change of treatment from finasteride tablets USP 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 1 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 finasteride tablets USP. 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 finasteride tablets USP. At 5 years, 100% of men in the placebo group demonstrated hair loss, compared with 35% of men treated with finasteride tablets USP.Figure 1
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 finasteride tablets USP. 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 finasteride tablets USP compared with placebo as early as 3 months (p<0.001). At 12 months, the investigators rated 65% of men treated with finasteride tablets USP as having increased hair growth compared with 37% in the placebo group. At 2 years, the investigators rated 80% of men treated with finasteride tablets USP as having increased hair growth compared with 47% of men treated with placebo. At 5 years, the investigators rated 77% of men treated with finasteride tablets USP 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 finasteride tablets USP 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 finasteride tablets USP, compared with 7% of men treated with placebo. At 5 years, 48% of men treated with finasteride tablets USP 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.
A 48-week, placebo-controlled study designed to assess by phototrichogram the effect of finasteride tablets USP 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 finasteride tablets USP 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 finasteride tablets USP.
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. Finasteride tablets USP 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 finasteride tablets USP 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 finasteride tablets USP 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 finasteride tablets USP and led to a net increase in scalp hair count and hair regrowth. In clinical studies for up to 5 years, treatment with finasteride tablets USP 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 (Finasteride tablets USP 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 finasteride tablets USP treatment, except for satisfaction of the frontal hairline and vertex in Black men, who were satisfied overall.
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