Summary of Research on the use of Dutasteride in AGA

· The treatment of androgenetic alopecia is not in the FDA-approved labeling for AvodartTM (dutasteride). Therefore, GlaxoSmithKline may not make recommendations on the use of Avodart for this purpose.

· Avodart inhibits the conversion of testosterone to dihydrotestosterone (DHT) resulting in decreased serum DHT concentrations. By this mechanism, Avodart appears to interrupt a key process in the development of androgenetic alopecia (AGA), also known as male pattern hair loss (MPHL).

· A phase II, multi-center, double blind, placebo-controlled study was conducted in 416 males with AGA, ages21 to 45 years, to evaluate the dose response relationship of Avodart on hair growth. Repeated doses of Avodart (0.05 mg, 0.1mg, 0.5mg, and 2.5mg daily) were compared to placebo for 6 months. Safety and tolerability of the varying doses of Avodart and finasteride 5 mg daily compared with placebo were also investigated.

· A dose-related increase in hair count was seen at week 12 and 24 in those patients receiving Avodart; significant increases were also observed in the finasteride treatment group. The increase in hair count was maintained after the cessation of treatment at week 36 (12 weeks after medication discontinuation) in the Avodart 0.5 mg and 2.5 mg treatment groups, but not in the finasteride or Avodart 0.05 mg and 0.1 mg treatment groups.

· The most common drug-related adverse events were decreased libido experienced by 13% of subjects receiving Avodart 2.5 mg/day, followed by headaches experienced by 8% of the Avodart 0.1 mg/day group and 6% of the Avodart 0.5 mg/day and 2.5 mg/day group.

· No large, prospective clinical trials have evaluated the use of Avodart for AGA.

· 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, and reduce the risk of the need for BPH-related surgery, Avodart is contraindicated for use in women and children and for patients with known hypersensitivity to dutasteride, other 5a-reductase inhibitors, or any component of the preparation.

BACKGROUND

Androgenetic alopecia (AGA), also known as male pattern hair loss (MPHL), is the most common form of hair loss, affecting approximately 50% of Caucasians over the age of 40 years (1). In males, AGA can begin as early as late adolescence; however, the usual onset is at around the age of 30 years (1). AGA results from naturally circulating androgens which progressively transform large terminal scalp follicles to smaller vellus ones, thus resulting in a visibly less dense scalp (2).

Testosterone is the major circulating androgen in the body, but must be converted to dihydrotestosterone (DHT) via the enzyme 5a-reductase in order to be active in the skin (3). Studies have shown that men with 5areductase deficiency do not develop AGA (3,4). Therefore, 5a-reductasein inhibitors have been evaluated for the treatment of AGA due to their ability to inhibit the conversion of testosterone to dihydrotestosterone (3,5). Two isoforms of 5a-reductase are known, referred to as type 1 and type 2. Type 2 is predominately located in human genital tissue. Type 1 is distributed through the body, and predominates in the skin and scalp. (3)

Avodart is a competitive inhibitor f 5a-reductase, the enzyme responsible for the conversion of testosterone to DHT in the prostate. It inhibits both enzyme types 1 and 2 and is indicated for the treatment of symptomatic BPH in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for BPH-related surgery. Avodart is contraindicated for use in women and children and for patients with known hypersensitivity to dutasteride, other 5a-reductase inhibitors, or any component of the preparation. (6).

One clinical trial evaluating the use of Avodart in AGA has been conducted and is discussed below. No large, prospective clinical trials have evaluated the use of Avodart for this use.

CLINICAL TRIAL

A phase II, multi-center, double blind, placebo-controlled study was conducted in 416 males with AGA, ages 21to 45 years, to evaluate the dose response relationship of repeated doses of Avodart (0.05 mg, 0.1 mg, 0.5 mg, and 2.5 mg daily) on hair count compared to placebo for 6 months. Safety and tolerability of the varying doses of Avodart and finasteride 5mg daily compared with placebo were also investigated. At the time this study was conducted, the 1 mg dosage strength of finasteride that is currently approved for the treatment of AGA was not available.

Patients were included in this study if they had MPHL, defined as type IIIv, IV, or V by the modified Norwood-Hamilton classification and had active hair loss of progression in the size of the balding area within the past 2 years. Patients were randomized into one of the following six treatment groups: Avodart 0.05 mg (n=71), Avodart 0.1 mg (n=72), Avodart 0.5 mg (n=68), Avodart 2.5 mg (n=71), finasteride 5 mg (n=70), or placebo (n=64) (7). Patients received oral doses once daily for 24 weeks.

The study also included an additional follow-up visit and evaluation of hair count at 36 weeks, 12 weeks after double-blind study medication had been stopped.

Efficacy was assessed by measuring hair counts of the vertex region of the scalp using macrophotographic techniques at baseline, 12 weeks, 24 weeks, and at the follow-up visits at 36 weeks (12 weeks after study medication discontinuation). The primary efficacy parameter was the hair count in a 1-inch diameter circle, with a target area of 0.79 square inches, surrounding a tattoo. Results are presented in Table I and reflect last observation carried forward (LOCF) (weeks12 and 24) or the at last visit (ALV) (week 36) analyses of the intent-to-treat population (7).

Table : 1

All results are reported as last observation carried forward (LOCF) values except for the    week 36 results, which are reported as at last visit (ALV) values; *difference between active treatment and placebo.

As noted in Table 1, dose-related increases in hair count were seen at 12 and 24 weeks across the Avodart treatment groups. Compared to placebo, these changes were significantly different in all Avodart treatment groups (p<0.001) except for in the 0.05 mg group at week 12 (p=0.065) (7). Hair count change from baseline in the finasteride group was also significantly greater than the placebo group at both 12 and 24 weeks (p<0.001).

At week 36 (12 weeks after cessation of daily medication), improvement in hair count was maintained at a similar level to that observed at week 24 in those patients receiving Avodart 0.5 mg (95.5 at week 24 and 84.3 at week 36) and 2.5 mg (109.8 at week 24 and 119.8 at week 36) daily. In contrast, improvement in hair count was not maintained in those patients receiving finasteride 5 mg at week 36 compared to week 24 (73.2 at week 24 and 13.2 at week 36,), Avodart 0.05 mg (24.8 at week 24 and -17.1 at week 36), or Avodart 0.1 mg (72.3 at week 24 and 16.8 at week 36). (7) Adverse Events

Twenty-five percent (102/416) of subjects experienced a total of 169 adverse events that were classified by the investigator as having a reasonable possibility of being drug-related (7). Those drug-related adverse events with an incidence >5% within any treatment group are presented in Table 2.

Table 2: Percent (%) of Subjects with Drug-Related Adverse Events (>5% of subjects Within Any Treatment Group)

The most common drug-related adverse events were decreased libido experienced by 13% of subjects receiving Avodart 2.5mg/day followed by headaches, experienced by 8% of the Avodart 0.1 mg/day group and 6% by both the Avodart 0.5mg/day and 2.5 mg/day group. There were no serious adverse events that were considered drug-related.

Partner Pregnancies

Five partner pregnancies were reported during the study. One female partner spontaneously aborted (study subject was on placebo) and one had a partial placenta previa with subsequent delivery of a normal male infant (study subject was on Avodart 0.5mg). The other three pregnancies were normal and resulted in the births of two males (two subjects on Avodart 0.5 mg and one subject on Avodart 2.5 mg) and one female (subject on Avodart 2.5mg). None of the infants had genital or other abnormalities at birth (7).

PRECAUTION

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. 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 (6).

REFERENCES

1 Meidan VM, Touitou E. Treatments for androgenetic alopecia and alopecia areata: current options and future prospects. Drugs 2001;61:53-69

2 Randall VA. Physiology and Pathophysiology of Androgenetic Alopecia. In: Endocrinology, 4th ed. Volume 3. DeGrrot LJ and Jameson JL (editors). W.B. Sanders Co, Philadelphia PA, 2001, pages 2257-2268

3 Rittmaster RS. Clinical relevance of testosterone and dihydrotestosterone metabolism in women. Am J Med 1995; 98 (Suppl 1A): 17S-21S.

4 Wilson JD, Griffin JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993; 13:1-14.

5 Rittmaster RS. Finasteride N Engl J Med 1994;330:120-125

6 Prescribing Information for Avodart

7 Data on File (Dutasteride, GM2000/00244/00, Study ARIA2004Report Synopsis, 2001)

8 Data on File (Dutasteride, GM2000/00244/00, Study ARIA2004 Report Synopsis. 2001)

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