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The use of Avodart with Male Pattern Baldness

Avodart (Dutasteride) – Introduction

Avodart® (Dutasteride 0.5mg): The first dual-acting 5 alpha-reductase inhibitor for benign prostatic hyperplasia (BPH), approved by the FDA. Avodart® reduces the 2 enzymes responsible for the conversion of testosterone to DHT – which is a primary concern in hair loss. Where Propecia (Finasteride) only blocks one enzyme, by blocking both Avodart’s® results could be better. We can expect to see Avodart® officially on the market as a hair loss medication in 2006 if approved.

No word yet on Avodart® being approved for hair loss by the FDA. Avodart®, manufactured by GlaxoSmithKline (GSK), was approved in February 2002 by the Food and Drug Administration (FDA), as a supplemental new drug application for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate. Dutasteride was originally assigned the tentative brand (trade) name of “Duogen.” The manufacturer GSK will market this drug, indicated for the treatment of BPH, under the name “Avodart™.” The drug became available in pharmacies in December 2002. This new medicine for these patients will improve urinary symptoms, reduce the risk of acute urinary retention (AUR), also reducing the risk of the need for BPH-related surgery.

Hair Loss Issues

GSK is believed to have entered Phase III trials with Dutasteride for hair loss. Their Supplemental New Drug Application for hair loss is thought to have been submitted to the FDA sometime in 2001. Avodart™ appears to have a much greater and longer inhibition of DHT than Propecia (Finasteride) in the early testing phases. Is Avodart better than Propecia, and are its side effects greater or more serious? These are questions that are unanswered at this time – but time will tell. It’s currently approved in a 0.5 mg soft gel form.

Avodart (Dutasteride), a second-generation 5 alpha-reductase inhibitor, is the first and only medicine to inhibit both the type 1 and type 2 enzymes responsible for the conversion of testosterone to DHT (dihydrotestosterone), the primary cause of prostate growth. Dutasteride’s dual inhibition has been found to decrease levels of DHT by 90 percent at two weeks and 93 percent at two years.

By reducing DHT levels, Avodart (dutasteride reduces the size of an enlarged prostate. This reduction in prostate volume was seen as early as one month with reductions continuing through treatment. Shrinking the enlarged prostate is beneficial for relieving urinary obstruction and improving urinary flow. While improving urinary symptoms Dutasteride also reduces the risk of AUR (the sudden complete inability to urinate), and BPH-related surgery, which are two potential long-term serious consequences of BPH. The pivotal phase III study data were published in this month’s edition of the journal Urology.1

“With dutasteride, we now have a medicine that reduces the production of DHT by more than 90 percent, helping to shrink the prostate,” said Claus Roehrborn, MD, a principal trial investigator, and professor and chairman of the Department of Urology at the University of Texas Southwestern Medical Center in Dallas, Texas. “By taking dutasteride, patients can improve urinary symptoms and reduce their risk of suffering from acute urinary retention – where you suddenly can’t urinate at all – or needing BPH-related prostate surgery.”

AvolveÒ, Sweden’s trade name for Dutasteride, was approved by the Swedish regulatory authority (MPA) on July 24th, 2002. The MPA agreed to act as the Reference Member State for the Mutual Recognition procedure within Europe and GSK plans to market the drug in all major European markets once approvals are finalized in 2003. The European trade name (Avolve) is still to be confirmed.

Dutasteride Results

The Phase II study results below are required for FDA approval. The Phase III trials for hair loss were scheduled for March of 2003 in the US. Avodart is expected to be on the market for hair loss in 2006 if approved.

Dutasteride Phase 2 Hair Counts

After six months of treatment, the hair counts measured in a 1-inch diameter circle increased by about ~96 hairs with 0.5mg Dutasteride, compared to about ~72 hairs with 5mg Finasteride. The hair counts increased significantly with an increase in dosage with the biggest gain being ~108 hairs with a dose of 2.5mg Dutasteride. So compared to 5mg Finasteride (Proscar), 2.5 mg Avodart grew about 1.5 times as many hairs. This is why there is so much excitement surrounding Dutasteride. However, there are still unknown questions about increased side effects compared to Finasteride. The Phase III study should tell much more.

Background on BPH

BPH is one of the most common health problems in older men.2 BPH often begins after age 50 and can progress and worsen as men age. More than half of men over age 60 experience BPH,3, and by age 80, nearly 80 percent of men have the disease.3,4 In the United States alone, 375,000 hospital stays each year involve a diagnosis of BPH.5

BPH is a progressive disease in which the prostate gland surrounding the urethra enlarges.6 As it grows, the prostate obstructs the urethra, the tube through which urine flows, causing urinary difficulties. BPH symptoms interfere with normal activities and reduce the sense of well-being.7 Symptoms of BPH vary, but the most common involve urinary problems, such as a hesitant, interrupted weak stream; urgency and leaking or dribbling; and more frequent urination, especially at night.5 In severe cases, the bladder and the kidney may become damaged.5

An enlarged prostate can continue to increase in size and may in severe cases lead to AUR and the need for BPH-related surgery.6 A 60-year-old man with a 20-year life expectancy has a 23 percent risk of developing acute urinary retention.8 Among men 60 years or older, with prostatic enlargement and obstructive symptoms, the 20-year probability of needing BPH-related surgery is 39 percent.9

To diagnose BPH, a physician will discuss urinary symptoms with a patient and conduct a digital rectal exam. A physician may also use a simple blood test that measures a protein called “prostate-specific antigen,” or PSA. PSA is produced by the prostate, and an increase in levels is associated with prostate growth.6 While PSA is primarily used as a screening tool for prostate cancer, it can also be used to determine prostate enlargement.

According to the Avodart website, Avodart alone and in combination with the alpha-blocker tamsulosin is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms. AVODART alone also reduces the risk of acute urinary retention (AUR) and prostate surgery.

SUMMARY

1. The treatment of androgenetic alopecia is not an FDA-approved indication for Avodart (dutasteride). Therefore, Glaxo Smith Kline may not make recommendations on the use of Avodart for the purpose.
2. 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).
3. A phase II, multi-center double-blind, placebo-controlled study was conducted in 416 males with AGA, ages 21-45 years, to evaluate the dose-response relationship of Avodart on hair growth. Repeated doses of Avodart (0.05mg), 0.5mg, and 2.5mg daily) were 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.
4. A dose-related increase in hair count was seen at weeks 12 and 24 in 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 aw=t week 36 (12 weeks after medication discontinuation) in the Avodart 0.5mg and 2.5mg treatment groups, but not in the finasteride or Avodart 0.05mg and 0.1mg treatment groups.
5. 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 0.1mg/day group and 6% of the Avodart 0.5mg/day, and 2.5mg/day group.
6. No large, prospective clinical trials have evaluated the use of Avodart for AGA.
7. 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 5?-reductase inhibitors, or any component of the preparation.

Some information contained in this response may be outside the approved prescribing information for Avodart. This response is not intended to offer recommendations for administering Avodart in a manner inconsistent with its approved labeling. In order for Glaxo Smith Kline to monitor the safety of Avodart, we encourage healthcare professionals to report adverse events or suspected overdoses to the company at 888-825-5249. Please consult the Prescribing Information for Avodart.

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 5 a -reductase in order to be active in the skin (3). Studies have shown that men with 5 a -reductase deficiency do not develop AGA (*3,4). Therefore, 5 a -reductase 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 5 a -reductase is known, type 1 and type 2. Type 2 is predominately located in human genital tissue. Type 1 is distributed throughout the body and predominates in the skin and scalp (3).

Avodart is a competitive inhibitor of 5 a -reductase, the enzyme responsible for the conversion of testosterone to dihydrotestosterone (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 5 a -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 information

A phase 2, multi-center, double-blind, placebo-controlled study was conducted in 416 males with AGA, ages 21 to 45 years, to evaluate the dose-response relationship of repeated doses of Avodart (0.05mg, 0.1mg,0.5mg, and2.5mg 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 (7).

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 or progression in the size of the balding area within the past 2 years.Patients were randomized into one of the following xix treatment groups:Avodart 0.05mg (n=71), Avodart 0.1mg (n=72), Avodart 0.5mg (n=71),finasteride 5mg (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) (7).

Efficacy was assessed by measuring hair counts of the vertex region of the scalp using macro photographic techniques at baseline, 12 weeks, 24 weeks, and at the follow-up visit 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 1 and reflect the last observation carried forward (LOCF) (weeks 12 and 24) or at the last visit (ALV)(week 36) analyses of the intent-to-treat population (7).

 
Table 1: Hair count: change from baseline using 0.79square inch target area

 

(Intent to Treat Population)*(7) 

Avodart

Time/Parameter

0.05mg/day

0.1mg/day

0.5mg/day

2.5mg/day

Finasteride

5mg/day

Placebo

Week 12

N

Mean *

Mean Difference **

p-value

 

61

5.0

27.9

0.065

 

65

54.3

77.2

<0.0001

 

59

71.9

94.8

<0.001

 

63

100.4

123.3

<0.001

 

68

52.1

75.0

<0.001

 

57

-22.9

Week 24

n

Mean*

Mean Difference**

p-value

 

62

24.8

54.4

<0.001

 

66

72.3

101.9

<0.001

 

63

95.5

125.1

<0.001

 

67

109.8

139.5

<0.001

 

69

73.2

102.8

<0.001

 

58

-29.6

Week 36

N

Mean*

Mean Difference**

p-value

 

47

-17.1

20.2

0.29

 

52

16.8

54.1

0.004

 

51

84.3

121.6

<0.001

 

54

119.8

157.1

<0.001

 

61

13.2

50.5

0.005

 

46

-37.3

which are reported as at last visit (ALV) values; * Adjusted for baseline values; ** difference between active treatment and placebo.]

As noted in Table 1, dose-related increases in hair count were seen at 12 and24 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 group at week 12 ( P<0. 065). 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)(7).

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 0.5mg (35.5 at week 24 and 84.3 at week 36) and 2.5mg(109.9-8 at week 24 and 119.8 at week 36) daily. In contrast, improvement in hair count was not maintained in those patients receiving finasteride 5mg at week 36 compared to week 24 (73.2 at week 24 and 13.2 at week 36), Avodart 0.05mg (24.8 at week 24 and -17.1 at week 36), or Avodart 0.1mg (72.3 at week 24and 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 having an incidence > 5% within any treatment group are presented in table 2.

 

Table 2: Percent (%) of Subjects with Drug-RelatedAdverse Events

( > 5% of Subjects Within Any Treatment Group)

Avodart

Adverse Event

0.05mg/day N=71

0.1mg/day N=72

0.5mg/day

N=68

2.5mg/day

 

N=71

Finasteride 5mg/day N=70

Placebo

N=64

Any Adverse Event

18

29

16

32

24

27

Altered (Decreased)

Libido

3

3

0

13

4

3

Impotence

1

0

0

0

1

5

Headaches

1

8

6

6

3

3

Nausea and Vomiting

0

0

1

1

0

5

Malaise and Fatigue

1

1

1

7

3

3

Abnormal Liver

Function Tests

3

1

0

0

0

5

The most common drug-related adverse event was decreased libido experienced by 13% of subjects receiving Avodart 2.5 mg/day followed by headaches, experienced by 8% of the Avodart 0.1mg/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 0.5 mg). The other three pregnancies were normal and resulted in the births of two males (two subjects on “Avodart 0.5mgand one on Avodart 2.5mg) and one female (a 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) REV0704

REFERENCES

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

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

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

•  Wilson Jd, Griffin Je, Russell DW. Steroid 5 alpha-reductase 2 deficiency.Endocr Rev 1993;13:1-14.

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

•  Prescribing Information for Avodart Ô.

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

Enclosures: Product Information for Avodart Ô

Time/Parameter

0.05mg/day

0.1mg/day

0.5mg/day

2.5mg/day

Finasteride

5mg/day

Placebo

Week 12

N

Mean *

Mean Difference **

p-value

 

61

5.0

27.9

0.065

 

65

54.3

77.2

<0.0001

 

59

71.9

94.8

<0.001

 

63

100.4

123.3

<0.001

 

68

52.1

75.0

<0.001

 

57

-22.9

Week 24

n

Mean*

Mean Difference**

p-value

 

62

24.8

54.4

<0.001

 

66

72.3

101.9

<0.001

 

63

95.5

125.1

<0.001

 

67

109.8

139.5

<0.001

 

69

73.2

102.8

<0.001

 

58

-29.6

Week 36

N

Mean*

Mean Difference**

p-value

 

47

-17.1

20.2

0.29

 

52

16.8

54.1

0.004

 

51

84.3

121.6

<0.001

 

54

119.8

157.1

<0.001

 

61

13.2

50.5

0.005

 

46

-37.3

Adverse Event

0.05mg/day N=71

0.1mg/day N=72

0.5mg/day

N=68

2.5mg/day

 

N=71

Finasteride 5mg/day N=70

Placebo

N=64

Any Adverse Event

18

29

16

32

24

27

Altered (Decreased)

Libido

3

3

0

13

4

3

Impotence

1

0

0

0

1

5

Headaches

1

8

6

6

3

3

Nausea and Vomiting

0

0

1

1

0

5

Malaise and Fatigue

1

1

1

7

3

3

Abnormal Liver

Function Tests

3

1

0

0

0

5

Time/Parameter

0.05mg/day

0.1mg/day

0.5mg/day

2.5mg/day

Finasteride

5mg/day

Placebo

Week 12

N

Mean *

Mean Difference **

p-value

 

61

5.0

27.9

0.065

 

65

54.3

77.2

<0.0001

 

59

71.9

94.8

<0.001

 

63

100.4

123.3

<0.001

 

68

52.1

75.0

<0.001

 

57

-22.9

Week 24

n

Mean*

Mean Difference**

p-value

 

62

24.8

54.4

<0.001

 

66

72.3

101.9

<0.001

 

63

95.5

125.1

<0.001

 

67

109.8

139.5

<0.001

 

69

73.2

102.8

<0.001

 

58

-29.6

Week 36

N

Mean*

Mean Difference**

p-value

 

47

-17.1

20.2

0.29

 

52

16.8

54.1

0.004

 

51

84.3

121.6

<0.001

 

54

119.8

157.1

<0.001

 

61

13.2

50.5

0.005

 

46

-37.3

Adverse Event

0.05mg/day N=71

0.1mg/day N=72

0.5mg/day

N=68

2.5mg/day

 

N=71

Finasteride 5mg/day N=70

Placebo

N=64

Any Adverse Event

18

29

16

32

24

27

Altered (Decreased)

Libido

3

3

0

13

4

3

Impotence

1

0

0

0

1

5

Headaches

1

8

6

6

3

3

Nausea and Vomiting

0

0

1

1

0

5

Malaise and Fatigue

1

1

1

7

3

3

Abnormal Liver

Function Tests

3

1

0

0

0

5

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