Eur Urol. 2003 Jul;44(1):82-8.
Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.
Andriole GL, Kirby R.
Division of Urologic Surgery, Washington University School of Medicine, 4960 Children's Place, Campus Box 8242, St. Louis, MO 63110, USA. andrioleg@msnotes.wustl.edu
OBJECTIVE: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5alpha-reductase inhibitor, dutasteride.
METHODS: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n=5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n=327), and several safety studies conducted in healthy volunteers.
RESULTS: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. Dutasteride reduced total serum PSA concentrations by approximately 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an alpha(1)-blocker, the drug-related adverse event profiles were as would be expected for the individual agents.
CONCLUSIONS: Considered together, these data demonstrate dutasteride to be well-tolerated.
Contrast with Dr Lee's analysis:-
"Let's compare some of the differences between Propecia (finasteride) and Avodart (dutasteride):
Method of Action
Both block the formation of DHT from Testosterone, by inhibiting the enzyme 5-alpha reductase. Unlike Propecia (Merck) which inhibits the 5 AR-2 enzyme only, Avodart (Glaxo Smith Kline) inhibits both 5AR-2 and 5AR-1 enzymes.
Biological Model
Finasteride has a biological model and dutasteride does not. This quite simply means that there is much more safety data on Propecia than Avodart right now. The effects of 5AR type 2 deficiency, (the same environment Propecia creates) have been thoroughly studied for over 25 years in a group of patients in the Dominican Republic. The long-term "side effects" are no hair loss, and no prostate cancer. Patients with genetic 5AR-2 deficiency have no life-threatening disorders and there is no 5AR-2 present in their brain tissue.
Conversely, there is no biological model for 5AR type 1 deficiency, which Avodart creates, and there are measurable levels of 5AR-1 in the human brain. Conclusion -- the blockage of 5AR-1 may have yet unknown neurological implications.
Dosage
Glaxo presented the results from the Phase II studies about 3 yrs. ago in a closed session only to the investigators involved in the study. From what was presented, the dutasteride side effects were very similar to the finasteride side effects (5 mg) tested dose. Dutasteride's sexual side effects were in the range of 3-4% versus 1-2% for finasteride 1mg (Propecia) and 3-4% for finasteride 5mg (Proscar). The results of the phase II trials did show that 2.5 mg of Avodart gave nearly 2-3 times more hair growth than finasteride did at a full 5 mg, resulting even in frontal hair growth in some men. However, these superior results were at a rather high 2.5mg dosage.
Both Finasteride and Dutasteride have originated as Prostate medications, but Dutasteride's prostate dose is actually lower than the tested dose for hair loss. Glaxo seems to be doing the exact opposite of Merck in this sense. Finasteride worked better on the prostate at the higher dose (5mg - Proscar), and for hair at a lower dose (1mg - Propecia). Dutasteride was released for the prostate at the lower dose (Avodart - 0.5mg), and was tested with results on hair loss at 5 times the dose (2.5mg). The higher the dose, the more potential for side effects.
Duration of Side Effects
The greatest concern however, is the potential duration of side effects. The long half life of dutasteride exceeds 240 hours vs. the rather short 6 to 8 hours for finasteride.
There have been some cases where the DHT levels were still had only returned to 25% of their original levels nearly a YEAR after having discontinued Dutasteride. As a result, any dangers or side effects that may be seen from Avodart, whether directly related or as a hypersensitive or allergic reaction may take literally months to resolve.
Cost
Using dutasteride at the 2.5 mg dose will be quite expensive. Since many people are considering taking the 2.5mg dose, and Avodart is sold in 0.5mg capsules at nearly $90 for 30, basic math reveals quite a hefty monthly expense for this off-label treatment.
Dosing Frequency
On the other hand, the good news is that due to the long duration of action, the optimal dosage frequency might be once weekly or even once monthly. However, the fact remains that there is no clinical data to look towards regarding less frequent dosage schedules, so we doctors, and our patients, will be on our own. The ideal patient may be the person who has used Propecia for extended periods of time and saw results with no side effects.
Perspective?
I find that many patients are reluctant to take Propecia because of the sexual side effect disclaimers from the original TV ads by Merck. As a result, I find this irrational fervor to take Avodart worrisome, because
we do not know about long-term side effects, nor how long the short-term side effects, if experienced, will last.
Conclusion
True, the preliminary results for hair growth are encouraging, but at what price? Glaxo has not done even presented the bare minimum needed as far as safety or dosing data for this drug to be used to treat hair loss. The most effective dose that carries the least chance of side effects. This is what Merck did for us with Propecia, and the data backing their recommendation is imperative to have. Perhaps the initial, ideal Dutasteride patient will be the one having had no problems with Propecia, who wants to improve their results. However, Dutasteride stays in the body for months, and maybe as long as a year. So if complications arise from its use, they will be around for a long time. Remember Fen-Fen for weight loss? Personally, I do not want my patients to be the guinea pigs."