Long-term safety data for dutasteride comes primarily from the 4-year CombAT trial (4,844 men) and the 4-year REDUCE trial (8,231 men). Two findings stand out in the FDA label. The first is a higher incidence of Gleason score 8-10 prostate cancer in REDUCE: 1.0% on dutasteride against 0.5% on placebo. The label states that whether prostate-volume reduction or study-related factors influenced that result “has not been established.” The second is a numerical imbalance in the composite term cardiac failure, in both CombAT and REDUCE, for which the label states no causal relationship has been established. Dutasteride is FDA-approved in the United States for bph/">benign prostatic hyperplasia only; use for hair loss is off-label.
4-Year CombAT Trial Safety Data
The CombAT trial followed 4,844 men taking dutasteride alone, tamsulosin alone, or the combination for 4 years. Table 2 of the FDA label reports adverse reactions by time of onset. For dutasteride monotherapy versus tamsulosin monotherapy during months 0-6:
- Impotence: 4.0% (vs 2.6% tamsulosin)
- Decreased libido: 3.1% (vs 2.0% tamsulosin)
- Breast disorders: 0.9% (vs 0.4% tamsulosin)
- Ejaculation disorders: 1.0% (vs 2.2% tamsulosin)
Rates of all four fell sharply after the first 6 months. One safety signal did emerge over the full 4 years: the label reports the composite term cardiac failure in 0.7% of the combination-therapy group (12 of 1,610) against 0.1% on dutasteride alone (2 of 1,623) and 0.6% on tamsulosin alone (9 of 1,611). It also states that a majority of subjects with cardiac failure in this study had co-morbidities associated with an increased risk of cardiac failure, that the clinical significance of the imbalance is unknown, and that no causal relationship has been established.
4-Year REDUCE Trial Safety Data
REDUCE randomised 8,231 men aged 50 to 75 with a PSA of 2.5 to 10 ng/mL and a negative biopsy in the previous 6 months. Over the whole trial, Gleason score 8-10 prostate cancer was found in 1.0% of men on dutasteride and 0.5% on placebo. In years 3 and 4 specifically, the published trial report records 12 such tumours in the dutasteride group against 1 in the placebo group (P=0.003). The label states plainly that dutasteride “is not approved for the prevention of prostate cancer,” and that whether prostate-volume reduction or study-related factors influenced the result has not been established. It also reports the composite term cardiac failure in 0.6% of men on dutasteride (26 of 4,105) against 0.4% on placebo (15 of 4,126), with no causal relationship established and no imbalance in overall cardiovascular adverse events. Full REDUCE trial analysis.
PSA Effects Over Time
Dutasteride reduces serum PSA by approximately 50% within 3 to 6 months of treatment. A new PSA baseline should be established at least 3 months after starting, and any confirmed increase from the lowest PSA value recorded on dutasteride should be evaluated for prostate cancer even if the value is still within the normal range for untreated men. To interpret an isolated PSA value after 3 months or more of treatment, the label directs that the value be doubled for comparison with normal ranges.
All side effects · Long-term safety meta-analysis
Sources
- FDA. Avodart (dutasteride) prescribing information, Adverse Reactions and Warnings and Precautions. accessdata.fda.gov
- Roehrborn CG, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57(1):123-31. PubMed
- Andriole GL, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362(13):1192-202. PubMed