Avodart (Dutasteride) Side Effects: Which Ones May Be Permanent?

Which side effects does the label say may persist?

The Avodart label's adverse reactions table carries a footnote on the sexual reactions: they are associated with dutasteride treatment (including monotherapy and combination with tamsulosin), they may persist after treatment discontinuation, and the role of dutasteride in that persistence is unknown [1]. That footnote is where the question of permanent side effects comes from. It states a possibility, not a rate [1].

Separately, the label's semen section reports an effect that had not returned to baseline at the end of follow-up, which is covered below [1].

How common are the sexual side effects during treatment?

The label pools three two-year placebo-controlled BPH trials: 2,167 men on Avodart and 2,158 on placebo, mean age 66 [1]. During the first six months, impotence was reported by 4.7% on Avodart versus 1.7% on placebo, decreased libido by 3.0% versus 1.4%, ejaculation disorders by 1.4% versus 0.5%, and breast disorders by 0.5% versus 0.2% [1].

Rates fell after the first six months for the sexual reactions, but not for breast disorders, which were 1.1% on Avodart versus 0.3% on placebo at months 13 to 18 [1]. Withdrawal from those trials for adverse reactions was 4% on Avodart and 3% on placebo, with impotence the most common reason, at 1% [1].

In the four-year CombAT trial, during months 0 to 6 ejaculation disorders were reported by 7.8% of men on combination therapy, 1.0% on dutasteride alone and 2.2% on tamsulosin alone; impotence by 5.4%, 4.0% and 2.6%; and decreased libido by 4.5%, 3.1% and 2.0% [1].

For hair loss, where dutasteride is not FDA-approved, a meta-analysis of 15 placebo-controlled trials (4,495 men) found a relative risk of sexual dysfunction of 1.37 for dutasteride 0.5 mg (95% CI 0.81 to 2.32), which was not statistically significant, with few dutasteride trials included [3].

Sperm count: the change that had not reversed at 24 weeks

Healthy men took dutasteride 0.5 mg daily for 52 weeks and were followed for 24 weeks after treatment [1]. Compared with placebo, dutasteride reduced total sperm count by 23%, semen volume by 26% and sperm motility by 18% [1]. Sperm concentration and sperm morphology were unaffected, and mean values for all semen parameters stayed within the normal range at every timepoint [1].

At the end of the 24-week off-drug follow-up, total sperm count was still 23% below baseline, and the label states that the effects on total sperm count were not reversible after 24 weeks of follow-up [1]. The label also states that the clinical significance of this effect for an individual man's fertility is not known [1]. Dutasteride is present in semen, at an average of 3.4 ng/mL at 12 months [1].

Breast changes and male breast cancer

The label's pooled trials show breast disorders (breast tenderness and enlargement) at 0.5% versus 0.2% on placebo in months 0 to 6, and 1.1% versus 0.3% in months 13 to 18 [1]. Across the three pivotal BPH trials there was one case of breast cancer in the dutasteride group and one in the placebo group, and the label states that the relationship between long-term dutasteride use and male breast neoplasia is currently unknown [1]. Male breast cancer is also listed among the label's postmarketing reports [1].

Mood and depression

The Avodart label lists depressed mood among postmarketing reports, and lists it without suicidal ideation [1]. A Swedish register cohort of 2.24 million men aged 50 to 90 identified 8,774 men who started dutasteride; among them, depression was diagnosed at a hazard ratio of 1.68 (95% CI 1.43 to 1.96), and the association between dutasteride use and depression remained approximately constant over time in this observational cohort [2]. Suicide was not associated with dutasteride use in that cohort (hazard ratio 0.98, 95% CI 0.62 to 1.54) [2]. The study is observational and mostly reflects older men treated for BPH [2].

Pregnancy exposure: potential harm to a male fetus

Dutasteride is contraindicated in pregnancy [1]. It blocks conversion of testosterone to DHT, a hormone the label describes as necessary for normal development of male genitalia, and in animal reproduction studies it inhibited normal development of external genitalia in male offspring [1]. The label says women who are or may be pregnant should not handle the capsules, and that the contact area should be washed immediately with soap and water if a pregnant woman touches a leaking capsule [1].

The label's human data put this in perspective: the highest measured semen concentration in treated men was 14 ng/mL, and the estimated blood concentration in a 50-kg woman exposed to 5 mL of semen with full absorption would be about 0.0175 ng/mL, roughly 100 times below blood concentrations that produced male genital abnormalities in animals [1]. More than 96% of the dutasteride in semen is protein bound [1].

High-grade prostate cancer: a risk signal, not a persisting symptom

In the four-year REDUCE trial, men aged 50 to 75 with one prior negative biopsy and a PSA of 2.5 to 10 ng/mL took dutasteride 0.5 mg or placebo [1][4]. Gleason 8 to 10 cancer was found in 1.0% of men on Avodart versus 0.5% on placebo [1][4]. The label states that 5-alpha reductase inhibitors may increase the risk of high-grade prostate cancer, and that whether the effect on prostate volume or trial-related factors influenced the results has not been established [1].

Overall, biopsy-detected cancer was lower on dutasteride: 659 of 3,305 men versus 858 of 3,424, a relative risk reduction of 22.8% (95% CI 15.2 to 29.8) [4]. Gleason 7 to 10 tumors across all four years numbered 220 versus 233 (P=0.81), while in years 3 and 4 there were 12 Gleason 8 to 10 tumors on dutasteride against 1 on placebo (P=0.003) [4]. Avodart is not approved for the prevention of prostate cancer [1].

Dutasteride lowers PSA by about 50% within 3 to 6 months. The label says to establish a new PSA baseline at least 3 months after starting and to double an isolated PSA value in a man treated for 3 months or more; it says any confirmed rise from the lowest on-treatment value should be evaluated even if it is within the normal range [1].

How long does dutasteride stay in the body?

Dutasteride's terminal half-life is about 5 weeks at steady state, and about 90% of steady state is reached after 3 months [1]. Serum levels stay above 0.1 ng/mL for up to 4 to 6 months after the last dose [1]. The label says men being treated should not donate blood until at least 6 months after their last dose, to avoid giving dutasteride to a pregnant transfusion recipient [1]. The label does not link the half-life to the persistence of side effects [1].