Avodart Anesthesia and Perioperative Interaction: What Patients and Clinicians Need to Know

Is there a dutasteride-anesthesia interaction?

Avodart is a 0.5 mg soft gelatin capsule of dutasteride, a 5-alpha reductase inhibitor that blocks both type 1 and type 2 forms of the enzyme [1]. It is FDA-approved only for symptomatic benign prostatic hyperplasia in men with an enlarged prostate, used alone or alongside tamsulosin, and it is not approved for the prevention of prostate cancer [1][2].

The label's drug interactions section covers a short list: potent, chronic CYP3A4 inhibitors such as ritonavir; the alpha blockers tamsulosin and terazosin; the calcium channel blockers verapamil and diltiazem; cholestyramine; digoxin; and warfarin [1]. No anesthetic is on it.

Dutasteride is extensively metabolized by CYP3A4 and CYP3A5 [1]. The label states that the effect of potent CYP3A4 inhibitors on dutasteride has not been studied, and it advises caution when Avodart is prescribed with potent, chronic inhibitors such as ritonavir [1].

Verapamil and diltiazem decrease dutasteride clearance and raise exposure; the label does not consider that change clinically significant and recommends no dose adjustment [1]. Separately, the FDA's drug interaction table lists midazolam and triazolam as index CYP3A substrates, and itraconazole, ketoconazole and verapamil among in vitro CYP3A4/5 inhibitors [3]. The Avodart label does not mention midazolam or triazolam [1].

PSA is lowered by dutasteride

Dutasteride lowers serum PSA by approximately 50% within 3 to 6 months [1]. The label says:

• a new PSA baseline should be established at least 3 months after starting treatment [1];
• an isolated PSA value in a man treated for 3 months or more should be doubled for comparison with normal values in untreated men [1];
• any confirmed increase from the lowest on-treatment PSA may signal prostate cancer and should be evaluated, even if the value is still within the normal range for men not taking a 5-alpha reductase inhibitor [1];
• percent free PSA remains constant, and no adjustment to it appears necessary [1];
• tamsulosin taken with dutasteride changes PSA the same way dutasteride alone does, and noncompliance may also affect PSA results [1].

The label also warns that 5-alpha reductase inhibitors may increase the risk of high-grade prostate cancer [1]. In the 4-year REDUCE trial of men aged 50 to 75 with a prior negative biopsy and a PSA of 2.5 to 10 ng/mL, Gleason 8 to 10 cancer was found in 1.0% of men on Avodart and 0.5% on placebo [1]. The published results: cancer detected in 659 of 3,305 men on dutasteride versus 858 of 3,424 on placebo, a 22.8% relative reduction, with 12 Gleason 8 to 10 tumors in years 3 and 4 on dutasteride against 1 on placebo (P=0.003) [4].

How long dutasteride stays in the body

At steady state the terminal half-life is about 5 weeks, with roughly 65% of steady state reached after 1 month and about 90% after 3 months [1]. Serum concentrations above 0.1 ng/mL can persist for up to 4 to 6 months after the last dose [1]. The label's blood donation rule: men being treated with Avodart should not donate blood until at least 6 months have passed since the last dose, to prevent giving dutasteride to a pregnant transfusion recipient [1].

Other drugs the label covers

• Tamsulosin and terazosin: dutasteride does not change their steady-state pharmacokinetics; the effect of the alpha blockers on dutasteride has not been evaluated [1]. The combination dose for symptomatic BPH is dutasteride 0.5 mg and tamsulosin 0.4 mg once daily [1].
• Warfarin: three weeks of dutasteride 0.5 mg daily with warfarin did not alter the steady-state pharmacokinetics of either warfarin isomer or warfarin's effect on prothrombin time [1].
• Digoxin: dutasteride 0.5 mg daily for 3 weeks did not alter steady-state digoxin pharmacokinetics [1].
• Cholestyramine: a single 5 mg dutasteride dose followed an hour later by 12 g of cholestyramine did not affect dutasteride bioavailability [1].

The cardiac failure numbers in the label

In the 4-year CombAT trial, the composite term cardiac failure was reported in 0.7% (12/1,610) of men on dutasteride plus tamsulosin, 0.1% (2/1,623) on dutasteride alone and 0.6% (9/1,611) on tamsulosin alone; in REDUCE it was 0.6% (26/4,105) on dutasteride versus 0.4% (15/4,126) on placebo [1]. The label states that the clinical significance is unknown and that no causal relationship has been established [1]. These trials did not test dutasteride with anesthesia, so they do not show whether the finding relates to anesthesia.

Steroid levels in spinal fluid during prostate surgery

One small case-control study enrolled 40 men with BPH who were scheduled for transurethral resection of the prostate or open prostatectomy. Twenty men with a prostate volume of 40 mL or less took alpha-blockers, and 20 with a larger prostate took dutasteride plus alpha-blockers for at least 6 months before surgery [5]. Blood was drawn the day before surgery, and cerebrospinal fluid was collected during spinal anesthesia on the day of surgery [5].

CSF testosterone and DHT were higher and CSF estradiol was lower in the alpha-blocker-only group than in the dutasteride group: testosterone 1446.6 vs 19.9 pg/mL and DHT 7.9 vs 1.4 pg/mL (both P<0.05), estradiol 26.0 vs 36.0 pg/mL (P<0.01) [5]. The study measured steroid concentrations, not whether dutasteride changed the anesthesia or the amount needed [5]. The authors concluded that dutasteride is associated with lower neuroactive steroids in cerebrospinal fluid and that this may be one mechanism behind erectile dysfunction and low sexual desire [5].