Avodart (Dutasteride) Geriatric Caregiver Administration Guide for Adults 65 and Older

What Avodart does, and who it is for

Dutasteride is a 5-alpha-reductase inhibitor approved for symptomatic BPH in men with an enlarged prostate, to improve symptoms and reduce the risk of acute urinary retention and of BPH-related surgery; it is also approved in combination with the alpha blocker tamsulosin [1]. It inhibits both type 1 and type 2 5-alpha-reductase, the enzymes that convert testosterone to dihydrotestosterone (DHT), and it does not bind the androgen receptor [1].

The DHT effect is large and fast. Median serum DHT fell 85% after 1 week and 90% after 2 weeks on 0.5 mg daily, was 94% below baseline at 1 year, and stayed at 93% to 95% through years 2 to 4; median testosterone rose about 19% to 26% but remained within the physiologic range [1].

Avodart is not approved for the prevention of prostate cancer, and hair-loss use is off-label in the US [1].

Who was actually studied

In the pooled 2-year BPH trials, 2,167 men received Avodart and 2,158 received placebo; participants were aged 47 to 94, with a mean age of 66 [1]. CombAT randomized 4,844 men aged 50 or older to dutasteride, tamsulosin, or both for 4 years [2]; the Avodart label gives its age range as 49 to 88, also with a mean age of 66 [1].

The daily dose a caregiver gives

One 0.5 mg soft gelatin capsule once daily, swallowed whole and not chewed or opened, with or without food [1]. With tamsulosin, the regimen is dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily [1].

The basics from the label's pharmacology section: peak serum level about 2 to 3 hours after a dose, food lowers that peak by 10% to 15% (not clinically significant), and the terminal half-life at steady state is about 5 weeks, with 65% of steady state reached after 1 month and about 90% after 3 months [1].

Is there a different dose for men over 65?

The dosing section of the Avodart label gives 0.5 mg once daily alone, or 0.5 mg with tamsulosin 0.4 mg, and lists no separate dose for older men [1].

If a dose is missed

The Avodart label's dosing section gives one capsule daily and no instruction for a missed dose [1]. The label does note that noncompliance with Avodart may affect PSA test results [1].

Handling the capsule

The Avodart label says capsules should be swallowed whole, not chewed or opened, because contact with the contents may irritate the oropharyngeal mucosa [1].

Separately, women who are pregnant or may be pregnant should not handle Avodart capsules: dutasteride can be absorbed through the skin, and if a pregnant woman comes into contact with a leaking capsule, the area should be washed immediately with soap and water [1]. Dutasteride use is contraindicated in pregnancy because animal reproduction studies showed inhibited development of the external genitalia of male offspring [1]. Prior clinically significant hypersensitivity to Avodart or another 5-alpha-reductase inhibitor, such as serious skin reactions or angioedema, is the other contraindication [1].

Dutasteride is present in semen. The highest measured semen concentration in treated men was 14 ng/mL; the label calculates that a 50-kg woman exposed to 5 mL of semen with 100% absorption would reach about 0.0175 ng/mL, roughly 100 times less than the blood concentrations that produced male genital abnormalities in animal studies, and dutasteride is more than 96% protein bound in semen [1].

Blood donation has its own rule: men being treated with Avodart should not donate blood until at least 6 months after the last dose, to prevent giving dutasteride to a pregnant transfusion recipient [1]. Serum levels stay detectable for up to 4 to 6 months after the last capsule [1].

PSA after dutasteride

Dutasteride reduces serum PSA by about 50% within 3 to 6 months of treatment, predictably across the PSA range in men with symptomatic BPH, although the size of the drop varies between individuals; it can also lower PSA when prostate cancer is present [1].

The prescribing information recommends establishing a new PSA baseline at least 3 months after starting, monitoring PSA periodically, evaluating any confirmed rise from the lowest on-treatment value, and doubling an isolated value after 3 months or more of treatment when comparing it with untreated reference ranges [1]. Percent free PSA is unaffected, and tamsulosin co-administration changes PSA the same way as dutasteride alone [1].

A 2006 review in The Journal of Urology proposed a different yardstick: a rise from nadir of 0.3 ng/mL or more, which maintained 71% sensitivity and 60% specificity for prostate cancer in men taking dutasteride, similar to the 4.0 ng/mL cutoff used in untreated men [3].

Side effects to watch for

In the pooled 2-year BPH trials, months 0 to 6, the label reports impotence in 4.7% on Avodart vs 1.7% on placebo, decreased libido 3.0% vs 1.4%, ejaculation disorders 1.4% vs 0.5%, and breast disorders (enlargement or tenderness) 0.5% vs 0.2% [1]. Rates fell after the first 6 months except breast disorders, which were 1.1% vs 0.3% at months 13 to 18 [1]. The label notes these sexual reactions may persist after discontinuation and that the role of dutasteride in that persistence is unknown [1].

With combination therapy in CombAT, months 0 to 6: ejaculation disorders 7.8% on combination vs 1.0% on dutasteride vs 2.2% on tamsulosin; impotence 5.4%, 4.0% and 2.6%; decreased libido 4.5%, 3.1% and 2.0%; dizziness 1.1%, 0.5% and 0.9% [1]. Withdrawal for adverse reactions was 6% on combination and 4% on either monotherapy, most often for erectile dysfunction [1].

Postmarketing reports in the Avodart label include hypersensitivity (rash, itching, hives, localized edema, serious skin reactions, angioedema), male breast cancer, depressed mood, and testicular pain and swelling [1]. A Swedish register cohort of 2,236,876 men aged 50 to 90 found dutasteride starters (8,774 men) had a depression hazard ratio of 1.68 (95% CI 1.43 to 1.96) with no association with suicide (HR 0.98, 95% CI 0.62 to 1.54); the study was observational [4].

On prostate cancer, in REDUCE Gleason 8 to 10 tumors occurred in 1.0% of men on Avodart vs 0.5% on placebo, and the label states that 5-alpha-reductase inhibitors may increase the risk of high-grade prostate cancer [1]. Among 6,729 men who underwent biopsy or prostate surgery, cancer was detected in 659 of 3,305 men taking dutasteride and 858 of 3,424 taking placebo, a 22.8% relative risk reduction over 4 years [5]. For cardiac failure, the REDUCE composite was 0.6% (26/4,105) on dutasteride vs 0.4% (15/4,126) on placebo; the label says the clinical significance is unknown and no causal relationship has been established [1].

Interactions to flag

• Potent, chronic CYP3A4 inhibitors such as ritonavir: the effect of potent CYP3A4 inhibitors on dutasteride has not been studied, and the label says to use caution [1].
• Verapamil and diltiazem: they decrease dutasteride clearance and raise exposure, a change the label does not consider clinically significant; no dose adjustment is recommended [1].
• Tamsulosin and terazosin: dutasteride does not affect their steady-state pharmacokinetics; the effect of these alpha blockers on dutasteride has not been evaluated [1].
• Digoxin and warfarin: no change in digoxin pharmacokinetics, and no change in R- or S-warfarin pharmacokinetics or in warfarin's effect on prothrombin time [1].
• Cholestyramine: a single 5-mg Avodart dose followed 1 hour later by 12 g of cholestyramine did not affect dutasteride bioavailability [1].