Generic Name: Dutasteride
Class: 5-alpha-Reductase Inhibitors
VA Class: HS900
Chemical Name: 5α,17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide
Molecular Formula: C27H30F6N2O2
CAS Number: 164656-23-9

Introduction

Selective inhibitor of steroid 5α-reductase isoenzymes, which are necessary for conversion of testosterone to 5α-dihydrotestosterone (DHT).1 4 9 14

Uses for Avodart

Benign Prostatic Hyperplasia (BPH)

Treatment of symptomatic BPH1 to improve symptoms and reduce the risk of acute urinary retention and the need for surgery.1 3 12 14 Ineffective in patients who do not have evidence of prostatic enlargement.11

Used alone or in combination with tamsulosin.1 3 12 13 14 15 17 Combined therapy with a 5α-reductase inhibitor and an α1-blocker has been more effective than therapy with either drug alone in preventing long-term BPH symptom progression.7 11 12 16 17 Men at risk for BPH progression are most likely to benefit from combined therapy.11 16

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Steroid 5α-reductase inhibitors may be a useful alternative to surgery in patients with obstructive manifestations who are unwilling to undergo surgical correction of BPH;8 may aid those who may be at increased risk from, but not necessarily candidates for, prostate surgery.4 8 10 Also may be considered in patients who have symptomatic prostatic enlargement but whose symptoms are not bothersome (i.e., do not interfere with activities of daily living) in order to prevent progression of the disease.11

Although drug therapy usually is not as effective as surgical therapy, it may provide adequate symptomatic relief with fewer and less serious adverse effects compared with surgery.11

Avodart Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1 14

Swallow capsules whole; do not chew or open.1 14 Contact with the capsule contents may irritate oropharyngeal mucosa.1

Dosage

Adults

Benign Prostatic Hyperplasia
Oral

0.5 mg once daily, alone or in combination with tamsulosin.1 12 13 14 17

While early symptomatic improvement (e.g., within 3 months) may occur, ≥6 months of therapy may be necessary to determine clinical benefit.2 17 Generally, therapy is continued for life.9 10

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required.1 14

Geriatric Patients

Dosage adjustment not required.1 14

Cautions for Avodart

Contraindications

  • Known or suspected pregnancy.1 (See Fetal/Neonatal Morbidity and also Pregnancy under Cautions.)

  • Use in women of childbearing potential.1

  • Use in children.1

  • Known hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride, other 5α-reductase inhibitors, or any ingredient in the formulation.1

Warnings/Precautions

Fetal/Neonatal Morbidity

May cause fetal harm; teratogenicity demonstrated in animals.1 Animal studies indicate adverse effects on embryofetal development of male fetuses exposed to the drug during pregnancy (e.g., abnormalities of the external genitalia, decreased prostatic and seminal vesicular weights, distended preputial glands, nipple development).1

Because of the potential for absorption through the skin and the subsequent potential risk to a male fetus, pregnant women or women who may become pregnant should not handle the capsules.1 2 13 If contact is made with leaking capsules, wash the affected area immediately with soap and water.1 2

If used during pregnancy or if pregnancy occurs, apprise the pregnant woman of potential fetal hazard to the male fetus.1

Seminal drug concentrations not sufficient to warrant the use of condoms to prevent exposure to dutasteride.10

Blood Donation

To prevent potential fetal exposure, men receiving the drug should not donate blood during dutasteride therapy and for at least 6 months following discontinuance of the drug.1

Patient Assessment

Evaluate candidates for dutasteride therapy for other urologic conditions that might mimic BPH, such as infection,4 prostate 1 4 or bladder cancer,4 stricture disease,4 uncontrolled diabetes mellitus,4 neurogenic bladder,4 or CHF.4 7

Perform digital rectal examinations, as well as other screening tests for prostate cancer (e.g., serum prostate-specific antigen [PSA] concentration), before initiating therapy and periodically thereafter.1 7 8 18 (See Prostate-specific Antigen under Cautions and also see Specific Drugs and Laboratory Tests under Interactions.)

High-grade Prostate Cancer

5α-Reductase inhibitors may increase risk of development of high-grade prostate cancer.1 18

In 2 placebo-controlled trials evaluating dutasteride (0.5 mg daily for 4 years) or finasteride (5 mg daily for 7 years) for prevention of prostate cancer, overall occurrence of prostate cancer was reduced (due to reduction in lower-grade tumors) but incidence of high-grade tumors (Gleason score 8–10) was increased in men receiving dutasteride or finasteride.1 14 Not known whether detection bias (e.g., drug-induced reduction in prostate volume might have aided biopsy detection) or study-related factors influenced results.1 20 22

Not FDA labeled for prevention of prostate cancer.1 18

Prostate-specific Antigen

Decreases PSA concentrations; may interfere with interpretation of serum PSA determinations.1 7 14 17 (See Specific Drugs and Laboratory Tests under Interactions.) Concurrent use of tamsulosin does not substantially alter dutasteride’s effect on PSA concentrations.1 12 14 17

May decrease serum PSA concentrations in men with prostate cancer; however, clinical benefit has not been demonstrated in patients with prostate cancer treated with dutasteride.1

Carefully evaluate any confirmed increase in serum PSA concentration during therapy, even if PSA value is within normal range for men not receiving 5α-reductase inhibitor therapy.1 18

Noncompliance may affect PSA concentrations; consider when evaluating test results.1

Breast Neoplasia

Breast cancer reported in 2 patients (1 receiving dutasteride, 1 receiving placebo) in long-term clinical trials.1 Not known whether a causal relationship exists between long-term dutasteride use and breast neoplasia in men.1 18

Effects on Semen Characteristics

Reductions in sperm count, semen volume, and sperm motility reported;1 14 sperm concentration and morphology not altered.1 Clinical relevance not established.1

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and also Contraindications under Cautions.)

Lactation

Not known whether dutasteride is distributed into milk, but the drug is contraindicated in women of childbearing potential.1 10

Pediatric Use

Safety and efficacy not established, but the drug is contraindicated in children.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger men, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 14 Increased exposure to the drug is probable.1 14 Use with caution.14

Common Adverse Effects

Impotence, decreased libido, ejaculation disorder, breast disorders (tenderness, enlargement).1 14

Interactions for Avodart

Metabolized by CYP isoenzymes 3A4 and 3A5 to active metabolites; not metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of CYP3A4 and CYP3A5 (decreased clearance and increased serum concentrations of dutasteride).1 14 Use with caution in patients receiving chronic therapy with potent CYP3A4 inhibitors.1 14

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Amlodipine

Pharmacokinetic interaction unlikely1

Cholestyramine

Pharmacokinetic or pharmacodynamic interaction unlikely1 14

Cimetidine

Possible decreased clearance and increased serum concentrations of dutasteride1 14

Use concomitantly with care1 14

Ciprofloxacin

Possible decreased clearance and increased serum concentrations of dutasteride1 14

Use concomitantly with care1 14

Digoxin

Effect on digoxin pharmacokinetics unlikely1 14

Diltiazem

Decreased clearance and increased serum concentrations of dutasteride1 14

Not considered clinically important1 14

Ketoconazole

Possible decreased clearance and increased serum concentrations of dutasteride1 14

Use concomitantly with care1 14

Ritonavir

Possible decreased clearance and increased serum concentrations of dutasteride1 14

Use concomitantly with care1 14

Tamsulosin

Effect on tamsulosin pharmacokinetics unlikely1

Terazosin

Effect on terazosin pharmacokinetics unlikely1

Test for PSA

50% decrease in serum PSA concentration within 3–6 months of treatment1 3 6 9 10

No substantial change in ratio of free to total PSA (percentage of free PSA)1

Do not interpret decrease in PSA value as a therapeutic effect on prostate cancer1

Establish a new baseline PSA 3–6 months after initiation of treatment1 14

For clinical interpretation of isolated PSA values in men receiving dutasteride for ≥3 months, double the reported PSA value for comparison with normal values in men not receiving the drug1 3 14 17

No adjustment of reported value of ratio appears to be necessary1

Verapamil

Decreased clearance and increased serum concentrations of dutasteride1 14

Not considered clinically important1 14

Warfarin

Effect on warfarin pharmacokinetics or pharmacodynamics unlikely1 14

Avodart Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is approximately 60%.1

Onset

Reduces serum and prostatic 5α-dihydroxytestosterone (DHT) concentrations maximally within 1–2 weeks of initiation of therapy.1

Duration

Serum drug concentrations are detectable for up to 4–6 months following discontinuance of therapy.1

Food

Decreases peak serum concentrations.1 Not considered clinically important.1

Distribution

Extent

Widely distributed; volume of distribution is 300–500 L.1

Distributes into semen.1

Plasma Protein Binding

Highly bound to albumin (99%) and α-1 acid glycoprotein (96.6%).1

Elimination

Metabolism

Metabolized by CYP3A4 and CYP3A5 to active metabolites.1

Elimination Route

Excreted in the feces (45%) and urine (<1%) mainly as metabolites; approximately 55% remained unaccounted.1

Half-life

Terminal half-life is approximately 5 weeks at steady state.1

Special Populations

In patients with hepatic impairment, pharmacokinetics not studied.1 Metabolized extensively in the liver, and increased exposure to the drug is probable in hepatic impairment.1

In adolescents (<18 years of age), pharmacokinetics not studied.1

In patients with renal impairment, pharmacokinetics not studied; however, <0.1% of a dose is excreted in urine in healthy individuals.1

In women, pharmacokinetics not studied; use contraindicated.1

Effects of race on pharmacokinetics not studied.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Competitive inhibitor of both the type 1 and type 2 isoenzymes of steroid 5α-reductase.1 9 14 These enzymes convert testosterone to DHT.1 9

  • Reduces serum and prostatic DHT concentrations substantially.1 DHT appears to be the principal androgen responsible for initial development and subsequent enlargement of the prostate gland.1 9

  • Increases serum testosterone (generally remaining within the normal range) and prostatic testosterone concentrations.1 3 9

Advice to Patients

  • Importance of obtaining and reading patient information on dutasteride before initiation of therapy and with each new prescription refill.1

  • Importance of informing patients that dutasteride decreases serum PSA concentrations.1 Importance of appropriate medical evaluation of any increase in PSA concentration.1 If a PSA test is performed, importance of patient informing the clinician that he is taking a 5α-reductase inhibitor.1 21

  • Importance of informing patients that the incidence of high-grade prostate cancer was increased in men receiving 5α-reductase inhibitors (including dutasteride) in clinical trials evaluating efficacy of these drugs for prostate cancer prevention.1

  • Risk to male fetuses.1 Importance of advising patients that pregnant women or women who may become pregnant should not handle the drug; if such contact occurs, wash affected area immediately with soap and water and inform clinician.1 (See Pregnancy under Cautions.)

  • Importance of not donating blood during and for ≥6 months following discontinuance of dutasteride therapy.1

  • Advise patients that a decrease in the volume of ejaculate may occur but that this does not appear to interfere with normal sexual function.1

  • Advise patients of the small possibility of impotence and decreased libido.1 10

  • Importance of promptly informing clinician of any changes in breasts (e.g., lumps, pain, nipple discharge), since breast changes (enlargement, tenderness, neoplasm) have been reported.1

  • Advise patients of possibility of allergic reactions (e.g., rash, pruritus, urticaria, swelling of lips or face).1

  • Advise patients that ≥6 months of therapy may be required before improvement in BPH symptoms occurs.2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dutasteride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

0.5 mg

Avodart

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avodart 0.5MG Capsules (GLAXO SMITH KLINE): 30/$128.99 or 90/$354.97

Jalyn 0.5-0.4MG Capsules (GLAXO SMITH KLINE): 30/$129.00 or 90/$369.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules prescribing information. Research Triangle Park, NC; 2011 Jun.

2. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules patient information. Research Triangle Park, NC; Undated. Available from website. Accessed 2006 Aug 15.

3. Roehrborn CG, Boyle P, Nickel JC et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002 60:434-41.

4. Dull P, Reagan RW, Bahnson RR. Managing benign prostatic hyperplasia. Am Fam Physician. 2002; 66:77-84, 87-8. [IDIS 483339] [PubMed 12126034]

5. Roehrborn CG, McConnell JD, Lieber M et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retenion and need for surgery in men with clinical benign prostatic hyperplasia. PLESS study group. Urology. 1999; 53:473-80. [PubMed 10096369]

6. Potts JM. Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol. 2000; 164:1550-3. [IDIS 455479] [PubMed 11025702]

7. de la Rossette JJ, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol. 2001; 40:256-63. [PubMed 11684840]

8. Agency for Health Care Policy and Research. Benign prostatic hyperplasia: diagnosis and treatment. J Am Geriatric Soc. 1998; 46:1163-5.

9. Anon. Dutasteride (avodart) for benign prostatic hyperplasia. Med Lett Drugs Ther. 2002; 44:109-10. [PubMed 12500154]

10. GlaxoSmithKline. Research Triangle Park, NC: Personal communication.

11. American Urological Association. Guideline on the management of benign prostatic hyperplasia (BPH) (2003/updated 2006). Available at AUA website. Accessed 2009 Feb 6 .

12. Roehrborn CG, Siami P, Barkin J et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008; 179:616-21; discussion 621. [PubMed 18082216]

13. Anon. Dutasteride (Avodart) with tamsulosin (Flomax) for benign prostatic hyperplasia. Med Lett Drugs Ther. 2008; 50:79-80. [PubMed 18833033]

14. Keam SJ, Scott LJ. Dutasteride: a review of its use in the management of prostate disorders. Drugs. 2008; 68:463-85. [PubMed 18318566]

15. Siami P, Roehrborn CG, Barkin J et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials. 2007; 28:770-9. [PubMed 17761460]

16. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003; 349:2387-98. [IDIS 508413] [PubMed 14681504]

17. Barkin J, Guimaráes M, Jacobi G et al. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur Urol. 2003; 44:461-6. [PubMed 14499682]

18. Food and Drug Administration. FDA drug safety communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer. Rockville, MD; 2011 Jun 9. From FDA website.

19. Roehrborn CG, Siami P, Barkin J 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; 57:123-31. [PubMed 19825505]

20. Andriole GL, Bostwick DG, Brawley ON et al. Effect of dutasteride on the risk of prostate cancer. N Enlg J Med. 2010; 362:1192-202.

21. Merck & Co., Inc. Patient information about Proscar (finasteride). Whitehouse Station, NJ; 2011 Jun.

22. Theoret MR, Ning YM, Zhang JJ et al. The risks and benefits of 5α-reductase inhibitors for prostate-cancer prevention. N Engl J Med. 2011; 365:97-9. [PubMed 21675880]

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