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
Brands: Avodart

Special Alerts:

[Posted 06/09/2011] ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).

BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Finasteride (Proscar), dutasteride (Avodart), and dutasteride in combination with tamsulosin (marketed combination product as Jalyn) are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Finasteride (Propecia) is approved to treat male pattern hair loss.

RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information. For more information visit the FDA website at: and .

Introduction

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

Uses for Dutasteride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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} Ineffective in patients who do not have evidence of prostatic enlargement.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

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

May consider combined therapy with an α₁-adrenergic blocker and 5α-reductase inhibitor for men with bothersome moderate to severe BPH and demonstrable prostatic enlargement.¹¹ Has been more effective than therapy with either drug alone in preventing long-term BPH symptom progression.¹¹ Men at risk for BPH progression are most likely to benefit from combination therapy.¹¹

Dutasteride Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.¹

The capsules should be swallowed whole.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adults

Benign Prostatic Hyperplasia

Oral

Initially and for maintenance therapy, 0.5 mg once daily.¹

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

Special Populations

Hepatic Impairment

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

Renal Impairment

Dosage adjustment not required.¹

Geriatric Patients

Dosage adjustment not required.¹

Cautions for Dutasteride

Contraindications

• 
  

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

  
  


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  Use in women or children.¹

  
  


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  Known hypersensitivity to dutasteride, other 5α-reductase inhibitors, or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

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}

If contact is made with leaking capsules, wash the affected area immediately with soap and water.^{1 2}

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

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

General Precautions

Patient Assessment

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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, before initiating therapy and periodically thereafter.^{1 7 8}

Monitor patients with a large residual urinary volume and/or severely diminished urinary flow carefully for obstructive uropathy.^{4 7} Such patients may not be candidates for dutasteride therapy,¹ and may require surgery.^{4 7}

Prostate-specific Antigen (PSA)

Decreases PSA concentrations; may interfere with interpretation of serum PSA determinations.¹ (See Specific Drugs and Laboratory Tests under Interactions.)

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 use of the drug is contraindicated in women.^{1 10}

Pediatric Use

Safety and efficacy not established, but the drug is not indicated for use in children.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger men.¹

Hepatic Impairment

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

Common Adverse Effects

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

Interactions for Dutasteride

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 (decreased clearance and increased serum concentrations of dutasteride).¹

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Amlodipine	Pharmacokinetic interaction unlikely1
Cholestyramine	Pharmacokinetic or pharmacodynamic interaction unlikely1
Cimetidine	Decreased clearance and increased serum concentrations of dutasteride1	Use concomitantly with care
Ciprofloxacin	Decreased clearance and increased serum concentrations of dutasteride1	Use concomitantly with care1
Digoxin	Pharmacokinetic or pharmacodynamic interaction unlikely1
Diltiazem	Decreased clearance and increased serum concentrations of dutasteride1	Not considered clinically important1
Ketoconazole	Decreased clearance and increased serum concentrations of dutasteride1	Use concomitantly with care1
Ritonavir	Decreased clearance and increased serum concentrations of dutasteride1
Tamsulosin	Pharmacokinetic or pharmacodynamic interaction unlikely1
Terazosin	Pharmacokinetic or pharmacodynamic interaction unlikely1
Test for PSA	50% decrease in serum PSA concentration after ≥6 months of treatment1 3 6 9 10 No substantial change in ratio of free to total PSA (percentage of free PSA)1	Establish a new baseline PSA 3–6 months after initiation of treatment1 For clinical interpretation of isolated PSA values in men receiving dutasteride for ≥6 months, double the reported value for PSA for comparison with normal values in men not receiving the drug1 3 No adjustment of reported value of ratio appears to be necessary1
Troleandomycin	Decreased clearance and increased serum concentrations of dutasteride1
Verapamil	Decreased clearance and increased serum concentrations of dutasteride1	Not considered clinically important1
Warfarin	Pharmacokinetic or pharmacodynamic interaction unlikely1

Dutasteride 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

ActionsActions

• 
  

  Competitive inhibitor of both the type 1 and type 2 isoenzymes of steroid 5α-reductase.^{1 9} 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}

  
  


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

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

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

  
  


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  Importance of advising pregnant women or women who may become pregnant to avoid handling the drug.¹ (See Pregnancy under Cautions.)

  
  


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  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}

  
  


• 
  

  Advise patients of possibility of developing enlarged or tender breasts.¹

  
  


• 
  

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

  
  


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

  
  


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

  
  


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  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 07/2011. 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/$129.98 or 90/$354.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 09, 2011. 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; 2005 May.

2. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules patient information. Research Triangle Park, NC; Undated. Available at: . 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: . Accessed 2006 Aug 10.

More Dutasteride resources

• Dutasteride Side Effects (in more detail)
• Dutasteride Dosage
• Dutasteride Use in Pregnancy & Breastfeeding
• Dutasteride Drug Interactions
• Dutasteride Support Group
• 14 Reviews for Dutasteride - Add your own review/rating

• Dutasteride MedFacts Consumer Leaflet (Wolters Kluwer)


• Dutasteride Professional Patient Advice (Wolters Kluwer)


• dutasteride Advanced Consumer (Micromedex) - Includes Dosage Information


• Avodart Prescribing Information (FDA)


• Avodart Consumer Overview

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