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Special Alerts
Five Alpha-Reductase Inhibitors (5-ARI): Increased Incidence of High-Grade Prostate Cancers
June 2011
The U.S. Food and Drug Administration (FDA) has notified healthcare providers about new safety information regarding the increased risk of being diagnosed with a more aggressive prostate cancer in patients taking 5-ARIs (eg, dutasteride, finasteride, and combinations containing a 5-ARI). Two large trials (Kaplan, 2009; Andriole, 2010) evaluated finasteride and dutasteride, respectively, in prostate cancer prevention. Results of both trials suggested that although the overall risk of being diagnosed with prostate cancer was low, the risk of a more aggressive prostate cancer diagnosis (Gleason Score [GS] 8-10) was increased. In the finasteride trial the incidence of GS 8-10 prostate cancer was 1.8% in the active treatment group versus 1.1% in the placebo group. Similarly in the dutasteride trial the risk of GS 8-10 prostate cancer diagnosis was higher in the active treatment group compared to placebo (0.9 % vs 0.6%). Although neither study demonstrated a statistical increase in risk, there was a trend that requires further evaluation.
The FDA is making the following suggestions for clinicians:
- Prior to initiating therapy with a 5-ARI, evaluate and rule out other urological etiologies including prostate cancer.
- 5-ARIs may reduce prostate-specific antigen (PSA) values by 50% within 6 months of initiation, although individual patients may experience varying decreases.
- Any confirmed increase in PSA in a patient maintained on a 5-ARI may be suggestive of prostate cancer and should be evaluated even if the PSA is within the normal range.
- 5-ARIs are not FDA-approved for prevention of prostate cancer .
For additional information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm.
Pronunciation
(doo TAS teer ide)
Generic Available (U.S.)
No
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Treatment of symptomatic benign prostatic hyperplasia (BPH) as monotherapy or combination therapy with tamsulosin
Use: Unlabeled
Treatment of male pattern baldness
Pregnancy Risk Factor
X
Pregnancy Considerations
Preclinical data (animal studies) suggests that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs and lead to feminization of a male fetus carried by a woman exposed to dutasteride. Pregnant woman and those who may become pregnant should not handle the capsules because dutasteride is absorbed through the skin. It is distributed into the semen.
Lactation
Excretion in breast milk unknown/contraindicated in women of childbearing potential
Contraindications
Hypersensitivity to dutasteride, other 5α-reductase inhibitors (eg, finasteride), or any component of the formulation; children; women of childbearing potential; pregnancy
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
• Women/pregnancy: Active ingredient can be absorbed through the skin; women should always use caution whenever handling. Pregnant women or women trying to conceive should not handle the product; if contact with a leaking capsule occurs, wash area immediately with soap and water; dutasteride may negatively impact fetal development.
Disease-related concerns:
• Diminished urinary flow: Carefully monitor patients with a large residual urinary volume or severely diminished urinary flow for obstructive uropathy; these patients may not be candidates for dutasteride therapy.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Prostate cancer: When compared to placebo, 5-alpha-reductase inhibitors (5-ARIs) have been shown to reduce the overall incidence of prostate cancer, although an increase in the incidence of high-grade prostate cancers has been observed; 5-ARIs are not approved in the U.S. or Canada for the prevention of prostate cancer.
Concurrent drug therapy issues:
• CYP3A4 inhibitors: Use with caution with concurrent use of potent, chronic CYP3A4 inhibitors.
Other warnings/precautions:
• Appropriate use: Other urological diseases, including prostate cancer, should be ruled out before initiating therapy.
• Blood donation: Avoid donating blood during or for 6 months following treatment cessation due to risk of administration to a pregnant female transfusion recipient.
• PSA monitoring: Reduces prostate specific antigen (PSA) by ~50% within 3-6 months of use. If following serial PSAs, re-establish a new baseline ≥3 months after treatment initiation; monitor PSA periodically thereafter. If interpreting an isolated PSA value in a patient treated for ≥3 months, then double the PSA value for comparison to a normal PSA value in an untreated man. Failure to demonstrate a meaningful PSA decrease (<50%) or a PSA increase while on this medication may be associated with an increased risk for prostate cancer (NCCN Prostate Cancer Early Detection Guidelines, v.1.2011). Patients on a 5-ARI with any increase in PSA levels, even if within normal limits, should be evaluated; may indicate presence of prostate cancer.
Adverse Reactions
1% to 10%: Endocrine & metabolic: Impotence (1% to 5%), libido decreased (≤3%), ejaculation disorders (≤1%), gynecomastia (including breast tenderness, breast enlargement; ≤1%)
<1%, postmarketing, and/or case reports: Angioedema, dizziness, cardiac failure, edema (localized), hypersensitivity, prostate cancer (high-grade), pruritus, rash, skin reactions (serious), TSH increased, urticaria
Note: Frequency of adverse events (except gynecomastia) tends to decrease with continued use (>6 months).
Metabolism/Transport Effects
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dutasteride. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: No effect or interaction noted.
Food: Maximum serum concentrations reduced by 10% to 15% when taken with food; not clinically significant.
Herb/Nutraceutical: St John's wort may decrease dutasteride levels. Avoid saw palmetto (concurrent use has not been adequately studied).
Storage
Store at controlled room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Dutasteride is a 4-azo analog of testosterone and is a competitive, selective inhibitor of both reproductive tissues (type 2) and skin and hepatic (type 1) 5α-reductase. This results in inhibition of the conversion of testosterone to dihydrotestosterone and markedly suppresses serum dihydrotestosterone levels.
Pharmacodynamics/Kinetics
Absorption: Absorbed via skin when handling capsules
Distribution: Vd: 300-500 L, ~12% of serum concentrations partitioned into semen
Protein binding: 99% to albumin; ~97% to α1-acid glycoprotein; >96% to semen protein
Metabolism: Hepatic via CYP3A4 isoenzyme; forms metabolites: 6-hydroxydutasteride has activity similar to parent compound, 4′-hydroxydutasteride and 1,2-dihydrodutasteride are much less potent than parent in vitro
Bioavailability: ~60% (range: 40% to 94%)
Half-life elimination: Terminal: ~5 weeks
Time to peak: 2-3 hours
Excretion: Feces (40% as metabolites, ~5% as unchanged drug); urine (<1% as unchanged drug); ~55% of dose unaccounted for
Dosage
Oral: Adults: Males: BPH: 0.5 mg once daily alone or in combination with tamsulosin
Dosage adjustment in renal impairment: No adjustment required
Dosage adjustment in hepatic impairment: Use caution; no specific adjustments recommended
Administration: Oral
May be administered without regard to meals. Capsule should be swallowed whole; do not chew or open; contact with opened capsule can cause oropharyngeal irritation. Should not be touched or handled by women who are pregnant or are of childbearing age.
Monitoring Parameters
Objective and subjective signs of relief of benign prostatic hyperplasia, including improvement in urinary flow, reduction in symptoms of urgency, and relief of difficulty in micturition; for serial PSA monitoring, establish a new baseline PSA level after 3 months of therapy and monitor PSA periodically thereafter.
Test Interactions
PSA levels decrease in treated patients. After 3 months of therapy, PSA levels stabilize to a new baseline that is ~50% of pretreatment values. If following serial PSAs in a patient, re-establish a new baseline after ≥3 months of use. If interpreting an isolated PSA value in a patient treated for ≥3 months, then double the PSA value for comparison.
Dietary Considerations
May be taken without regard to meals.
Geriatric Considerations
No dosage adjustment necessary.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
Nefazodone may increase dutasteride levels
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, softgel, oral:
Avodart®: 0.5 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Avodart)
0.5 mg (30): $128.99
References
Andriole G, Bostwick D, Brawley O, et al, “Chemoprevention of Prostate Cancer in Men at High Risk: Rationale and Design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial,” J Urol, 2004, 172(4 Pt 1):1314-7.
Andriole G, Bostwick DG, Brawley OW, et al, “Effect of Dutasteride on the Risk of Prostate Cancer,” N Engl J Med, 2010, 362(13):1192-202.
Andriole G, Roehrborn C, Schulman C, et al, “Effect of Dutasteride on the Detection of Prostate Cancer in Men With Benign Prostatic Hyperplasia,” Urology, 2004, 64(3):537-41.
Kramer BS, Hagerty KL, Justman S, et al, “Use of 5-α-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline,” J Clin Oncol, 2009, 27(9):1502-16.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Prostate Cancer Early Detection,” Version 1.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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