http://www.fda.gov/Drugs/DrugSafety/ucm258314.htm
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FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer
Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
References
Safety Announcement
[6-9-2011] The U.S. Food and Drug Administration (FDA) is informing 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). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.
Facts about 5-ARIs
Drugs in this class are finasteride (marketed as Proscar [finasteride 5 mg] and Propecia [finasteride 1 mg]) and dutasteride (marketed as Avodart). Dutasteride is also available in combination with tamsulosin, under the brand-name Jalyn.
Proscar, Avodart, and 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.
Propecia is approved to treat male pattern hair loss.
Approximately 5 million male patients received a prescription for a 5-ARI between years 2002 to 2009. Of these, nearly 3 million patients were between the ages of 50 to 79 years.1
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––which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment (see Data Summary below). This overall reduction was due to a decreased incidence of lower risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment.
For more information about this safety issue, also refer to the Questions and Answers.
Additional Information for Patients
Drugs in the 5-ARI class are finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn.
Finasteride is available in two different strengths: Proscar 5 mg tablets and Propecia 1 mg tablets.
Discuss any questions or concerns about 5-ARIs with your healthcare professional.
Report any side effects you experience to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
Additional Information for Healthcare Professionals
Be aware that 5-ARIs may increase the risk of high-grade prostate cancer.
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).
Be aware that treatment with 5-ARIs causes an approximate 50% reduction in prostate-specific antigen (PSA) values by 6 months; however, individual patients receiving 5-ARIs may experience varying decreases in PSA values. Therefore, any confirmed increase in PSA while on a 5-ARI may signal the presence of prostate cancer and should be evaluated, even if that PSA is in the normal range of men not taking a 5-ARI.
Know that 5-ARIs are not approved for the prevention of prostate cancer.
Report any adverse events involving 5-ARIs to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
Data Summary
The PCPT was a randomized, double-blind, placebo-controlled, multicenter trial in 18,882 men age 55 or older with a normal digital rectal examination and PSA levels ≤ 3 ng/mL. Men at higher risk for developing prostate cancer, such as those men with prior prostate biopsies demonstrating high-grade prostatic intraepithelial neoplasia, were excluded from the study. The trial compared the use of finasteride 5 mg (n=9423) to placebo (n=9459) for the reduction in the risk of prostate cancer. Treatment was continued for seven years following randomization or until diagnosis of prostate cancer, initiation of treatment for BPH with a 5-ARI, or unacceptable side effects. The study protocol specified that transrectal ultrasound and sextant prostate biopsy were to be performed for an elevation in PSA level or an abnormal digital rectal examination during the study. All participants who were not previously diagnosed with prostate cancer were to undergo transrectal ultrasound and sextant core prostate biopsy after completing 7 years on study.
The results of the PCPT showed that men on the finasteride arm had a 26% overall lower risk of being diagnosed with prostate cancer when compared to the placebo arm (p<0.0001). The reduction in risk of prostate cancer was limited to Gleason score (GS) 6 or lower prostate cancers. However, there was an increased incidence of GS 8-10 prostate cancers with finasteride versus placebo (1.8% versus 1.1%, respectively).
The REDUCE trial was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of once daily dosing of dutasteride in reducing the risk of biopsy-detectable prostate cancer in men 50-75 years of age considered to be at increased risk for prostate cancer. The trial allocated 8231 men to receive either placebo (n=4126) or dutasteride 0.5 mg (n=4105) once daily for a total of four years. Prostate biopsies were performed at 2 years and 4 years. Unscheduled biopsies in addition to the protocol-mandated Year 2 or 4 biopsies were allowed if clinically indicated at the discretion of the investigator, but were discouraged.
The results of the REDUCE trial showed that men on dutasteride had a 23% overall lower risk of being diagnosed with biopsy detectable prostate cancer when compared to men on placebo (p<0.0001). This overall risk reduction was limited to a decrease in GS 6 or lower prostate cancers. In contrast, there was an increased incidence of GS 8-10 cancers with dutasteride versus placebo (1% versus 0.5%, respectively).
Data from the PCPT and REDUCE trials were discussed at the FDA’s Oncologic Drugs Advisory Committee, held on December 1, 2010 (for complete safety reviews and background information discussed at this meeting see: December 1, 2010 AC meeting).
References
1. SDI, Vector One®: Total Patient Tracker (TPT). Years 2002-2009. Data extracted 5-24-11.
-
Related Information
Questions and Answers: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer
6/9/2011
December 1, 2010: Oncologic Drugs Advisory Committee Meeting Announcement
5-Alpha Reductase Inhibitor Information
-
Contact Us
Report a Serious Problem
1-800-332-1088
1-800-FDA-0178 Fax
MedWatch Online
Regular Mail: Use postage-paid FDA Form 3500
Mail to: MedWatch 5600 Fishers Lane
Rockville, MD 20857
Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
References
Safety Announcement
[6-9-2011] The U.S. Food and Drug Administration (FDA) is informing 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). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.
Facts about 5-ARIs
Drugs in this class are finasteride (marketed as Proscar [finasteride 5 mg] and Propecia [finasteride 1 mg]) and dutasteride (marketed as Avodart). Dutasteride is also available in combination with tamsulosin, under the brand-name Jalyn.
Proscar, Avodart, and 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.
Propecia is approved to treat male pattern hair loss.
Approximately 5 million male patients received a prescription for a 5-ARI between years 2002 to 2009. Of these, nearly 3 million patients were between the ages of 50 to 79 years.1
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––which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment (see Data Summary below). This overall reduction was due to a decreased incidence of lower risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment.
For more information about this safety issue, also refer to the Questions and Answers.
Additional Information for Patients
Drugs in the 5-ARI class are finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn.
Finasteride is available in two different strengths: Proscar 5 mg tablets and Propecia 1 mg tablets.
Discuss any questions or concerns about 5-ARIs with your healthcare professional.
Report any side effects you experience to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
Additional Information for Healthcare Professionals
Be aware that 5-ARIs may increase the risk of high-grade prostate cancer.
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).
Be aware that treatment with 5-ARIs causes an approximate 50% reduction in prostate-specific antigen (PSA) values by 6 months; however, individual patients receiving 5-ARIs may experience varying decreases in PSA values. Therefore, any confirmed increase in PSA while on a 5-ARI may signal the presence of prostate cancer and should be evaluated, even if that PSA is in the normal range of men not taking a 5-ARI.
Know that 5-ARIs are not approved for the prevention of prostate cancer.
Report any adverse events involving 5-ARIs to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
Data Summary
The PCPT was a randomized, double-blind, placebo-controlled, multicenter trial in 18,882 men age 55 or older with a normal digital rectal examination and PSA levels ≤ 3 ng/mL. Men at higher risk for developing prostate cancer, such as those men with prior prostate biopsies demonstrating high-grade prostatic intraepithelial neoplasia, were excluded from the study. The trial compared the use of finasteride 5 mg (n=9423) to placebo (n=9459) for the reduction in the risk of prostate cancer. Treatment was continued for seven years following randomization or until diagnosis of prostate cancer, initiation of treatment for BPH with a 5-ARI, or unacceptable side effects. The study protocol specified that transrectal ultrasound and sextant prostate biopsy were to be performed for an elevation in PSA level or an abnormal digital rectal examination during the study. All participants who were not previously diagnosed with prostate cancer were to undergo transrectal ultrasound and sextant core prostate biopsy after completing 7 years on study.
The results of the PCPT showed that men on the finasteride arm had a 26% overall lower risk of being diagnosed with prostate cancer when compared to the placebo arm (p<0.0001). The reduction in risk of prostate cancer was limited to Gleason score (GS) 6 or lower prostate cancers. However, there was an increased incidence of GS 8-10 prostate cancers with finasteride versus placebo (1.8% versus 1.1%, respectively).
The REDUCE trial was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of once daily dosing of dutasteride in reducing the risk of biopsy-detectable prostate cancer in men 50-75 years of age considered to be at increased risk for prostate cancer. The trial allocated 8231 men to receive either placebo (n=4126) or dutasteride 0.5 mg (n=4105) once daily for a total of four years. Prostate biopsies were performed at 2 years and 4 years. Unscheduled biopsies in addition to the protocol-mandated Year 2 or 4 biopsies were allowed if clinically indicated at the discretion of the investigator, but were discouraged.
The results of the REDUCE trial showed that men on dutasteride had a 23% overall lower risk of being diagnosed with biopsy detectable prostate cancer when compared to men on placebo (p<0.0001). This overall risk reduction was limited to a decrease in GS 6 or lower prostate cancers. In contrast, there was an increased incidence of GS 8-10 cancers with dutasteride versus placebo (1% versus 0.5%, respectively).
Data from the PCPT and REDUCE trials were discussed at the FDA’s Oncologic Drugs Advisory Committee, held on December 1, 2010 (for complete safety reviews and background information discussed at this meeting see: December 1, 2010 AC meeting).
References
1. SDI, Vector One®: Total Patient Tracker (TPT). Years 2002-2009. Data extracted 5-24-11.
-
Related Information
Questions and Answers: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer
6/9/2011
December 1, 2010: Oncologic Drugs Advisory Committee Meeting Announcement
5-Alpha Reductase Inhibitor Information
-
Contact Us
Report a Serious Problem
1-800-332-1088
1-800-FDA-0178 Fax
MedWatch Online
Regular Mail: Use postage-paid FDA Form 3500
Mail to: MedWatch 5600 Fishers Lane
Rockville, MD 20857
0
Comments
-
Good Post, but.....
I think these cautious notes from FDA are proper to alert the so many millions of patients taking the drugs. However, I am not so sure if it is correct to declare that these drugs (Finasteride and Dutasteride) can BE the CAUSE behind any increase of cancer grade (ex; grade 3 turn into grade 5). In fact, FDA recognises that these drugs are effective in the control of lower PCa grades (Gr
).
What I got from the so many studies on these 5-alfa reductase inhibitors is that they provide a “clue” to guys on Active Surveillance that cancer activity is PRESENT when PSA shows even a slight increase. The logic is that the antigen serum under the influence of the drug, is supposed to be related to cancer alone. Benign PSA should not increase (keep a flat level) due to the effectiveness of the drug.
This also can theoretically explain that guys taking the drug (5-ARI) continuously get a Gleason score with higher grades because the lower ones have been “supressed” to a certain extent. This could be taken as the reason for FDA’s alert comment in the probability of a patient;
“…being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer)…”
then the real one. Initial Gleasons 8 to 10 therefore would not alter.
A well-known PCa survivor (Jim) in his twelve years on ADT3 (as a solo treatment) reports taking finasteride since 2000 and relates his success to this drug. He is very educated in matters related to prostate cancer. You can read his comment on the FDA’s affair at this site;
http://www.healthboards.com/boards/showthread.php?t=854993
VGama0 -
more informationVascodaGama said:Good Post, but.....
I think these cautious notes from FDA are proper to alert the so many millions of patients taking the drugs. However, I am not so sure if it is correct to declare that these drugs (Finasteride and Dutasteride) can BE the CAUSE behind any increase of cancer grade (ex; grade 3 turn into grade 5). In fact, FDA recognises that these drugs are effective in the control of lower PCa grades (Gr).
What I got from the so many studies on these 5-alfa reductase inhibitors is that they provide a “clue” to guys on Active Surveillance that cancer activity is PRESENT when PSA shows even a slight increase. The logic is that the antigen serum under the influence of the drug, is supposed to be related to cancer alone. Benign PSA should not increase (keep a flat level) due to the effectiveness of the drug.
This also can theoretically explain that guys taking the drug (5-ARI) continuously get a Gleason score with higher grades because the lower ones have been “supressed” to a certain extent. This could be taken as the reason for FDA’s alert comment in the probability of a patient;
“…being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer)…”
then the real one. Initial Gleasons 8 to 10 therefore would not alter.
A well-known PCa survivor (Jim) in his twelve years on ADT3 (as a solo treatment) reports taking finasteride since 2000 and relates his success to this drug. He is very educated in matters related to prostate cancer. You can read his comment on the FDA’s affair at this site;
http://www.healthboards.com/boards/showthread.php?t=854993
VGama</p>
Avodart linked to increased heart failure risk.
http://www.oregonlive.com/health/index.ssf/2010/03/prostate_drug_avodart_linked_t.html0 -
5 alpha R inhibitor (Avodart)
This warning is from a confusion of relationship with causation. Men with prostate hyperplasia (enlarged prostate) take Avodart to reduce the prostate and aid in voiding for urination and continence. These men are very likely to be under the care of a urolgist. Since Avodart is known to reduce the natural psa of such men as a result of its action, psa standards are not the same for such men. In all cases, these men are much, much more likely to have a biopsy of the prostate than men in the general population. Since their prostate has been shrunk as a result of the Avodart any biopsy will be more likely to encounter suspect tissues than without the Avodart effect. Any biopsy takes an infinitesimal portion of tissue from the gland and with a shrunken prostate this portion is now increased, thus the chance of finding any grade of PCa is increased, just as the chance of finding any higher grade is increased, if any is, in fact, present.
These men are already under the care of a urologist. (Key issue)
These men have prostate issues beforehand
These men have unreliable psa standards.
These men have a much higher chance of biopsy.
These men have a smaller to much smaller gland than they naturally would as a result of the drug.
A biopsy of a smaller gland will access a larger percentage of the gland than otherwise available.
Thus, any suspect tissue in the prostate of a man under treatment with Avodart is more likely to be found, and some of that will be higher grade.
Avodart did not MAKE that finding, it ALLOWED the finding.0
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