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June 2016
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Our columnists explain what you need to know
Coding 20
The Bottom Line 23
Washington and You 43
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Expert clinical analysis. Practice advice. Policy perspectives.
UrologyTimes.com
VOL. 44, NO. 7
with
Readers*
Since 2001
‘Apology’ dilemma evolves
Urologist-led study supports value of apology laws, but others say they raise liability risk
Randy Dotinga |
UT CORRESPONDENT
APOLOGY LAWS BY STATE DO THEY MAKE A DIFFERENCE?
National Report—To Victor Cotton, MD, JD, an
attorney and former practicing physician, practicing medicine means never having to say you’re
sorry.
“In simple terms, a doctor who gives his or her
best effort does not owe the patient an apology for
anything,” he said.
For decades, however, apologies have been on
the minds of researchers and lawmakers, if not
necessarily on the lips of physicians themselves.
First, a slew of new state laws attempted to
make it easier for medical professionals to apologize without having to worry about making themselves vulnerable in malpractice lawsuits. The wave
of legislation has waned. But now there’s a new
trend: communication-and-resolution programs
that encourage physicians and medical facilities
Thirty-eight states currently
have apology laws. A University
of Wisconsin study found:
Full apology law
No apology law
NH
WA
BEFORE AND AFTER
Litigation length was
4.4±3.3 years before the laws
were enacted and 3.3±2.0 years
afterwards (p<.001).
Partial apology law
MT
OR
ND
ID
WY
NV
VT
WI
SD
CA
CO
MI
IL
KS
AZ
OK
NM
IN
OH
WV
TN
VA
NC
SC
AR
MS AL
TX
PA
KY
MO
LAW TYPE
Litigation length was shorter
(2.6±1.4 years) in states with
full apology laws than those with
partial laws (3.3±2.0, p<.001).
NY
IA
NE
UT
ME
MA
MN
RI
CT
NJ
DE
MD
GA
LA
FL
AK
Source: Graphic reprinted with permission
of Patrick McKenna, MD, and Christina Sauder, MS
HI
Please see APOLOGY, on page 36
Inside
HANDS ON
18
How to manage recurrent UTIs
in postmenopausal women
MALPRACTICE
44
Could necrotizing fasciitis have been
diagnosed sooner?
HIFU-treated patients see drop in positive Bx cores
Randy Dotinga |
UT CORRESPONDENT
San Diego—As the controversy over the use of
high-intensity focused ultrasound (HIFU) continues, efficacy research from a device manufacturer
offers new insight into how low-risk, low-grade
prostate cancer patients fare under the treatment.
The researchers reported that transrectal HIFU
produced a statistically significant increase—
from 70.8% to 92.3%—in per-core negative biopsy rates. But lead study author Cary Robertson,
MD, cautioned that the findings, from 2007 to
2010, shouldn’t necessarily encourage urologists
to embrace HIFU treatment for low-risk patients.
“The landscape is changed, and the patient with
intermediate cancer is probably the ideal patient,”
said Dr. Robertson, associate professor of surgery
(urology) at Duke University Medical Center and
Duke Cancer Institute, Durham, NC. He spoke
with Urology Times about his study, which was
presented at the AUA annual meeting in San Diego.
Last fall, the FDA cleared SonaCare Medical to
market its Sonablate 450 device for ablation of prostate tissue. It later approved the marketing of EDAP
TMS SA’s Ablatherm for the same indication.
Please see HIFU, on page 39
NO GLASS
NO BREAKAGE
smooth sailing
Prefilled. Preassembled. Preferred by 80%1 of polled U.S. urologists and urology nurses.
CHOOSE THE GLYDO® PREFILLED SYRINGE FOR
RELIABILITY, CONVENIENCE AND SAVINGS.
SAGENT Pharmaceuticals® is proud to offer GLYDO (lidocaine HCl jelly, 2%),
a sterile urethral anesthetic lubricant provided in prefilled plastic syringes.
The GLYDO prefilled syringe is the nonbreakable, cost-saving 2 alternative
to competitive glass vial-based syringes that can inadvertently break. The
plastic GLYDO syringe is shatter-proof. If you’re tired of experiencing
broken glass prior to use, try GLYDO.
The novel GLYDO syringe is prefilled, preassembled and ready to use,
providing efficiency and convenience from use through disposal. It has
been used in 40 countries, with more than 500 million applications and
40 years of experience.3
GLYDO is available in 11 mL and 6 mL easily disposable syringes in sterile
individual packs.
1
A description of GLYDO was preferred by 159/193 clinicians
in a June 2014 survey.
2
Data on file, Sagent Pharmaceuticals, Inc., 2015.
3
Data on file, Sagent Pharmaceuticals, Inc., 2014.
Visit www.glydo.com for more details, as well as information on how to receive GLYDO samples and how to order GLYDO.
Please see a brief summary of prescribing information for GLYDO (lidocaine HCl jelly USP, 2%) on the next page.
FEATURING
PreventIV Measures
Packaging and Labeling
SM
SAGENT Pharmaceuticals is a registered trademark of Sagent Pharmaceuticals, Inc.
SAGENT Urology is a trademark of Sagent Pharmaceuticals, Inc.
PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.
GLYDO is a registered trademark of FARCO-PHARMA GmbH.
©2016 Sagent Pharmaceuticals, Inc. Printed in USA 2131
GLYDO (lidocaine HCl jelly USP, 2%)
Brief Summary of Prescribing Information
INDICATIONS AND USAGE
GLYDO (lidocaine HCl jelly USP, 2%) is indicated for prevention and control of pain in procedures
involving the male and female urethra, for topical treatment of painful urethritis, and as an anesthetic
lubricant for endotracheal intubation (oral and nasal).
CONTRAINDICATIONS
Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of
the amide type or to other components of GLYDO.
WARNINGS
EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS
AND SERIOUS ADVERSE EFFECTS. PATIENTS SHOULD BE INSTRUCTED TO STRICTLY ADHERE TO THE
RECOMMENDED DOSAGE AND ADMINISTRATION GUIDELINES AS SET FORTH IN THIS PACKAGE
INSERT.
THE MANAGEMENT OF SERIOUS ADVERSE REACTIONS MAY REQUIRE THE USE OF RESUSCITATIVE
EQUIPMENT, OXYGEN, AND OTHER RESUSCITATIVE DRUGS.
GLYDO should be used with extreme caution in the presence of sepsis or severely traumatized mucosa in
the area of application, since under such conditions there is the potential for rapid systemic absorption.
When used for endotracheal tube lubrication care should be taken to avoid introducing the product into
the lumen of the tube. Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the
inner lumen, the jelly may dry on the inner surface leaving a residue which tends to clump with flexion,
narrowing the lumen. There have been rare reports in which this residue has caused the lumen to
occlude. (See also ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
PRECAUTIONS
General
The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate
precautions, and readiness for emergencies. (See WARNINGS and ADVERSE REACTIONS.) The
lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious
adverse effects. Repeated doses of lidocaine may cause significant increases in blood levels with each
repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood
levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children
should be given reduced doses commensurate with their age and physical status. Lidocaine should also
be used with caution in patients with severe shock or heart block.
GLYDO should be used with caution in patients with known drug sensitivities. Patients allergic to
para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross
sensitivity to lidocaine.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial
malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this
reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it
is suggested that a standard protocol for management should be available. Early unexplained signs
of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature
elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect
triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive
measures and dantrolene (consult dantrolene sodium intravenous package insert before using).
Information for Patients
When topical anesthetics are used in the mouth, the patient should be aware that the production of
topical anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason,
food should not be ingested for 60 minutes following use of local anesthetic preparations in the mouth
or throat area. This is particularly important in children because of their frequency of eating.
Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma.
Food and chewing gum should not be taken while the mouth or throat area is anesthetized.
Carcinogenesis—Long-term studies in animals have not been performed to evaluate the carcinogenic
potential of lidocaine.
Mutagenesis—The mutagenic potential of lidocaine has been tested in the Ames Salmonella reverse
mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo
mouse micronucleus assay. There was no indication of any mutagenic effect in these studies.
Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model.
Administration of 30 mg/kg, s.c. (180 mg/m2) to the mating pair did not produce alterations in fertility or
general reproductive performance of rats. There are no studies that examine the effect of lidocaine on
sperm parameters. There was no evidence of altered fertility.
Use in Pregnancy
Teratogenic Effects: Pregnancy Category B
Reproduction studies for lidocaine have been performed in both rats and rabbits. There was no evidence
of harm to the fetus at subcutaneous doses of up to 50 mg/kg lidocaine (300 mg/m2 on a body surface
area basis) in the rat model. In the rabbit model, there was no evidence of harm to the fetus at a dose
of 5 mg/kg, s.c. (60 mg/m2 on a body surface area basis). Treatment of rabbits with 25 mg/kg (300
mg/m2) produced evidence of maternal toxicity and evidence of delayed fetal development, including
a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull
and sternebral defect, reduced ossification of the phalanges). The effect of lidocaine on post-natal
development was examined in rats by treating pregnant female rats daily subcutaneously at doses of 2,
10, and 50 mg/kg (12, 60, and 300 mg/m2) from day 15 of pregnancy and up to 20 days post partum. No
signs of adverse effects were seen either in dams or in the pups up to and including the dose of 10 mg/
kg (60 mg/m2); however, the number of surviving pups was reduced at 50 mg/kg (300 mg/m2), both at
birth and the duration of lactation period, the effect most likely being secondary to maternal toxicity. No
other effects on litter size, litter weight, abnormalities in the pups and physical developments of the pups
were seen in this study.
A second study examined the effects of lidocaine on post-natal development in the rat that included
assessment of the pups from weaning to sexual maturity.
Rats were treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine (60 mg/m2 and 180 mg/m2 on a body
surface area basis, respectively). This time period encompassed 3 mating periods. There was no evidence
of altered post-natal development in any offspring; however, both doses of lidocaine significantly
reduced the average number of pups per litter surviving until weaning of offspring from the first 2
mating periods.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Labor and Delivery
Lidocaine is not contraindicated in labor and delivery. Should GLYDO be used concomitantly with other
products containing lidocaine, the total dose contributed by all formulations must be kept in mind.
Nursing Mothers
Lidocaine is secreted in human milk. The clinical significance of this observation is unknown. Caution
should be exercised when lidocaine is administered to a nursing woman.
Pediatric Use
Although, the safety and effectiveness of GLYDO in pediatric patients have not been established, a
study of 19 premature neonates (gestational age <33 weeks) found no correlation between the plasma
concentration of lidocaine or monoethylglycinexylidide and infant body weight when moderate amounts
of lidocaine (i.e. 0.3 mL/kg of lidocaine gel 20 mg/mL) were used for lubricating both intranasal and
endotracheal tubes. No neonate had plasma levels of lidocaine above 750 mcg/L. Dosages in children
should be reduced, commensurate with age, body weight, and physical condition. (See DOSAGE AND
ADMINISTRATION.)
ADVERSE REACTIONS
Adverse experiences following the administration of lidocaine are similar in nature to those observed
with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and
may result from high plasma levels caused by excessive dosage or rapid absorption, or may result from
a hypersensitivity, idiosyncrasy, or diminished tolerance on the part of the patient. Serious adverse
experiences are generally systemic in nature. The following types are those most commonly reported:
There have been rare reports of endotracheal tube occlusion associated with the presence of
dried jelly residue in the inner lumen of the tube. (See also WARNINGS and DOSAGE AND
ADMINISTRATION.)
Central Nervous System
CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness,
nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or
double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions,
unconsciousness, respiratory depression, and arrest. The excitatory manifestations may be very brief or
may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into
unconsciousness and respiratory arrest.
Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the
drug and may occur as a consequence of rapid absorption.
Cardiovascular System
Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension,
and cardiovascular collapse, which may lead to cardiac arrest.
Allergic
Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid reactions.
Allergic reactions may occur as a result of sensitivity either to the local anesthetic agent or to other
components in the formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare
and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing
is of doubtful value.
OVERDOSAGE
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during
therapeutic use of local anesthetics. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.)
Management of Local Anesthetic Emergencies
The first consideration is prevention, best accomplished by careful and constant monitoring of
cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local
anesthetic administration. At the first sign of change, oxygen should be administered.
The first step in the management of convulsions consists of immediate attention to the maintenance
of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable
of permitting immediate positive airway pressure by mask. Immediately after the institution of these
ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that
drugs used to treat convulsions sometimes depress the circulation when administered intravenously.
Should convulsions persist despite adequate respiratory support, and if the status of the circulation
permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a
benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar,
prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory
depression may require administration of intravenous fluids and, when appropriate, a vasopressor as
directed by the clinical situation (e.g., ephedrine).
If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia,
acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard
cardiopulmonary resuscitative measures should be instituted.
Dialysis is of negligible value in the treatment of acute overdosage with lidocaine.
The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214
(159 to 324) mg/kg (as the salt) in fasted female rats.
Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Mfd. by Klosterfrau Berlin GmbH
Made in Germany
©2014 Sagent Pharmaceuticals, Inc.
March 2014
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
Please see full prescribing information for GLYDO (lidocaine HCl jelly USP, 2%).
FEATURING
PreventIV Measures
Packaging and Labeling
SM
SAGENT Pharmaceuticals is a registered trademark of Sagent Pharmaceuticals, Inc.
SAGENT Urology is a trademark of Sagent Pharmaceuticals, Inc.
PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.
GLYDO is a registered trademark of FARCO-PHARMA GmbH.
©2016 Sagent Pharmaceuticals, Inc. Printed in USA 2131
www.SagentPharma.com | www.glydo.com
4
❳Perspective❲
JUNE 2016
∣
UrologyTimes.com
Prostate HIFU lands in the U.S. Now what?
T
he first prostate high-intensity
focused ultrasound (HIFU) units
were approved in Europe in 2000
and in Canada in 2003. HIFU is now
available to men who live in the United States
to be treated in the U.S.
The two devices approved in 2015 by the FDA
are the Sonablate 450 HIFU system (SonaCare
Medical) and the Ablatherm Robotic HIFU
(EDAP Technomed). Recently, EDAP filed for
FDA approval for its Focal One HIFU, which
combines MRI-ultrasound fusion to target specific prostate lesions. This unit is approved in
several countries outside the U.S. (See related
article on page 1.)
This FDA approval did not specify “prostate
cancer” but rather “prostate tissue ablation,” a
source of some confusion. FDA determined
that HIFU was a safe and effective tool for the
destruction of prostate tissue but was unconvinced that the data supported a prostate cancerspecific approval. While the short-term PSA
and biopsy data (1-2 years) were encouraging for
Leonard G. Gomella, MD
Dr. Gomella, a member of the Urology
Times Editorial Council, is chairman of
the department of urology and senior
director for clinical affairs, Jefferson
Sidney Kimmel Cancer Center, Thomas
Jefferson University, Philadelphia.
prostate cancer treatment, it would take many
years and many patients to demonstrate HIFU’s
superiority for localized disease.
The HIFU side effect profile appears similar to that of other localized prostate cancer
treatments. As noted by several authorities,
this HIFU approval is analogous to a scalpel—
a tool that can effectively cut tissue but not
approved to treat a specific disease. HIFU
involves the use of ultrasound to induce tissue
damage by thermal and mechanical effects and
cavitation.
With this broad approval, it is now up to
the urologic community to further define
JUNE 2016 VOL. 44, NO. 7
❳Mission❲
Urologists and allied health professionals rely on Urology Times for analysis, perspective, and
practical advice about current health policy, clinical, and business challenges. As the #1 read
publication in the field and a leading online resource, our goal is to keep practitioners up to date
while helping them practice more efficiently.
❳Editorial Consultants❲
Leading urologic surgeons, with broad experience,
who help ensure the quality of our editorial
how to best use HIFU. With over 20 years of
international experience, we must objectively
study the world literature to optimize patient
outcomes. For prostate cancer, should HIFU
be complete, hemi-gland ablation, or focal
therapy? What are the optimum patient and
tumor characteristics? With our expanding
understanding of immunotherapy, is there a
role for prostate ablation as an immune primer
for treating metastatic disease?
With all this uncertainty, the good news is
that men will no longer need to travel to Canada
or elsewhere for prostate HIFU therapy.
Leonard G. Gomella, MD
❳Clinical Practice Board❲
Feedback Send your comments to Dr. Gomella
c/o Urology Times, at [email protected]
Urologists who inform the editors of issues facing
physicians “in the trenches”
Sheila K. Gemar, MD Willmar, MN
Daniel M. Kaplon, MD Sarasota, FL
Sivaprasad D. Madduri, MD Poplar Bluff, MO
Henry M. Rosevear, MD Colorado Springs, CO
❳Content❲
Barry R. Rossman, MD Princeton, NJ
Neal D. Shore, MD Myrtle Beach, SC
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800-225-4569 | E-mail: [email protected]
Sara Michael VP, Content & Strategy
Ray Painter, MD/Mark Painter Coding/Reimbursement Columnists
J. Brantley Thrasher, MD Professor and Chair of Urology | University of Kansas Medical Center, Kansas City
Teresa A. McNulty Group Content Director
Bob Gatty UT Washington Correspondent
Philip M. Hanno, MD, MPH Emeritus Professor of Urology | University of Pennsylvania, Philadelphia
Richard R. Kerr Content Channel Director
Nancy Bitteker Director, Design and Digital Production
Stephen Y. Nakada, MD Professor and Chairman | Department of Urology | University of Wisconsin, Madison
440-891-2758 | [email protected]
❳Editorial Council❲
Experts in 12 key subspecialties of urology who direct
in-depth coverage of their field
MEN’S HEALTH/BPH Steven A. Kaplan, MD Professor of Urology | Icahn School of Medicine at Mount Sinai, New York
MEN’S HEALTH/PROSTATE CANCER Stacy Loeb, MD, MSc Assistant Professor of Urology | New York University School of Medicine, New York
CLINICAL EPIDEMIOLOGY Peter C. Albertsen, MD Chief of Urology | University of Connecticut Health Center, Farmington
Robert McGarr Art Director
Benjamin P. Saylor Content Managing Editor
440-891-2780 | [email protected]
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440-891-2613 | [email protected]
SEXUAL DYSFUNCTION Arthur L. Burnett, II, MD, MBA Professor of Urology | Johns Hopkins University School of Medicine, Baltimore
732-346-3044 | [email protected]
FEMALE UROLOGY Shlomo Raz, MD Professor of Surgery/Urology | University of California School of Medicine, Los Angeles
Bill Markowitz Associate Publisher
MEN’S HEALTH/INFERTILITY James M. Hotaling, MD, MS Assistant Professor of Surgery (Urology) | University of Utah, Salt Lake City
732-346-3083 | [email protected]
Reprints services: Wright’s Media 877-652-5295 ext. 121
PEDIATRIC UROLOGY Barry A. Kogan, MD Chief of Urology | Albany Medical College, Albany, NY
Joanna Shippoli Account Manager, Recruitment
[email protected] | Outside US, UK, direct dial:
281-419-5725. Ext. 121
HEALTH POLICY/SOCIOECONOMICS Jeffrey E. Kaufman, MD | Private Practice, Santa Ana, CA
STONES/ENDOUROLOGY Dean G. Assimos, MD Professor and Chair of Urology | University of Alabama, Birmingham
TRAUMA/RECONSTRUCTION Allen F. Morey, MD Professor of Urology | UT Southwestern Medical Center, Dallas
UROLOGIC CANCER Leonard G. Gomella, MD Professor and Chairman of Urology | Thomas Jefferson University, Philadelphia
UROLOGIC LAPAROSCOPY J. Stuart Wolf, Jr, MD Professor of Urology | University of Michigan, Ann Arbor
440-891-2615 | [email protected]
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UROLIFT IS
CHANGING
THE GAME
®
RAPID BPH SYMPTOM RELIEF BACKED BY STRONG CLINICAL DATA
• 16 peer-reviewed publications
• 4 years of clinical data1
• Excellent safety profile • Typically no catheter required after treatment2,4
• Preservation of sexual function3 • Rapid and significant relief in AUASI, Qmax and QoL2,4
Most common adverse events reported include hematuria, dysuria, micturition urgency, pelvic
pain, and urge incontinence. Most symptoms were mild to moderate in severity and resolved
within two to four weeks after the procedure.
Pre-procedure
Post-procedure
IMPROVE YOUR BPH GAME TODAY. Check out the data and learn more at UroLift.com
Follow us on
@UroLift
1. Roehrborn. AUA 2016. 4 year LIFT study results. Data on file. 2. Shore, 2014 Can J Urology
3. McVary, 2014 J Sexual Medicine 4. Roehrborn, 2013 J Urol.
©2016 NeoTract, Inc. All rights reserved. MAC00197-02 Rev D
6
❳Inter
ctive❲
Your guide to what’s happening online at UrologyTimes.com
tube
JUNE 2016
∣
Urology Times
‘Y’tube is a video resource for urologists and other physicians who focus on
men’s health. Videos cover surgical aspects of a variety of men’s health issues, with
the goal of providing clinicians a current reference.
UROLOGYTIMES.COM/YTUBE
James M. Hotaling, MD, MS, | Section Editor
THIS MONTH’S INSTALLMENT
Techniques help transition this procedure from the OR to an office setting
Neil Baum, MD
Steven N. Gange, MD
Lance P. Walsh, MD, PhD
compares UroLift with TURP and discusses
his experience with the use of nitrous
oxide as an effective sedative.
demonstrates UroLift placement
under topical anesthesia and includes
comments from several patients.
provides an overview of the
UroLift procedure, highlighting the
entire cycle of patient care.
JUNE’S QUESTION OF THE MONTH
AACU LEGISLATIVE UPDATE
Feds flex muscle on health care mergers
With increasing frequency, the Federal Trade Commission exerts its influence on issues that
impact the practice of medicine, including health system mergers, facility regulation, and
non-physician provider scope of practice. This all falls under the agency’s goal to maintain
competition by preventing anticompetitive mergers and exploitative business practices.
Does fear of being sued often
affect how you practice?
Not Sure
6%
No
21%
urologytimes.com/health-mergers
73%
Yes
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Working on the night shift - not so good for sexual
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#AUA16 too many presentations with complex
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Perioperative blood transfusion impairs oncological
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UrologyTimes.com
∣
❳ Clinical Updates ❲
JUNE 2016
7
Stone Disease Reintervention rate comparable for two approaches
Renal calculi: Dusting, basketing both have roles
Randy Dotinga
UT CORRESPONDENT
San Diego—The rise of laser lithotripsy has rev-
olutionized the treatment of larger kidney stones,
but there’s been a big mystery: Is it better to pulverize the stone into bits and leave them in the
kidney (“dusting”) or pull the fragments out via
ureteroscope (“basketing”)? Dusting is quicker
and possibly less damaging, while basketing gets
rid of remnants that could cause trouble later.
Now, a new study, presented at the AUA
annual meeting in San Diego, offers insight into
the outcomes of both procedures after 4 to 6
weeks. The verdict: “At first blush, there’s not
a difference between patients who were dusted or basketed,” said study co-author Mitchell
Humphreys, MD, professor of urology at Mayo
Clinic, Phoenix. “I can’t say one is clearly better
than the other. This shows that both techniques
have a role in stone disease.”
According to Dr. Humphreys, dusting has
become a feasible option thanks to the advent
of high-powered lasers that offer flexibility in
terms of increasing frequency rather than hertz.
“Some people dusted before, but it wasn’t as
efficient because you could only take your hertz
up so much,” he said. Now, basketing is feasible
too, and the question is: Which one is better?
“People who do basketing feel that the
patient has a better chance of not having any
subsequent stone episodes: ‘If I leave something
behind, that will turn into another stone,’ ” Dr.
Humphreys said. “Plus, patients like hearing
Clinical Updates
Prostate Cancer
page 10
Female Urology
page 14
Sexual Dysfunction
page 16
Pediatric Urology
page 17
For up-to-date news, visit
urologytimes.com/InBrief
that all the stone is out.”
But proponents of dusting
Table Dusting vs. basketing
are skeptical that the fragments
in laser lithotripsy
will become problematic, he
said, and they like the potential
Dusting Basketing
for savings due to not needing
56.1%
80.7%
Fragment-free rate
accessory devices such as a ureNumber
of
patients
requiring
teroscopic access sheath or bas2
3
reintervention
ket. And, he said, they like not
Patients with fragments who
having to make “trips” in and out
4/20
3/9
suffered from symptoms
of the kidney with the extra risk
Source: Mitchell Humphreys, MD
of damage to the ureter, although
Dr. Humphreys said that might
be alleviated by the ureteroscopic
access sheath.
basketing patients. The readmission rate to
In the study, Dr. Humphreys, representing hospital or emergency room was 14% to 15%
the Endourology Disease Group for Excellence in both groups; postoperative creatinine and
research consortium, prospectively enrolled stone analyses were the same in both groups.
152 patients at high-volume stone centers with
Three of nine patients who were basketed
well-established standardized protocols—three and had leftover fragments suffered from sympdusting sites and five basketing sites.
toms, Dr. Humphreys said, and four out of 20
who were dusted and had leftover fragments
suffered from symptoms.
“All in all, if you have fragments left, you’ve
“If you have fragments left, you’ve
got a good chance of having symptoms,” he
said, “but it made no difference whether you got
got a good chance of having
dusted or basketed, at least in the short term.”
symptoms, but it made no difference
Dr. Humphreys acknowledged that the study
doesn’t include a cost analysis because it would
whether you got dusted or basketed, be too complex to complete due to the number
of different price structures involved. But the
at least in the short term.”
authors hope to analyze expenses in the future.
Also, he said, long-term analyses still need to
MITCHELL HUMPHREYS, MD
be completed.
“Most people do one technique,” Dr. HumWhat should urologists take from the
phreys said, “and maybe the other in special research?
circumstances.”
“For patients who are dusted, it’s quicker,
Of the subjects, 48% were male and 52% you can attack bigger stones, and you have no
female; all had renal stones measuring between increased risk of complications,” he said. “But
5 and 20 mm. All received laser lithotripsy, you’re leaving fragments behind, and we don’t
were stented postoperatively, and received an know about the long-term consequences.”
alpha-blocker for 30 days. All underwent KUB
In comparison, basketing doesn’t appear
and ultrasound imaging within 3 months.
to translate to extra benefits in the immediate
The authors found that the dusting patients weeks after procedures, he said.
had slightly larger stones, and significantly more
Dr. Humphreys cautioned that each techlaser energy was needed to perform dusting ver- nique might have value in certain situations.
sus basketing. Not surprisingly, the basketing
Patients with narrow ureters and big stones
procedures took longer, Dr. Humphreys said.
may do better with dusting because it doesn’t
pose the risk of repeated trauma from basketing
Little difference in fragment impact seen
or the need for a ureteroscopic access sheath,
Of the basketing patients, 80.7% were fragment- he said. And basketing may be best for patients
free compared to 56.1% of the dusting patients who have a stone that’s easy to get to, very hard,
at first follow-up.
and likely to break into discrete fragments. A
In terms of these outcomes, the authors patient with a solitary kidney may be another
found little clinical difference in the impact of good option for basketing, he said, because it’s
the residual fragments. Two dusting patients especially important to remove fragments and
required reintervention compared with three avoid future problems. UT
❳ UT
❲
8
❳ Clinical Updates ❲
JUNE 2016
∣
Urology Times
Urinary proteome may guide stone prevention strategy
Research reveals significant differences in COM-binding proteins in adults, children
Cheryl Guttman Krader
UT CONTRIBUTING EDITOR
San Diego—Analyses of urine samples col-
lected from children and adults provide the
first comprehensive catalog of urinary calcium
oxalate monohydrate (COM) binding proteins
and reveal significant differences in the level
and make-up of these proteins between the two
populations, urologists from Washington University School of Medicine, St. Louis, reported
at the AUA annual meeting in San Diego.
The study, which included subjects with no
history of urinary stone disease (USD), is part
of a larger ongoing project aiming to characterize the urinary proteome in children and adults
for insights on USD pathogenesis as well as
age-related clinical differences, and eventually to guide development of better prognostic
approaches and therapeutic strategies.
“In previous work, we demonstrated there
UTSTAT
The total concentration of COM-binding
proteins was significantly higher in the
adults than in the children, and the
proportion of high affinity COMbinding proteins was 39% greater
in adults.
are populations of proteins within human urine
that have very high affinity for COM. In addition, we showed that some of these proteins
inhibit crystal adhesion and crystal growth and
aggregation in solution,” said first author Joel
Koenig, MD, pediatric fellow at Washington
University.
“So far, in this phase of our research, we have
found there are age-related differences in the
urinary proteome and specifically with regard
to COM-binding proteins. Moving ahead, we
are conducting additional analyses to better
characterize the differences,” added Dr. Koenig, who worked on the study with Paul Austin,
MD, and colleagues.
Findings from basic chemistry studies done
to measure the concentration of various proteins in the urine samples along with affinity
chromatography performed using control and
COM crystal-loaded columns showed that in
both the pediatric and adult subjects, proteins
with a high selective affinity for COM comprised a minor proportion of the total protein
content of the urine. Consistent with some previous research, the proportion of proteins with
a high selective affinity for COM accounted for
only about 10% to 20% of total protein in the
urine, Dr. Koenig reported.
Higher protein concentration in adults
However, the total concentration of COMbinding proteins was significantly higher in
the adults than in the children, and the propor-
tion of high affinity COM-binding proteins was
39% greater in adults.
Currently, the investigators are performing
HPLC-mass spectrometry for high throughput identification of the urinary proteins and
immunoblotting and ELISA for protein-specific analyses.
In terms of clinical application of their
research, they hypothesize that urinary proteins found to have a strong effect for preventing COM crystal adherence and/or aggregation
could be used as biomarkers to predict risk of
stone recurrence and also provide therapeutic
targets.
“Hopefully, with the identification of such
proteins, a quick spot test of a urine specimen could reduce the need for a cumbersome
24-hour collection,” Dr. Koenig explained.
“And our ultimate goal is to use the findings from our studies to design a therapeutic
intervention that might increase the secretion
of the protective proteins as an approach for
preventing kidney stone formation.”
As next steps, they will expand their research
by comparing the urinary proteome of populations of patients with and without a history of
USD and also study patients with a history of
recurrent USD.
“The finding of differences in these initial
groups of children and adults with no history
of stone formation encourages us to keep our
project going,” Dr. Koenig told Urology
Times. UT
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FDA approves advanced
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Atezolizumab targets the PD-1/PD-L1
pathway and in doing so may help the
The FDA has granted accelerated
immune system fight cancer cells, accordapproval to atezolizumab (TECENing to an FDA press release. In all patients in
TRIQ) for the treatment of patients with
a clinical trial, 14.8% experienced at least a
locally advanced or metastatic urothelial car- partial shrinkage of their tumors. In patients
cinoma who have disease progression during who were positive for PD-L1 expression, 26%
or following platinum-based chemotherapy,
showed a tumor response (vs. 9.5% of those
or whose disease has worsened within 12
who were negative for PD-L1 expression).
months of receiving platinum-based neoadjuvant or adjuvant chemotherapy.
Urology Times brings home
Atezolizumab is the first FDA-approved
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1
10
❳ Clinical Updates ❲
JUNE 2016
∣
Urology Times
Prostate Cancer Findings suggest not all Gleason 6 cancers are indolent
Prostate cancer clones trackable by fusion biopsy
Cheryl Guttman Krader
UT CONTRIBUTING EDITOR
San Diego—Researchers using cutting-edge
diagnostic techniques demonstrated that repeat
sampling of the same clonal focus of prostate
cancer can be achieved over time using magnetic resonance imaging/ultrasound fusion biopsy
(“fusion biopsy”). In addition, their findings
strongly suggest that high-grade prostate cancer
may arise clonally from a low-grade cancer.
“Our study provides the first definitive evidence that serial biopsies can be obtained from
the same prostate cancer clonal focus through
fusion biopsy, and so it supports use of this technique for following men during active surveillance,” said Ganesh S. Palapattu, MD, associate professor of urology and chief of urologic
oncology at the University of Michigan, Ann
Arbor.
“It also raises the provocative idea that not
all Gleason 6 prostate cancers may be indolent. Our findings point to the need for further
research focusing on better characterizing these
‘high-risk low-grade’ cancers. Ultimately, these
are the ones we need to follow.”
Conducted as a collaboration between urologists at the University of Michigan and the University of California, Los Angeles, the study
included 31 men (mean age, 65 years, mean
PSA at diagnosis, 4.6 ng/mL) with low-volume,
Gleason 6 prostate cancer who were enrolled in
an active surveillance program. All men underwent an initial diagnostic MR/fusion biopsy
with individual needle core tracking and had a
follow-up fusion biopsy of the same region. The
median time between biopsies was 12 months.
Clonality of the initial and follow-up biopsies
was assessed using immunohistochemistry to
assay ERG status. In addition, targeted RNA/
DNA next-generation sequencing (NGS) was
performed to identify common oncogenic
mutations in routine formalin-fixed paraffinembedded biopsy tissues.
“Active surveillance for men with low-grade
cancer is based on the notions that we are able
to sample the same clonal focus of cancer over
time and that low-grade disease can progress to
high-grade disease,” said Dr. Palapattu.
“Ours is a first-in-kind study providing evidence to support these ideas through the use of
sophisticated molecular techniques.”
Twenty-six of the 31 men had tissue that was
evaluable for molecular studies at both the diagnostic and follow-up biopsies, and 10 men had
progression to Gleason 7 or higher cancer on
targeted surveillance biopsy.
96% ERG expression concordance seen
Immunohistochemical analysis demonstrated
ERG expression concordance between serially
obtained samples in 25 (96%) of the 26 men
with evaluable tissues and in all 10 men whose
cancer progressed.
“The 96% ERG expression concordance
between the initial and surveillance targeted
biopsy is a much higher rate than could be
attributable to chance, strongly suggesting that
the same clonal focus was sampled over time,”
Dr. Palapattu said.
“Furthermore, the concordance of ERG status between the samples from the men whose
cancer progressed strongly suggests that the
higher grade cancer originated from the Gleason 6 cancer.”
While approximately 50% of paired samples
displayed oncogenic mutations, no consistent
mutational event that predicted grade progression was observed.
“Our research is also noteworthy for establishing the feasibility of identifying somatic
genetic alterations with high confidence using
very minute tissue samples obtained through
prostate biopsy as well as for showing that
deleterious genetic alterations can be present
in low-volume low-grade prostate cancer,” Dr.
Palapattu said.
He acknowledged the study has two main
limitations. One is its small cohort size, and the
other relates to sampling bias; ie, the possibility that tissue assayed in the follow-up biopsy
was in fact present at the initial biopsy but simply not sampled. UT
Post-TRUS Bx infection linked to higher transfusion risk
Oncologic, functional outcomes similar between study groups, data indicate
Mac Overmyer
UT CONTRIBUTING EDITOR
San Diego—Infections that follow transrectal
ultrasound (TRUS)-guided prostate biopsies
are associated with an increased risk of blood
transfusions and increased readmission following radical prostatectomy, even though the
infections may have been clinically resolved
well before the procedure was conducted,
according to a study from the Institute for
Clinical Evaluative Sciences and the University of Western Ontario, London, Ontario,
Canada.
Paradoxically, the authors did not find a
negative effect in the functional outcomes they
analyzed. Results also showed that the risk of
additional oncologic therapies was similar
despite the presence of an infectious compli- functional outcomes were similar. Physicians
cation after prostate biopsy.
should inform patients who experience infec“It may be that infectious complications tious complications following a prostate biopsy
affect the complexity of the case to increase
Please see TRUS, page 11
blood transfusion rates following
radical prostatectomy. But at the
end, the proportion of the evaluTable Biopsy-related infection:
ated surgical complications was
Effect on outcomes
similar,” said first author Daniel
Patients with
Patients with no
Olvera-Posada, MD, an endoubiopsy-associated biopsy-associated
rology fellow from the Univerinfection
infection
sity of Western Ontario.
19.6%
13.1%
Transfusion rate
“Using administrative data
30-day post-RP
from the province of Ontario,
6.6%
3.3%
readmission
we found that infectious complirate
cations significantly increased
Source: Daniel Olvera-Posada, MD
along the years of the study
even though oncological and
❳ UT
❲
UrologyTimes.com
∣
❳ Clinical Updates ❲
JUNE 2016
TRUS: ‘Real-world data’ from multiple centers
continued from page 10
that although prostatectomy outcomes are similar, there is a slightly increased risk of the need
for blood transfusion,” Dr. Olvera-Posada told
Urology Times.
No effect on 30-day post-op mortality
The study, which was presented at the AUA
annual meeting in San Diego, noted that no
differences were found in the proportion of
patients requiring adjuvant radiation, hormonal
therapy, or surgical procedures to treat incontinence or erectile dysfunction. The 30-day
post-op mortality was not affected. Outcomes
were assessed in the first 12 to 24 months after
radical prostatectomy.
The study was extensive. Using data from
the Institute for Clinical Evaluation Services
(ICES), the authors identified a populationbased cohort of 27,637 patients from Ontario
who had undergone a radical prostatectomy
between April 2002 and March 2013. Infectious
complications were defined as hospitalization
with evidence of a urinary tract infection or
sepsis within 30 days of a TRUS-guided prostate biopsy.
A total of 530 patients (1.9%) had an infectious event following biopsy. The primary endpoint was a composite of surgical complications
that included the need for postoperative treatment of urinary fistula, intestinal diversion,
upper urinary tract obstruction, or ureteral
repair.
Patients with a biopsy-associated infection
showed a 19.6% rate of transfusion, compared to
13.1% of the non-infectious complication group.
The 30-day post-prostatectomy hospital readmission rate for those with infections following
biopsy was twice that of those with no recorded
infections (6.6% vs. 3.3%; OR: 2.06, 95% CI:
1.46-2.93, p<.0001). The statistical difference
in the length of hospital stay was not clinically
meaningful.
“The analyzed data come from many centers with dozens of surgeons using different
approaches. It is real-world data that includes
outcomes from community and teaching hospitals. Unfortunately, the information did not
contain patient-level data; however, populationbased information represents the real world,”
said Dr. Olvera-Posada, working with Stephen
E. Pautler, MD, and colleagues.
“We were using administrative information
and were unable to see important variables such
as the pathological stage, prostate volume, or
baseline urinary function. Those and other variables should be taken into consideration to get a
better answer to the clinical questions the study
raised,” Dr. Olvera-Posada said.
Dr. Olvera-Posada said the research was con-
ducted to add more information regarding the
deleterious impact of infectious complications
following prostate biopsy. The initial research
that raised this issue, published by Nam et al in
the Journal of Urology (2010; 183:963-8), found
that hospital readmission rates for men undergo-
Flexor Parallel
®
ing TRUS biopsies in Ontario had quadrupled
from 1.0% to 4.1% between 1996 and 2005 (p
for trend <.0001) The vast majority (72%) of
the readmission rates were related to infections.
“We knew that there is an increased rate of
infectious complications following a prostate
biopsy. We wanted to find out what effects those
complications might have on surgical outcomes
following radical prostatectomies,” said Dr.
Olvera-Posada. UT
™
R A P I D R E L E A S E ™ U R E T E R A L A C C E S S S H E AT H
MEDICAL
11
12
❳ Clinical Updates ❲
JUNE 2016
∣
Urology Times
Assay predicts outcomes in men taking mCRPC agent
AR-V7 detection associated with 0% PSA response, significantly inferior survival
Wayne Kuznar
UT CORRESPONDENT
San Francisco—Expression of androgen recep-
tor splice variant 7 (AR-V7) in whole blood predicts worse cancer-related outcomes in patients
with metastatic castration-resistant prostate
cancer (mCRPC) who are treated with abiraterone acetate (ZYTIGA).
Using a real-time polymerase chain reaction
(RT-PCR) assay, detection of AR-V7 transcripts
in whole blood was associated with a 0% PSA
response rate and significantly inferior progression-free survival and overall survival in
patients treated with abiraterone, Australian
researchers reported at the Genitourinary Cancers Symposium in San Francisco.
AR-V7, a truncated form of the androgen
receptor that lacks the ligand-binding domain,
is relatively common among men with mCRPC.
The missing C-terminal of AR-V7 is important
because it’s the part of the androgen receptor
that androgen receptor inhibitors bind. Previous
work at Johns Hopkins University, Baltimore
has shown that AR-V7 expression in circulating
tumor cells was associated with resistance to
abiraterone and enzalutamide (XTANDI) (N
Engl J Med 2014; 371:1028-38). In this study,
PSA response rates were also 0% in AR-V7positive patients who were treated with either
abiraterone or enzalutamide.
“Ours is a small cohort at only 37 patients, but
in our patients who have AR-V7-positive disease, we’re seeing similar results in terms of no
PSA response rate and poorer survival,” said coauthor Arun Azad, MD, a medical oncologist
at Monash University, Melbourne, Australia.
“You might ask what’s the benefit of our
study on top of what we already know from the
Johns Hopkins study,” he said. “The difference
here is the assay. This is a whole blood RNA
assay using PAXgene tubes, which are not time
sensitive, unlike the AdnaGen test that was used
in the Johns Hopkins study, which also requires
collection of circulating tumor cells.”
PAXgene RNA tubes are collected using 2.5
mL of whole blood. The tube is inverted eight to
10 times and then placed into a –70ºC freezer,
after which it can be analyzed at any time up
to 7 years later.
‘A very user-friendly assay’
“It’s a very user-friendly assay, unlike the AdnaGen, which needs to be done within 4 hours and
has a lot of other steps in terms of processing,”
said Dr. Azad.
Using this assay, while at the British Colum-
bia Cancer Agency in
Vancouver, BC, he and
Table AR-V7 expression and
colleagues including
outcomes in men with mCRPC
Tilman Todenhöfer,
AR-V7-posi- AR-V7-negaMD (who led develtive patients tive patients p-value
opment of the assay),
0%
41.9%
.04
sought to correlate
PSA50 response rate
AR-V7 expression with
0%
52%
.051
PSA30 response rate
outcomes in 37 patients
Median progression0.7
4
<.001
with mCRPC treated
free survival (months)
with abiraterone aceMedian overall survival
6.6
22.1
.0004
tate. RT-PCR was per(months)
formed for the following
Source: Arun Azad, MD
genes: AR-V7, FOXA1,
GR H L2, HOX B13,
K LK2, K LK3, and
TMPRSS2:ERG. For each gene, the highest com- cial or other relationship with Astellas Pharma,
puted tomography value among 20 normal con- Janssen Pharmaceuticals, Janssen Oncology,
trols was set as the threshold for a positive test.
and/or other pharmaceutical companies. UT
Median patient age was 70 years and 59%
had received prior docetaxel (Taxotere). None
had received abiraterone or enzalutamide previously. Four patients (11%) were AR-V7-positive.
AR-V7-positive patients were more likely to
have high levels of alkaline phosphatase (p=.04)
By Lisette Hilton
and lactate dehydrogenase (p=.07) and more
often had Eastern Cooperative Oncology Group
In a study of 8,820 men with metastatic castrationPerformance Status ≥2 (p=.052) than those who
resistant prostate cancer, researchers found the
were AR-V7-negative.
prognosis differs substantially based on where the
The PSA50 response rate, defined as PSA
cancer has spread.
decline ≥50% confirmed ≥3 weeks later, was
Spread to the liver is associated with shorter sur0% in AR-V7-positive patients compared with
vival than lung and bone spread, and patients with
41.9% in AR-V7-negative patients (p=.04).
lymph node metastases only have the best overall
PSA30 response rates were 0% and 52%
survival, according to co-author Andrew Armstrong
(p=.051) in the AR-V7-positive and AR-V7MD, ScM, of Duke Cancer Institute, Durham, NC.
negative patients, respectively.
The study, which was published in the Journal
Median progression-free survival was
of Clinical Oncology (2016; 34:1652-9), is based on a
0.7 months in AR-V7-positive patients and 4
substantial sample of men who received docetaxel
months in AR-V7-negative patients (p<.001).
(Taxotere) chemotherapy in nine phase III trials,
Median overall survival was 6.6 months in the
according to the study’s abstract.
AR-V7-positive patients and 22.1 months in the
The authors categorized the sites of metastases
AR-V7-negative patients (p=.0004).
as lymph node only, bone with or without lymph
Significant predictors of worse overall surnode (with no visceral metastases), any lung metasvival were AR-V7-positive status (p=.007), an
tases (but no liver), and any liver metastases.
increased level of ALP (p=.02), ≤36 months on
They found that more than 72% of those studied
primary hormone therapy (p=.03), >2 markhad bone with or without lymph node metastases,
ers that were positive (p=0.03), and HOXB13
9.1% had lung metastases, 8.6% had liver metastasis,
positivity (p=.02).
and 6.4% had lymph node-only disease.
“It’s reassuring that the PAXgene tubes assay
The highest median survival of about 32 months
is showing similar results to what has been seen
occurred in the lymph node-only group. Overall
with the AdnaGen assay, but it’s potentially
median survival for the majority who had bone
more user friendly and therefore more useful
metastases was just over 21 months. Men with lung
as a companion diagnostic down the line,” said
metastases had a median survival of 19 months. And
Dr. Azad.
men with liver metastasis fared the worst with a
Dr. Azad has received honoraria from Jansmedian survival of nearly 14 months.
sen-Cilag and is a consultant/adviser for Astellas
Pharma. Several of his co-authors have a finan-
❳ UT
❲
PCa: Site of metastases
impacts prognosis
NOW APPROVED
Learn more at TECENTRIQ.com/info
© 2016 Genentech USA, Inc. All rights reserved. PDL/111215/0102
14
❳ Clinical Updates ❲
JUNE 2016
∣
Urology Times
AS successful among very low-, low-risk PCa patients
Surveillance also found viable in select men with intermediate-/high-risk disease
Wayne Kuznar
UT CORRESPONDENT
San Diego—Active surveillance (AS) as a man-
agement paradigm is associated with low rates
of mortality and metastases among patients
with very low- or low-risk prostate cancer,
and also among selected men with intermediate- and high-risk disease, according to a chart
review of patients managed with AS at Cleveland Clinic.
The investigators also cited the high success
of patients with deferred therapy, supporting
the safety of AS in appropriate prostate cancer
patients.
“What you can gather from our experience,
with regards to the safety of AS, is that rarely
do men chosen for surveillance have mortality
as a result of their cancer,” said lead investigator
Yaw Nyame, MD, who presented the findings
at the AUA annual meeting. “It happens, but
it’s just not common.”
Follow-up data from 635 men managed with
AS for localized prostate cancer from 2002 to
2015 were reported. Patients selected for AS
are managed with interval PSA measurement
and prostate biopsy at the discretion of 11 different urologists. Curative treatment was recommended with an increase in disease grade
or volume (>50% of total cores).
Of the 635 men, 514 were classified as very
low risk/low risk (median age at diagnosis, 65.1
years) and 117 as intermediate risk/high risk
(median age at diagnosis, 68.6 years). Data were
insufficient to classify four of the men.
“When we first were offering active surveillance in our institution, we used criteria that
had been established by clinicians at Johns
Hopkins, and a lot of the patients that we were
surveilling were not only low risk but they were
very low risk because that’s where the data was
most supportive of less intervention,” said Dr.
Nyame, a urology resident at the Glickman
Urological and Kidney Institute at Cleveland
Clinic working with Eric A. Klein, MD, and
colleagues.
“So if you look at our experience, we have a
higher percentage of low-risk and very low-risk
patients in our early experience that are being
offered surveillance. At the same time, there
were these rare patients that were a little older
and a little sicker that were intermediate risk
that we were offering surveillance to because
we felt that the morbidity of surgery and risk of
surgery outweighed the risk of prostate cancer
mortality.”
About one-third of men in the intermediate-/
high-risk category had a serum PSA of 10.1 to
20.0 ng/mL and an additional 6.8% had serum
PSA >20.0 ng/mL. Some 57.3% of this group
had Gleason 3+4 disease and 9.4% had a Gleason 4+3 pattern. More than 90% (92.3%) of the
intermediate-/high-risk group were considered
intermediate risk by National Comprehensive
Cancer Network (NCCN) criteria and 7.7%
were NCCN high risk.
The median follow-up was 50.5 months (51.2
months in the very low-risk/low-risk cohort;
44.2 months in the intermediate-/high-risk
cohort). The primary outcome was mortality
and the development of metastasis.
No PCa-specific deaths reported
All-cause mortality while on AS was 2.5% (16
deaths), with no prostate cancer-specific deaths,
and 0.8% (4/533) developed metastatic disease.
By risk category, the cumulative incidence of
mortality at 5 years was 0.37% in the very lowrisk/low-risk patients and 1.38% in the intermediate-/high-risk patients. The 5-year incidence
of local or distant metastases was 0.15% and
0.24% in the two risk groups, respectively.
About one-third of men (35.2%) received
treatment with curative intent, with a median
time to treatment of 16 months. The most common primary therapy was radical prostatectomy (46.1%) followed by brachytherapy (37.1%),
external beam radiation (7.8 %), and cryoablation (6.4%).
“Roughly sixty percent of the 635 men at 5
years didn’t require an operation or radiation,
and that’s significant,” said Dr. Nyame. “Our
data are very similar to what has been reported
previously even though we had a more heterogeneous risk group, but longer follow-up is
needed with our intermediate-/high-risk
patients to ensure they have similar outcomes
reported from the Toronto and Hopkins
cohorts.” UT
Female Urology Benefit seen in patients with UI, UF, or both
Neuromodulation: QoL improvement seen at 3 years
Randy Dotinga
UT CORRESPONDENT
San Diego—A new industry-funded study has
found that sacral neuromodulation patients with
urgency incontinence, urgency frequency, or
both—almost all of whom were women—
report improvement in quality of life measures
after 3 years of treatment.
The patients had failed an average of two
medications, said lead author Karen Noblett,
MD, professor of clinical obstetrics and gynecology and chair of obstetrics and gynecology at
the University of California Riverside School of
Medicine, Riverside. According to Dr. Noblett,
the findings “suggest we probably should move
to third-line therapies more quickly and not prescribe medication after medication if they’ve
failed a couple.”
T he I nterSt i m system
(Medtronic, Minneapolis) is
FDA-approved for urinary
incontinence, urgency-frequency, urinary retention, and fecal
incontinence.
“It’s a third-line therapy
Dr. Noblett
after behavioral therapy and
medications,” Dr. Noblett told Urology Times,
and unique because patients can test the therapy
over a trial period to see if it helps them. If the
treatment works, then the device is implanted
permanently in the body.
“It’s a very minimally invasive outpatient
procedure, done with just local anesthesia and
IV sedation,” she said.
The new study, presented at the AUA annual
meeting in San Diego, is a retrospective subanalysis of a 5-year prospective study into the
use of tined leads to hold the device in tissue.
This research satisfies the FDA’s request for
post-approval analysis, she noted.
“We saw significant improvement,” Dr.
Noblett said, “and we wanted to see if that would
differ in patients with just urgency frequency
versus those with urgency incontinence.”
The study examined 272 subjects, 91% of
whom were female, with an average age of
Please see NEUROMODULATION, page 15
UrologyTimes.com
∣
❳ Clinical Updates ❲
JUNE 2016
15
Renal mass biopsy: How it impacts management
Strong positive predictive value when paired with size-based management algorithm
Robert M. Turner, II, MD
SPECIAL TO UROLOGY TIMES
Ann Arbor, MI—At the 2015 Society of Urologic
Oncology annual meeting in Washington, J.
Stuart Wolf, Jr., MD, addressed concerns about
the diagnostic inaccuracies of core renal biopsy
in the diagnosis of small renal masses.
In his presentation, Dr. Wolf argued, “Biopsy does not need to perfectly identify histologic
type and grade when it is paired with a riskstratified, size-based management algorithm.”
In a study conducted at the University of
Michigan, Ann Arbor, where Dr. Wolf is professor of urology, investigators considered
an approach that combined core biopsy risk
stratification with an algorithm based on size
(J Urol 2013; 189:441-6). To test reliability of
the approach, the authors compared the treatment assignment (surveillance vs. excision) in
151 patients based on size and biopsy histology
with the appropriateness of that assignment as which incorporates both size and biopsy histoldetermined by final pathology after surgical ogy, been applied preoperatively.
“The greatest liability [of incorporation of
excision. Dr. Wolf demonstrated that use of
renal mass biopsy, combined with a size-based renal mass biopsy in treatment decisions] is
management algorithm, has an excellent posiPlease see RENAL MASS BX, page 16
tive predictive value (100%
in that study) but an imperfect negative predictive value
(86%).
The combination of renal
mass biopsy with a size-based
management algorithm was
also applied to a multi-institutional database compiled by
active robotic partial nephrectomy surgeons (J Urol 2014;
192:1337-42). In that study,
the authors concluded that
Crafted for Perfection.
about half the patients theoretically could have avoided
Created for Performance.
surgery had the algorithm,
Lipshultz
Epididymovasostomy
Microdissection Scissors
are like Diamonds...
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the way you do.
NEUROMODUL AT ION
continued from page 14
57 years. Of the subjects, 104 (51%) had both
incontinence and frequency symptoms, while
54 (27%) had incontinence only, and 44 (22%)
had frequency symptoms only.
All groups showed significant improvement
over baseline at 36 months in Health Related
Quality of Life and ICIQ-OABqol subscales of
Concern, Coping, Sleep, Social, and Interference (all p<.0001).
“Not only are their diaries showing that
they have fewer bladder symptoms, but these
improvements are having a significant effect on
their quality of life,” Dr. Noblett said.
However, incontinence-only patients showed
less improvement than the other groups in the
Sleep subscale (p<.02), and they scored lower
on the Coping subscale than those with both
conditions.
Nearly 80% improvement in Interference
On the Interference measure, which refers to
interference with daily activities, about 80%
of the subjects in all three groups reported
they improved or greatly improved. This is
an intriguing finding because some observers
might assume that patients with incontinence
would experience the greatest benefit due to
the effects of leaking urine, Dr. Noblett said.
While patients often don’t have full relief from
urinary symptoms, she said,
patients are often still pleased.
“They’ve gone from wearing a diaper to a panty liner.
If you’re an adult woman,
and you don’t have a diaper
anymore, that will have a
significant impact on quality of life.”
Overall, she said, “We
were very happy to see the
response was so robust and
well-maintained over the 48
months we’ve collected the
data,” she said. “We’ll continue to compile outcome
data at 48 months and at 60
months of the 5-year period.
We want to identify the ideal
candidates for this therapy
and predict who may respond
more than others.”
The study was funded by
Medtronic. Dr. Noblett
serves on the advisory board
for the company and was a
participant in the InSite trial
of the InterStim system. Several of Dr. Noblett’s coauthors were consultants/
advisers and/or investigators
for or employees of Medtronic. UT
Larry I. Lipshultz, M.D.,
Professor of Urology,
Baylor College
of Medicine
Gentle curve at the
tip assures perfect
elliptical cut.
SDC-15R VL
Micropoint tip.
Enables the careful dissection of the tunica of the
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16
❳ Clinical Updates ❲
JUNE 2016
∣
Urology Times
Sexual Dysfunction Curvature reduced most dramatically after first cycle
Peyronie’s treatment cycles evaluated in study
UT CONTRIBUTING EDITOR
San Diego—Findings of a retrospective review
of men receiving intralesional collagenase clostridium histolyticum (CCH; Xiaflex) for Peyronie’s disease may help inform therapeutic
decisions on number of cycles.
Conducted by researchers at Tulane University School of Medicine in New Orleans,
the study analyzed serial and total changes in
penile curvature in 77 men, of whom 41 (53%)
completed four cycles of CCH treatment (eight
total injections). The findings were presented at
the AUA annual meeting in San Diego.
Overall, mean curvature decreased significantly from 58.2° at baseline to 41.0° after the
last cycle of injections. Comparing men who
achieved a ≥20° change from baseline to those
with less curvature reduction based on a number of variables showed the two groups differed
significantly only in the amount of curvature
reduction achieved after the first treatment
cycle (–16.2° vs. –5.9°, respectively; p<.001).
Analysis of change in penile curvature after
each injection cycle was done using a repeated
measures model. It showed mean curvature was
reduced most dramatically after the first cycle
(–12.0°), and there was continued improvement between the second and third and third
and fourth sets of injections (mean reduction of
–4.6° and –4.8°, respectively). However, there
was essentially no significant change in penile
curvature as a result of the fourth cycle, said
first author James Anaissie, a fourth-year medi-
RE N A L M A S S B X
continued from page 15
false negatives,” Dr. Wolf conceded. He noted that, in his updated series, 17% of patients
would have been incorrectly assigned to surveillance, and in fact harbored worse pathology
than suggested by biopsy. He was reassured,
however, that those patients who underwent
delayed intervention had similar rates of partial nephrectomy and adverse pathology when
compared with those patients who underwent
early intervention.
Furthermore, in patients undergoing surveillance, increasing growth rate was associated
with adverse pathology. In data from the University of Michigan, there was a 10% increase
in odds of adverse pathology for each 1 mm/
year change in growth rate.
cal student at Tulane University.
“CCH can be an effective treatment
for Peyronie’s disease, but the response
is variable, it is expensive, and the injections are painful,” he said.
of CCH on mean
❳ UT Figure ❲ Effect
curvature in Peyronie’s
80
How to counsel patients
58.2°
60
“Our study indicates that urologists may
counsel patients who have a strong response
to the first cycle that they are likely to have
41.0°
a better final outcome, so they may feel
40
more confident about continuing. On the
other hand, men who had a more modest
change in curvature could be told they may
20
still achieve significant benefit with further
cycles, but that they are less likely to have
a bigger response at the end.”
Senior author Wayne J.G. Hellstrom,
0
Baseline
After last cycle of
MD, noted that four CCH cycles has
treatment
become standard of care for treating PeySource: James Anaissie and Wayne J.G. Hellstrom, MD
ronie’s disease because it was the regimen used in the large Investigation for
Maximal Peyronie’s Reduction Efficacy
and Safety Studies (IMPRESS). The findings tors of final curvature reduction ≥20° included
of this retrospective study, however, call the patient age, duration of Peyronie’s disease, pretreatment curvature, curvature direction, degree
four-cycle protocol into question.
“What constitutes the optimal number of of fibrosis, vascular findings from duplex DopCCH cycles has not been systematically inves- pler examination, and number of treatment cycles.
tigated. Our study does not provide conclusive Aside from response to the first cycle, none of the
data to state definitively that a fourth cycle is factors was found to differ significantly comparnot effective,” said Dr. Hellstrom, professor of ing men with a final curvature reduction ≥20°
urology and chief of andrology at Tulane Uni- with those having a lesser response.
versity School of Medicine.
Dr. Hellstrom was lead investigator for the
In addition to change in curvature after the first IMPRESS trials and is a speaker for Endo Pharcycle, the variables analyzed as possible predic- maceuticals. UT
Mean curvature
Cheryl Guttman Krader
Based on these findings, Dr. Wolf concluded
that patients incorrectly assigned to surveillance can be adequately salvaged, mitigating
much of the concern about
false negative renal biopsy.
Renal mass biopsy also
informed type of treatment in
those patients who were ultimately treated, said Dr. Wolf.
Using a subset of the University
of Michigan small renal mass
Dr. Wolf
database, he demonstrated
that worse pathology on biopsy was associated
with increased rate of radical nephrectomy in
patients aged 55-75 years.
Referring to this and other work, Dr. Wolf
concluded, “The clinical utility of biopsy is
greatest in patients 55 to 75 years of age with
tumors 2-4 cm in size.”
Lastly, Dr. Wolf made a case that renal mass
biopsy has not been useful to identify those
patients who are likely to be maintained on
active surveillance. He pointed to data from
his institution that demonstrated that size and
growth rate, but not biopsy pathology, was
associated with delayed intervention in those
patients on surveillance.
Dr. Wolf left the audience with an air of
optimism about the future of renal mass biopsy. He previewed yet-to-be presented data
introducing a multi-gene signature with a
highly discriminative association with renal
cancer recurrence and cancer specific mortality. “We may finally be at the doorstep of the
holy grail of renal mass biopsy, which is to
get molecular markers to really help us determine the risk for [an individual] patient,” he
said. UT
For men with mCRPC who have progressed on ADT
Z Y T I G A® & P R E D N I S O N E
LET’S
STRONG
DO
THIS
TOGETHER
INDICATION
ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC).
IMPORTANT SAFETY INFORMATION
Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X)
when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.
Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with
a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure,
hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence
of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with
LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure
(in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct
hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention
at least monthly.
Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after
an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and
signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress.
Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients
treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be
used before, during, and after stressful situations.
mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.
Please see additional Important Safety Information on the next pages.
Please see brief summary of full Prescribing Information on subsequent pages.
For men with mCRPC who have progressed on ADT
ZYTIGA® & PREDNISONE:
(abiraterone acetate)
In the final analysis of the pivotal phase 3 trial*…
ZYTIGA® + prednisone achieved a median OS of almost 3 years
(34.7 months) after a median 4 years (49 months) of follow-up†
4.4 months improvement in median
–
overall survival—34.7 months with
ZYTIGA® + prednisone vs 30.3 months
with placebo + prednisone (active compound)‡
— Co-primary end point—median OS:
hazard ratio (HR)=0.81; 95% CI: 0.70,
0.93; P=0.0033
–Co-primary end point—at the prespecified
rPFS analysis, median not reached for ZYTIGA®
+ prednisone vs a median of 8.28 months for
placebo + prednisone; HR=0.425; 95% CI: 0.347,
0.522; P<0.0001§II
IMPORTANT SAFETY INFORMATION
Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as
recommended (see Prescribing Information for more information). Measure serum transaminases
[alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior
to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and
monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs
suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline
should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper
limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and
closely monitor liver function.
Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or
discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection
and contusion.
The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase,
hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST,
hypophosphatemia, elevated ALT and hypokalemia.
Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction
trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone
by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong
CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only
during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug
interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically
meaningful effect on the pharmacokinetics of abiraterone.
continued on next page
Janssen Biotech, Inc.
© Janssen Biotech, Inc. 2016 02/16 044350-151207
Please see brief summary of
full Prescribing Information
on subsequent pages.
Let’s do this
Prespecified secondary end point¶
ZYTIGA® + prednisone significantly delayed median time to
initiation of cytotoxic chemotherapy
ZYTIGA® + prednisone vs placebo + prednisone:
25.2 vs 16.8 MONTHS
Secondary end point—HR=0.580; 95% CI: 0.487, 0.691; P<0.0001
IMPORTANT SAFETY INFORMATION—continued
Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe
hepatic impairment (Child-Pugh Class C).
034441-150514
Drug Interactions—continued
ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8.
Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If
alternative treatments cannot be used, exercise caution and consider a dose reduction of the
CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of
pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single
dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a
CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.
OS = overall survival; rPFS = radiographic progression-free survival.
*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, doubleblind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy
(N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously
treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily
+ prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily +
prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and rPFS. Select
exclusion criteria included aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥2.5X
ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, prior ketoconazole treatment for
prostate cancer, a history of adrenal gland or pituitary disorders, and visceral organ metastases. Concurrent
use of spironolactone was not allowed during the study period.
†
At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone
compared with 71% (387/542) of patients treated with placebo + prednisone had died.
‡
Prednisone, as a single agent, is not approved for the treatment of prostate cancer.
§
rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification
of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or
modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions.
Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.
II
At the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%)
of patients treated with placebo + prednisone had
radiographic progression.
¶
The secondary efficacy analysis presented here is
as of the December 20, 2011, cutoff date.1
Reference: 1. Data on file. Janssen Biotech, Inc.
Learn more today at www.zytigahcp.com
STRONG T O G E T H E R
ZYTIGA® (abiraterone acetate) Tablets
Brief Summary of Prescribing Information.
ZYTIGA® (abiraterone acetate) Tablets
INDICATIONS AND USAGE
ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the
treatment of patients with metastatic castration-resistant prostate cancer.
CONTRAINDICATIONS
Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant
woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in
women who are or may become pregnant. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, apprise the patient of
the potential hazard to the fetus and the potential risk for pregnancy loss [see
Use in Specific Populations].
Two randomized placebo-controlled, multicenter clinical trials enrolled
patients who had metastatic castration-resistant prostate cancer who were
using a gonadotropin-releasing hormone (GnRH) agonist or were previously
treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was
administered at a dose of 1,000 mg daily in combination with prednisone
5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg
twice daily was given to control patients.
The most common adverse reactions (≥10%) reported in the two randomized
clinical trials that occurred more commonly (>2%) in the abiraterone
acetate arm were fatigue, joint swelling or discomfort, edema, hot flush,
diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection
and contusion.
The most common laboratory abnormalities (>20%) reported in the two
randomized clinical trials that occurred more commonly (≥2%) in the
abiraterone acetate arm were anemia, elevated alkaline phosphatase,
hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia,
elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled
1195 patients with metastatic CRPC who had received prior docetaxel
chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the
absence of liver metastases. Patients with liver metastases were excluded if
AST and/or ALT >5X ULN.
Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred
with a ≥2% absolute increase in frequency compared to placebo or were
events of special interest. The median duration of treatment with ZYTIGA
was 8 months.
WARNINGS AND PRECAUTIONS
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid
Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as
a consequence of increased mineralocorticoid levels resulting from CYP17
inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In
the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of
patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in
1% of patients treated with ZYTIGA [see Adverse Reactions].
Co-administration of a corticosteroid suppresses adrenocorticotropic
hormone (ACTH) drive, resulting in a reduction in the incidence and severity of
these adverse reactions. Use caution when treating patients whose underlying
medical conditions might be compromised by increases in blood pressure,
hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial
infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a
history of cardiovascular disease. The safety of ZYTIGA in patients with left
ventricular ejection fraction <50% or New York Heart Association (NYHA)
Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in
Study 2) was not established because these patients were excluded from
these randomized clinical trials [see Clinical Studies (14) in full Prescribing
Information]. Monitor patients for hypertension, hypokalemia, and fluid
retention at least once a month. Control hypertension and correct hypokalemia
before and during treatment with ZYTIGA.
Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two
randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of
patients taking placebo. Adrenocortical insufficiency was reported in patients
receiving ZYTIGA in combination with prednisone, following interruption of daily
steroids and/or with concurrent infection or stress. Use caution and monitor for
symptoms and signs of adrenocortical insufficiency, particularly if patients are
withdrawn from prednisone, have prednisone dose reductions, or experience
unusual stress. Symptoms and signs of adrenocortical insufficiency may be
masked by adverse reactions associated with mineralocorticoid excess seen
in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests
to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of
corticosteroids may be indicated before, during and after stressful situations
[see Warnings and Precautions].
Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST
increases (at least 5X ULN) were reported in 4% of patients who received
ZYTIGA, typically during the first 3 months after starting treatment. Patients
whose baseline ALT or AST were elevated were more likely to experience
liver test elevation than those beginning with normal values. Treatment
discontinuation due to liver enzyme increases occurred in 1% of patients
taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to
hepatotoxicity events.
Measure serum transaminases (ALT and AST) and bilirubin levels prior to
starting treatment with ZYTIGA, every two weeks for the first three months of
treatment and monthly thereafter. In patients with baseline moderate hepatic
impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST,
and bilirubin prior to the start of treatment, every week for the first month,
every two weeks for the following two months of treatment and monthly
thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical
symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST,
ALT, or bilirubin from the patient’s baseline should prompt more frequent
monitoring. If at any time AST or ALT rise above five times the ULN, or the
bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and
closely monitor liver function.
Re-treatment with ZYTIGA at a reduced dose level may take place only after
return of liver function tests to the patient’s baseline or to AST and ALT less
than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN
[see Dosage and Administration (2.2) in full Prescribing Information].
The safety of ZYTIGA re-treatment of patients who develop AST or ALT
greater than or equal to 20X ULN and/or bilirubin greater than or equal to
10X ULN is unknown.
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid
Excess [see Warnings and Precautions].
• Adrenocortical Insufficiency [see Warnings and Precautions].
• Hepatotoxicity [see Warnings and Precautions].
Clinical Trial Experience: Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.
Table 1: Adverse Reactions due to ZYTIGA in Study 1
ZYTIGA with
Placebo with
Prednisone (N=791)
Prednisone (N=394)
System/Organ Class
All Grades1 Grade 3-4 All Grades Grade 3-4
Adverse reaction
%
%
%
%
Musculoskeletal and
connective tissue disorders
Joint swelling/discomfort2
29.5
4.2
23.4
4.1
Muscle discomfort3
26.2
3.0
23.1
2.3
General disorders
Edema4
26.7
1.9
18.3
0.8
Vascular disorders
Hot flush
19.0
0.3
16.8
0.3
Hypertension
8.5
1.3
6.9
0.3
Gastrointestinal disorders
Diarrhea
17.6
0.6
13.5
1.3
Dyspepsia
6.1
0
3.3
0
Infections and infestations
Urinary tract infection
11.5
2.1
7.1
0.5
Upper respiratory tract
infection
5.4
0
2.5
0
Respiratory, thoracic and
mediastinal disorders
Cough
10.6
0
7.6
0
Renal and urinary disorders
Urinary frequency
7.2
0.3
5.1
0.3
Nocturia
6.2
0
4.1
0
Injury, poisoning and
procedural complications
Fractures5
5.9
1.4
2.3
0
Cardiac disorders
Arrhythmia6
7.2
1.1
4.6
1.0
Chest pain or chest
discomfort7
3.8
0.5
2.8
0
Cardiac failure8
2.3
1.9
1.0
0.3
1 Adverse events graded according to CTCAE version 3.0
2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,
Musculoskeletal discomfort, and Musculoskeletal stiffness
4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized
edema
5 Includes all fractures with the exception of pathological fracture
6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular
tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter,
Bradycardia, Atrioventricular block complete, Conduction disorder, and
Bradyarrhythmia
7 Includes terms Angina pectoris, Chest pain, and Angina unstable.
Myocardial infarction or ischemia occurred more commonly in the placebo
arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).
8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular
dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and
Ejection fraction decreased
ZYTIGA® (abiraterone acetate) Tablets
ZYTIGA® (abiraterone acetate) Tablets
Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4
low serum phosphorus (7%) and low potassium (5%) occurred at a greater
than or equal to 5% rate in the ZYTIGA arm.
Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm
of Study 2
Abiraterone (N=542)
Placebo (N=540)
Laboratory
Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Abnormality
%
%
%
%
Hematology
Lymphopenia
38.2
8.7
31.7
7.4
Chemistry
56.6
6.5
50.9
5.2
Hyperglycemia1
High ALT
41.9
6.1
29.1
0.7
High AST
37.3
3.1
28.7
1.1
Hypernatremia
32.8
0.4
25.0
0.2
Hypokalemia
17.2
2.8
10.2
1.7
1Based on non-fasting blood draws
Table 2: Laboratory Abnormalities of Interest in Study 1
Abiraterone (N=791)
Placebo (N=394)
Laboratory
All Grades Grade 3-4 All Grades Grade 3-4
Abnormality
(%)
(%)
(%)
(%)
Hypertriglyceridemia
62.5
0.4
53.0
0
High AST
30.6
2.1
36.3
1.5
Hypokalemia
28.3
5.3
19.8
1.0
Hypophosphatemia
23.8
7.2
15.7
5.8
High ALT
11.1
1.4
10.4
0.8
High Total Bilirubin
6.6
0.1
4.6
0
Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088
patients with metastatic CRPC who had not received prior cytotoxic
chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and
patients were excluded if they had liver metastases.
Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred
with a ≥2% absolute increase in frequency compared to placebo. The
median duration of treatment with ZYTIGA was 13.8 months.
Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in
Study 2
ZYTIGA with
Placebo with
Prednisone (N=542)
Prednisone (N=540)
System/Organ Class
All Grades1 Grade 3-4 All Grades Grade 3-4
Adverse reaction
%
%
%
%
General disorders
Fatigue
39.1
2.2
34.3
1.7
25.1
0.4
20.7
1.1
Edema2
Pyrexia
8.7
0.6
5.9
0.2
Musculoskeletal and
connective tissue disorders
30.3
2.0
25.2
2.0
Joint swelling/discomfort3
Groin pain
6.6
0.4
4.1
0.7
Gastrointestinal disorders
Constipation
23.1
0.4
19.1
0.6
Diarrhea
21.6
0.9
17.8
0.9
Dyspepsia
11.1
0.0
5.0
0.2
Vascular disorders
Hot flush
22.3
0.2
18.1
0.0
Hypertension
21.6
3.9
13.1
3.0
Respiratory, thoracic and
mediastinal disorders
Cough
17.3
0.0
13.5
0.2
Dyspnea
11.8
2.4
9.6
0.9
Psychiatric disorders
Insomnia
13.5
0.2
11.3
0.0
Injury, poisoning and
procedural complications
Contusion
13.3
0.0
9.1
0.0
Falls
5.9
0.0
3.3
0.0
Infections and infestations
Upper respiratory tract
infection
12.7
0.0
8.0
0.0
Nasopharyngitis
10.7
0.0
8.1
0.0
Renal and urinary disorders
Hematuria
10.3
1.3
5.6
0.6
Skin and subcutaneous tissue
disorders
Rash
8.1
0.0
3.7
0.0
1 Adverse events graded according to CTCAE version 3.0
2 Includes terms Edema peripheral, Pitting edema, and Generalized edema
3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
Table 4 shows laboratory abnormalities that occurred in greater than 15% of
patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo
in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high
alanine aminotransferase (6%) occurred at a greater than 5% rate in the
ZYTIGA arm.
Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2,
cardiac failure occurred more commonly in patients treated with ZYTIGA
compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4
cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to
5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred
in 0.2% of patients taking placebo. There were no treatment discontinuations
and one death due to cardiac failure in the placebo group.
In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was
one death associated with arrhythmia and one patient with sudden death
in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%)
deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%)
deaths in the placebo arms. Myocardial ischemia or myocardial infarction
led to death in 3 patients in the placebo arms and 2 deaths in the
ZYTIGA arms.
Post Marketing Experience
The following additional adverse reactions have been identified during post
approval use of ZYTIGA. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
Musculoskeletal and Connective Tissue Disorders: myopathy, including
rhabdomyolysis.
DRUG INTERACTIONS
Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA
is a substrate of CYP3A4.
In a dedicated drug interaction trial, co-administration of rifampin, a strong
CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid
concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong
CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing
frequency [see Dosage and Administration (2.3) and Clinical Pharmacology
(12.3) in full Prescribing Information].
In a dedicated drug interaction trial, co-administration of ketoconazole, a
strong inhibitor of CYP3A4, had no clinically meaningful effect on the
pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full
Prescribing Information].
Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an
inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In
a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan
(CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when
dextromethorphan was given with abiraterone acetate 1,000 mg daily and
prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate
with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).
If alternative treatments cannot be used, exercise caution and consider a
dose reduction of the concomitant CYP2D6 substrate drug [see Clinical
Pharmacology (12.3) in full Prescribing Information].
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of
pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone
was given together with a single dose of 1,000 mg abiraterone acetate.
Therefore, patients should be monitored closely for signs of toxicity
related to a CYP2C8 substrate with a narrow therapeutic index if used
concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full
Prescribing Information]. USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause
fetal harm when administered to a pregnant woman based on its mechanism of
action and findings in animals. While there are no adequate and well-controlled
studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in
women, it is important to know that maternal use of a CYP17 inhibitor could
ZYTIGA® (abiraterone acetate) Tablets
ZYTIGA® (abiraterone acetate) Tablets
affect development of the fetus. Abiraterone acetate caused developmental
toxicity in pregnant rats at exposures that were lower than in patients
receiving the recommended dose. ZYTIGA is contraindicated in women who
are or may become pregnant while receiving the drug. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
apprise the patient of the potential hazard to the fetus and the potential risk for
pregnancy loss. Advise females of reproductive potential to avoid becoming
pregnant during treatment with ZYTIGA.
In an embryo-fetal developmental toxicity study in rats, abiraterone acetate
caused developmental toxicity when administered at oral doses of 10, 30 or
100 mg/kg/day throughout the period of organogenesis (gestational days
6-17). Findings included embryo-fetal lethality (increased post implantation
loss and resorptions and decreased number of live fetuses), fetal
developmental delay (skeletal effects) and urogenital effects (bilateral ureter
dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at
≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses
≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in
systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively,
the AUC in patients.
Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known
if abiraterone acetate is excreted in human milk. Because many drugs are
excreted in human milk, and because of the potential for serious adverse
reactions in nursing infants from ZYTIGA, a decision should be made to
either discontinue nursing, or discontinue the drug taking into account the
importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have
not been established.
Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3
trials, 73% of patients were 65 years and over and 30% were 75 years and
over. No overall differences in safety or effectiveness were observed between
these elderly patients and younger patients. Other reported clinical experience
has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients with Hepatic Impairment: The pharmacokinetics of abiraterone
were examined in subjects with baseline mild (N=8) or moderate (N=8)
hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy
control subjects with normal hepatic function. The systemic exposure
(AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased
by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate
baseline hepatic impairment, respectively compared to subjects with normal
hepatic function.
In another trial, the pharmacokinetics of abiraterone were examined in
subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C)
and in 8 healthy control subjects with normal hepatic function. The systemic
exposure (AUC) of abiraterone increased by approximately 7-fold and the
fraction of free drug increased 2-fold in subjects with severe baseline hepatic
impairment compared to subjects with normal hepatic function.
No dosage adjustment is necessary for patients with baseline mild hepatic
impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once
daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment
(Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin
>3X ULN occur in patients with baseline moderate hepatic impairment,
discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and
Clinical Pharmacology (12.3) in full Prescribing Information].
For patients who develop hepatotoxicity during treatment, interruption of
treatment and dosage adjustment may be required [see Dosage and
Administration (2.2) in full Prescribing Information, Warnings and Precautions,
and Clinical Pharmacology (12.3)] in full Prescribing Information.
Patients with Renal Impairment: In a dedicated renal impairment trial,
the mean PK parameters were comparable between healthy subjects with
normal renal function (N=8) and those with end stage renal disease (ESRD)
on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage
adjustment is necessary for patients with renal impairment [see Dosage
and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing
Information].
Based on its mechanism of action, ZYTIGA may harm a developing fetus.
Therefore, women who are pregnant or women who may be pregnant should
not handle ZYTIGA without protection, e.g., gloves [see Use in Specific
Populations].
OVERDOSAGE
Human experience of overdose with ZYTIGA is limited.
There is no specific antidote. In the event of an overdose, stop ZYTIGA,
undertake general supportive measures, including monitoring for arrhythmias
and cardiac failure and assess liver function.
Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions
permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled
room temperature].
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
• Patients should be informed that ZYTIGA and prednisone are used
together and that they should not interrupt or stop either of these
medications without consulting their physician.
• Patients receiving GnRH agonists should be informed that they need to
maintain this treatment during the course of treatment with ZYTIGA and
prednisone.
• Patients should be informed that ZYTIGA should not be taken with food
and that no food should be consumed for at least two hours before the
dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA
is taken. They should be informed that the tablets should be swallowed
whole with water without crushing or chewing. Patients should be
informed that taking ZYTIGA with food causes increased exposure and this
may result in adverse reactions.
• Patients should be informed that ZYTIGA is taken once daily and
prednisone is taken twice daily according to their physician’s instructions.
• Patients should be informed that in the event of a missed daily dose of
ZYTIGA or prednisone, they should take their normal dose the following
day. If more than one daily dose is skipped, patients should be told to
inform their physician.
• Patients should be apprised of the common side effects associated with
ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated
liver function tests, and urinary tract infection. Direct the patient to a
complete list of adverse reactions in PATIENT INFORMATION.
• Patients should be advised that their liver function will be monitored using
blood tests.
• Patients should be informed that ZYTIGA may harm a developing fetus;
thus, women who are pregnant or women who may be pregnant should
not handle ZYTIGA without protection, e.g., gloves. Patients should also be
informed that it is not known whether abiraterone or its metabolites are
present in semen and they should use a condom if having sex with a
pregnant woman. The patient should use a condom and another effective
method of birth control if he is having sex with a woman of child-bearing
potential. These measures are required during and for one week after
treatment with ZYTIGA.
Manufactured by:
Patheon Inc.
Mississauga, Canada
Manufactured for:
Janssen Biotech, Inc.
Horsham, PA 19044
©Janssen Biotech, Inc. 2012
Revised: Dec 2015
044724-151215
UrologyTimes.com
∣
❳ Clinical Updates ❲
JUNE 2016
17
Pediatric Urology Prevention of future UTI is parents’ most important consideration
VUR decision tool incorporates parent preference
Cheryl Guttman Krader
UT CONTRIBUTING EDITOR
San Diego—Researchers developing a stan-
dardized shared decision-making tool for use
by urologists and parents of children with vesicoureteral reflux (VUR) expect that it will be
helpful for improving the quality of the provider-family discussion on VUR management
options and ultimately parental satisfaction
with care.
The purpose of the tool is to enable parents
and physicians to identify issues that are most
important to the family when deciding on treatment. It would thereby allow a more robust and
thoughtful conversation regarding treatment
options that is framed around a particular family’s prioritization of risks and benefits.
At the AUA annual meeting in San Diego, the
authors presented the findings from completion
of the first phase of the project that entailed
detailed content analysis of semi-structured
parental qualitative interviews to identify core
themes describing parental preferences.
“Management options for children with
VUR include watchful waiting, antibiotic prophylaxis, and surgery. However, these choices
may offer a similar risk-benefit balance, and
so there is often no one right answer for a given child, but there may be a best answer that
accounts for the family’s values and preferences. To date, however, there are no clinical
tools that can assist parents in formulating
an evidence-based decision while simultaneously taking their preferences into account,”
said senior author Hillary L. Copp, MD, MS,
“Our hypothesis is that using the
tool to allow more informed decisionmaking will lead to improvement
in overall decision quality and also
parental satisfaction with care.”
HILLARY L. COPP, MD, MS
associate professor of urology at the University
of California, San Francisco.
“Such a decision-making tool is only as good
as the foundation on which it is built. We are
confident that we have now identified the different attributes of decision-making that are
important to parents of children with VUR
and have a solid base for creating the decisionmaking tool.”
To identify core themes describing issues
important to parents of children with VUR,
Dr. Copp conducted semi-structured, qualitative interviews with parents of children who
had been managed with the various treatment
options. She continued to conduct interviews
until no new ideas or concepts emerged. Then,
transcripts of the interviews were reviewed and
statements specifically differentiating between
treatment options were extracted and grouped
into themes by two independent researchers.
13 major themes identified
Through that process, 13 major themes were
identified, Dr. Copp said. The most frequently
cited related to the ability of the option to prevent future urinary tract infections (85%). Other dominant themes related to each treatment
option’s unique efficacy rate (85%), compliance
burdens (77%), risk of antibiotic resistance
(69%), risk of chronic kidney damage (62%),
providing the feeling of taking action (62%),
invasiveness (58%), and anesthesia requirement
(50%).
After building the decision tool, the authors
will evaluate it in the clinic to determine when
and how it is best used. In addition, they are
planning to conduct clinical trials in which
parents might be randomly assigned to receive
standard information about VUR management
options alone or with use of the decision-making tool in order to assess if the tool affects
issues such as decisional quality, conflict, and
regret.
“Our hypothesis is that using the tool to allow
more informed decision-making will lead to
improvement in overall decision quality and
also parental satisfaction with care,” Dr. Copp
told Urology Times.
Dr. Copp’s collaborators in this project
include Christopher Saigal, MD, MPH, of the
University of California Los Angeles, who
developed a shared decision-making tool for
men with prostate cancer; Anand Bodapati,
PhD, MS, of Anderson School of Management, University of California Los Angeles,
who has expertise in conjoint analysis for
marketing science; Jonathan C. Routh, MD,
MPH, of Duke University; and Geraldine
Tran, of the University of California, San
Francisco. UT
Guidelines needed for pediatric counseling on fertility, sexual function
In a commentary published online ahead of print in Pediatrics (May 19, 2016), researchers call for the creation of
a panel of experts to develop communication guidelines
for providers to use when counseling young patients on
fertility and sexual function.
The authors cite a growing body of literature on the
long-term impact of various pediatric conditions and
treatments on fertility and sexual function. Thus far, the
main focus of research has been on fertility preservation prior to cancer therapy, according to a press release
from Moffitt Cancer Center, Tampa, FL, which was one of
the institutions involved with the commentary. There is
minimal guidance for providers with regard to discuss-
ing issues related to fertility and sexual function with
pediatric patients after cancer treatment has ended,
and on an ongoing basis in other pediatric populations.
Although awareness about reproductive and sexual
health is gradually increasing in the care of patients with
rheumatic diseases, hematologic conditions, disorders of
sex development, transgender health, and many genetic
conditions, consistent practices regarding counseling are
still lacking, the authors say. In some cases, the initial
discussions about fertility may take place in infancy or
early childhood, resulting in a situation where the patient
could remain unaware of these implications until much
later in life.
The authors suggest that an interdisciplinary task
force should be formed to develop specific guidelines
for fertility and sexual function counseling in at-risk
pediatric populations. They urge that these guidelines
specify key points to cover at different developmental
stages, discuss which health care provider holds responsibility for these communications, and provide direction
on how to balance the goals of parents and patients.
“Acknowledging the impact of reproductive and
sexual function on patients’ long-term quality of life
and incorporating routine counseling on these issues
into treatment plans is essential to achieving optimal
outcomes,” the authors concluded.
18
❳Hands On❲
TH E L ATEST I N U RO LO G I C SU RG I C AL TECH N I Q U E S
AN D O FFICE - BA S E D PRO CE D U R E S
JUNE 2016
∣
Urology Times
How to manage recurrent UTIs
in postmenopausal women
Successful strategies incorporate treatment of contributing factors, preventive regimens
Wade Bushman, MD, PhD
▪
Brian V. Le, MD, MA
R
Dr. Bushman
Dr. Le
Dr. Bushman is professor of
urology and Dr. Le is assistant
professor of urology at the
University of Wisconsin, Madison.
ecurrent urinary tract infections
(UTIs) in postmenopausal women
can be a particularly challenging
problem. We acknowledge there is
no clear-cut solution to this vexing
problem, but various strategies can be employed
that have found success.
Asymptomatic bacteriuria is common in
postmenopausal women, and the incidence
increases with age, diabetes, and sexual activity. There is a correlation of bacteriuria with
risk for symptomatic UTI; however, it is not
recommended to treat asymptomatic bacteriuria, as it may paradoxically increase the risk
of symptomatic UTI. The goal, then, is to treat
as necessary but to avoid overtreatment.
UTIs in postmenopausal women may occur
with typical symptoms (urgency, frequency,
dysuria, incontinence, and foul odor) or fever.
In some patients, such as those with impaired
mentation, the diagnosis can be less obvious
and is often implicated as a causative factor
in temporary decreased cognition. In patients
with a history of lower urinary tract symptoms
(LUTS), symptoms may be exacerbated by
UTI, but in the absence of typical UTI symptoms it is often difficult to determine whether
an up-tick in LUTS is really due to UTI or is
simply symptomatic fluctuation superimposed
on asymptomatic bacteriuria.
Detailed history
Section Editor
Christopher M.
Gonzalez, MD,
MBA, is professor and chairman
of urology at
University Hospitals Case Medical Center and Case
Western Reserve University School
of Medicine, Cleveland.
The appropriate management of a patient presenting with “recurrent UTIs” starts with an
appropriate evaluation.
First, a detailed history must be taken to elicit
symptoms, severity (fevers, hospitalizations,
ER visits), frequency (weekly, monthly), microbiology (organisms and resistance patterns),
comorbidities, prior evaluations, treatments,
and responses to date. Contributing conditions
may be identified on physical examination,
bimanual and vaginal exam, and post-void
residual measurement.
A key step is to elicit the symptoms associated with reported UTI episodes and match
them with laboratory findings. Many times,
the patient’s urinary symptoms are not due to
bacterial infection. This distinction is critical
to make, since prevalence of both asymptom-
atic bacteriuria and LUTS is high in elderly
women and bacteriuria may be inappropriately
implicated as the cause of the patient’s troubles.
In fact, patients may have primary voiding
dysfunction and the diagnosis of “recurrent
UTIs” may result from the follow-up cultures
obtained by a diligent primary care physician
after antibiotic treatment that really only shows
re-colonization with asymptomatic bacteriuria.
A key step in taking a
patient’s history is to elicit
the symptoms associated with
reported UTI episodes and
match them with laboratory
findings.
If a history is obtained that is consistent with
recurrent bacterial UTIs with associated symptoms and prompt response to culture-directed
antimicrobial therapy, then the next step is to
rule out recurrent UTIs due to a hidden nidus
of infection such as a stone, tumor, or foreign
body. The tip-off is quickly relapsing infection with the same organism. If this is found,
then a complete urologic evaluation with upper
tract imaging and cystoscopy is indicated. In
patients with recurrent UTIs with a variety of
organisms and no history of febrile infection,
neither cystoscopy nor upper tract imaging is
necessary and the focus moves to management:
treatment of contributing factors, prevention,
and antibiotic treatment.
Treatment of contributing factors
Vaginal atrophy is common in postmenopausal
women and can be identified on pelvic examination by the appearance of dry, friable, and
thin mucous membranes. The pathogenesis of
recurrent UTIs is believed to be due to alterations in bacterial flora, changes in vaginal pH,
and breakdown of natural mucosal barriers pre-
UrologyTimes.com
∣
❳Hands On❲
JUNE 2016
venting ascending infection. The mechanism
of local estrogen replacement stimulates blood
flow, increases pH, and aims to restore mucosal
barriers. A Cochrane review from 2008 cited
two randomized clinical trials (RCTs) showing
that vaginal estrogens reduced the recurrence
of UTIs compared to placebo with RR of 0.25
and 0.64 in each study (Cochrane Database
Syst Rev 2008:CD005131). No such benefit was
found with oral estrogens.
In our practice, if there is evidence of vaginal atrophy on pelvic examination, we strongly
consider such an approach. The risks for local
therapy are very low, with the most common
side effect being local irritation.
Preventive strategies
The use of probiotics is controversial. Some
RCTs show benefit while others do not. A
major confounder is that the term “probiotics” is not specific. It includes oral and vaginal
administration and may utilize either specific
or multi-strain regimens. Thus, meta-analysis
interpretation is limited. Furthermore, few
studies looked specifically at UTIs in postmenopausal women. The purported mechanism of action of probiotics is to establish
vaginal colonization that acts as a barrier to
ascending infection, prevent re-colonization
of the vagina by potential uropathogens, and
modulate host defenses.
The most compelling evidence is for use
of intravaginal suppositories of Lactobacillus crispatus. In a recent RCT, use of such an
approach had a relative risk of 0.50 in young
women (Clin Infect Dis 2011; 52:1212-7).
Given the low risk-benefit profile of intravaginal suppositories taken on a weekly basis
after treatment of the acute UTI, this tends
to be an attractive option for patients interested in non-antibiotic-based approaches. If
intravaginal Lactobacillus suppositories are
not available at a retail pharmacy, patients
may be directed to online retailers such as
Amazon.
Cranberry extracts or cocktails taken on a
daily basis are believed to reduce the risk of
recurrent UTIs. The magnitude of their effect
is somewhat under question as highlighted by
a recent Cochrane analysis, but several RCTs
and meta-analyses have demonstrated benefit
compared to placebo (Cochrane Database
Syst Rev 2012; 10:CD001321). Some of this
variation may be due to lack of standardization of treatment. Nevertheless, cranberry
extracts are an inexpensive, well-tolerated
dietary supplement that has evidence supporting its use.
Antibiotic strategies
Antibiotic prophylaxis is a highly effective
way to reduce the incidence of recurrent UTI.
19
❳ UT Table ❲ Antibiotic prophylaxis for recurrent UTI
Agent
Brand name(s)
Dosage
Precautions
Side effects
Severe allergic
reaction, fever,
rash, GI
symptoms
GI symptoms,
dizziness, seizure,
arthralgia, tendon
rupture
Trimethoprimsulfamethoxazole
Bactrim,
Sulfatrim
400/80
mg
Sulfa-allergy, liver
or kidney
dysfunction
Ciprofloxacin
Cipro, Proquin
250 mg
Cephalexin
Keflex
250 mg
Interactions with
medications
affecting
absorption, renal
dysfunction
(None)
Nitrofurantoin
Macrobid,
Furadantin,
Macrodantin
100 mg
Kidney
dysfunction
GI symptoms,
severe allergic
reaction, rash
Pulmonary
fibrosis (rare),
interstitial
pneumonitis,
abnormal urine
color
Source: Wade Bushman, MD, PhD, Brian V. Le, MD, MA
The agents most commonly used are trimethoprim-sulfamethoxazole or trimethoprim
(Bactrim, Sulfatrim), ciprofloxacin (Cipro,
Proquin), cephalexin (Keflex), and nitrofurantoin (Macrobid, Furadantin, Macrodantin) (table). Standard dosing regimens use
low-dose nightly administration to produce
effective antibiotic concentrations in the urine
without inducing resistance in the gut flora.
This is critical since the gut is the source of
potential uropathogens and higher doses will
compromise the effectiveness of the prophylactic regimen.
The recommended doses are trimethoprimsulfamethoxazole, 400/80 mg; ciprofloxacin, 250 mg; and cephalexin, 250 mg. Trimethoprim, 80 mg can be used in patients with
sulfa allergy.
Nitrofurantoin is a very useful prophylactic
agent, especially because it is effective against
many extended spectrum beta lactamase-producing Escherichia coli and is less likely to
breed resistance, but use in the elderly is generally discouraged because of a relatively higher
risk of serious side effects, including pulmonary fibrosis. Its use should therefore be based
on a careful consideration of benefit versus
risk. In postmenopausal women whose UTIs
are clearly related to sexual activity, post-coital
prophylaxis can be prescribed.
Several studies have demonstrated that
women, when appropriately counseled, can
reliably recognize the symptoms of UTI and
initiate empiric treatment. The concept of
self-start therapy is to provide the patient with
a treatment for early intervention for UTIs
that occur with modest frequency (3-6 times
per year). They are prescribed a single agent,
and at the earliest signs of infection start therapy for a full treatment course—typically 3
days for an uncomplicated UTI. If symptoms
do not respond quickly or are associated with
fever, then they must seek prompt medical
attention.
Self-start therapy often alleviates patient
anxiety, reduces the time-to-treat, and provides
the patient with a sense of control. However, it
must be emphasized that this strategy is recommended only for a highly reliable patient who
has been thoroughly evaluated and appropriately counseled.
Conclusions
Recurrent UTI in the postmenopausal woman
is a common problem that can be effectively
addressed by a step-wise approach that produces historical and laboratory evidence for
recurrent symptomatic UTIs, rules out bacterial persistence and relapsing infections that
merit further diagnostic evaluation, identifies
and addresses contributing conditions, and
offers the patient an effective regimen of prophylaxis or self-start therapy. This entity should
be distinguished from asymptomatic bacteriuria, which should be managed conservatively
without antibiotics. UT
20
❳Business of Urology❲
JUNE 2016
∣
Urology Times
MIPS: A first look at how it will
affect your practice
‘Four-legged stool’ replaces PQRS, meaningful use, value-based payment modifier
T
he Centers for Medicare &
Medicaid Services (CMS)
has released a proposed rule
regarding the implementation
of the Medicare Access and
CHIP Reauthorization Act (MACRA) of
2015. This article will summarize some of
the details of the proposed rule, including
an outline of the Merit-Based Incentive
Payment System (MIPS), one of the key
components of MACRA.
It is important to remember the MACRA legislation was focused solely on
Medicare and replacing the sustainable
growth rate. In short, MACRA is not up
for repeal, nor is this a piece of legislation
tied to the Affordable Care Act directly;
therefore, it is not expected to change even
if there is a change following the presidential election.
The proposed rule, released on April
27, 2016, is in fact the first step in introducing the rules for MIPS. As with any
proposed rule from the Medicare system,
there is a 90-day comment period allowing any interested party to criticize the
rule, point out any inconsistencies, suggest changes, and propose modifications.
The AUA, American Medical Association, American College of Surgeons, and
other specialty organizations will be
submitting comments by the deadline of
June 27, 2016. As a participating provider,
you have the opportunity to provide comments directly to CMS or to any one of
the organizations that you feel may represent you.
CMS expects a number of comments
will be received and that modifications
to this initial proposal will follow. CMS
also indicated that it expects this program
Ray Painter, MD, Mark Painter
Urologist Ray Painter, MD, is president of Physician
Reimbursement Systems, Inc., in Denver and is also
publisher of Urology Coding and Reimbursement
Sourcebook. Mark Painter is CEO of PRS
Urology SC in Denver.
will be modified as it is implemented over
a period of several years.
MIPS: The four-legged stool
One of the key provisions of MACRA was
the replacement of the current Physician
Quality Reimbursement System, meaningful use, and value-based payment mod-
❳
❯❯ THE BOT TOM LINE
❯❯ MONE Y MAT TERS
29 Health savings account provides triple benefit
Please see MIPS, page 22
Proposed data submission
❲ clinicians reporting individually
UT Table 1 mechanisms for MIPS-eligible
Performance category/submission
Combinations accepted
Quality
Data submission mechanisms
Claims
Qualified Clinical Data Registry (QCDR)
Qualified registry
EHR
Administrative claims (no submission required)
Resource Use
Administrative claims (no submission required)
Advancing Care Information
Attestation
QCDR
Qualified registry
EHR
Clinical Practice Improvement
Activities
Attestation
QCDR
Qualified registry
EHR
Administrative claims (if technically feasible, no
submission required)
Business of Urology
23 MACRA pay models: What you can expect
ifier—the three-legged “quality” stool—
with MIPS, a four-legged stool comprising
Quality, Resource Use, Clinical Practice
Improvement Activities, and Advancing
Care Information.
For reporting under MIPS, CMS has
indicated that it will continue to accept
virtually all MIPS-required reporting via
multiple formats. Similar to the reporting for the value-based payment modifier (VBM) today, some reporting will be
considered automatic or administrative,
meaning CMS will use information submitted to CMS via claims to calculate a
portion of the composite program score
(CPS). The CPS is a single scoring system
that will be used for eligible clinicians.
One of the stated goals of the new system is to eliminate overlap and decrease
the workload of providers. (The jury is
definitely still out on this projection.)
Bonuses and penalties have been consolidated in the new system with a stair
step approach to an eventual potential
9% bonus or a 9% penalty for all Medicare payments. Bonuses/penalties will be
Coding and
Reimbursement
Source: Centers for Medicare & Medicaid Services
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6S`TW\Z(TLYPJH0UJ;YHKLTHYRVYYLNPZ[LYLK;YHKLTHYRVM6S`TW\ZHUKP[ZH
SPH[LKLU[P[PLZPU[OL<:HUKVYV[OLYJV\U[YPLZVM[OL^VYSK(SSWH[LU[ZHWWS`6(0<96(+
❳Business of Urology❲
22
JUNE 2016
Quality, EHR use among CPS components
continued from page 20
awarded based on a sliding scale and are budget
neutral, which means you will be in competition with your colleagues.
Tables 1 and 2 demonstrate the group and
individual reporting methods proposed for
MIPS.
The four elements of the CPS
The proposed rule outlines the components of
the MIPS CPS (table 3). Initially, the CPS will
consist of the following elements:
Quality Performance. CMS has touted that
MIPS lowers the administrative burden. The
Quality Performance area does provide a small
amount of relief because although measures are
still required (similar to and including exist-
❳
❲
ing PQRS measures), there will “only” be six
measures required, down from nine under the
current PQRS.
Additionally, the Quality Performance component allows for more flexibility as the restriction of three cross-cutting measures has been
removed. Now, the six measures must include
only one cross-cutting measure and one outcome measure, if available. If an outcome measure is not available, the eligible clinician may
select a “high-priority” measure.
As you can see from the tables, practices
will be allowed to report in multiple ways.
However, Medicare proposes to provide bonus
points in the CPS for quality if you report
through a qualified clinical data registry
Proposed data submission mechanisms
UT Table 2 for groups
Performance category/submission
Combinations accepted
Quality
Data submission mechanisms
QCDR
Qualified registry
EHR
CMS web interface (groups of 25 or more)
CMS-approved survey vendor for CAHPS for MIPS (must be reported in conjunction with another data submission mechanism)
Administrative claims (no submission required)
Resource Use
Administrative claims (no submission required)
Advancing Care Information
Attestation
QCDR
Qualified registry
EHR
CMS web interface (groups of 25 or more)
Clinical Practice Improvement
Activities
Attestation
QCDR
Qualified registry
EHR
CMS web interface (groups of 25 or more)
Administrative claims (if technically feasible, no submission
required)
Source: Centers for Medicare & Medicaid Services
❳ UT Table 3 ❲ Components of MIPS
MIPS component
Quality Performance
Resource Use
Clinical Practice Improvement Activities
Advancing Care Information
Comments
Percentage of total CPS
Replaces PQRS and part of the VBM
50%
Replaces part of the VBM
10%
No current measures in this area
15%
Replaces MU program
25%
Source: Centers for Medicare & Medicaid Services
∣
Urology Times
(QCDR), certified EHR, qualified registry,
or web interface.
Resource Use. This component as proposed
currently continues to employ similar formulas and methods currently in use in the VBM.
CMS has acknowledged the system is flawed
and is vowing to make some changes, but in
the form of additional measures for episodes of
care. This component is measured on the claims
submitted to Medicare for each beneficiary and
includes not only those services submitted by
urologists but also services submitted by others.
No additional reporting is required.
Clinical Practice Improvement Activities (CPIA).
CPIA is a new measure under MACRA. The
proposed rule allows for points for participating
in any CPIA selected from a list to add points
to increase your score in this component. Individuals and groups will be essentially graded
on a curve compared to others. Medical home
participants and those in alternative payment
models will be required/encouraged to participate by including CPIAs in the requirement for
those programs.
The Quality Performance component
of MIPS allows for more flexibility as
the restriction of three cross-cutting
measures has been removed.
CPIAs include tasks like using telehealth
for treatment, developing patient surveys and
improvement protocols based on results, participation in population health review and
study, improved coordination of care, active
engagement of Medicare beneficiaries, patient
safety protocols and practice assessment, and
participation in a QCDR. In all, there are 90
proposed CPIAs with varying values that
can be implemented for a period of 90 days.
Medicare has encouraged more input in this
area, and more clarification and education
undoubtedly will be required once the final
rule is published.
Advancing Care Information (ACI). Primarily,
this portion of the CPS is to continue to encourage (insist/implore/require) the use of electronic health records based on the objectives
of the HITECH Act, which provided incentives
to adopt an EHR. As such, the proposed rule
modifies the existing requirements for meanPlease see MIPS, page 23
The information in this column is designed to be authoritative,
and every effort has been made to ensure its accuracy at the
time it was written. However, readers are encouraged to check
with their individual carrier or private payers for updates and to
confirm that this information conforms to their specific rules.
UrologyTimes.com
∣
23
JUNE 2016
MACRA pay models:
What you can expect
CMS estimates >8,000 urologists will be subject to merit-based
incentive payment system
M
ore than 1 year ago, President
Obama signed into law the
Medicare Access and CHIP
Reauthorization Act of 2015
(MACRA). This legislation
was the product of overwhelmingly bipartisan
support and was lauded by many health care
stakeholders because it repealed the unpopular sustainable growth rate (SGR) method for
updating the Medicare physician fee schedule.
As physicians well know, the SGR led to uncertainty, threats of major pay cuts, and annual
corrections known as the “doc fix.”
MACRA is most notable for its sweeping
changes to the way health care will be reimbursed
in the future, and many have awaited details of its
implementation. Those details began to emerge
on April 27, 2016, when the Centers for Medicare & Medicaid Services (CMS) released its
proposed rule for implementing MACRA.
In a series of articles this year, I will examine
what you need to know about the law, what the
CMS proposed rule for implementation implies
for the near and long-term future, and—when
it is issued later this year—what the final rule
means to your urology practice. (For more on the
MACRA rollout, see “MIPS: A first look at how it
will affect your practice, page 20, and “MACRA
proposed rule brings new decisions,” page 43.)
What MACRA does
Here are the basics of the law: MACRA
repealed the SGR updates to the Medicare
Physician Fee Schedule and replaced it with
a flat 0.5% annual fee increase until 2019; no
further increases will occur until 2026. In 2019
and beyond, physician reimbursement will be
tied to quality through participation in either
the Merit-Based Incentive Payment System
(MIPS) or an Advanced Alternative Payment
Model (APM). Finally, in 2026, the Physician
Fee Schedule will begin to increase again,
but slightly faster for physicians in Advanced
APMs than those in MIPS.
Who is in MIPS versus an Advanced APM?
According to the law, all eligible professionals
will be subject to MIPS unless they meet one of
three exceptions: They are in their first year of
participation in Medicare; they do not exceed a
low volume threshold of Medicare payments or
patients; or they are a qualifying participant in
an Advanced APM. In the proposed rule, CMS
has suggested that the low volume threshold
be less than or equal to $10,000 in Medicare
payments or 100 Medicare patients.
It is important to understand that MIPS is
the default pathway, and it is only by qualifying for an exception that a professional can be
excluded from MIPS. Most urologists are not in
their first year of Medicare participation, and
most urologists would exceed the low volume
thresholds being proposed by CMS. The proposed criteria for being a qualifying participant
in an Advanced APM are constraining for many
specialists, including urologists.
Therefore, it is widely believed (including
AMA identifies several problematic issues
continued from page 22
ingful use. The reporting period under MIPS is
for a full calendar year. Clinical quality measures, computerized physician order entry, and
clinical decision support have been removed as
specific reporting measures.
The CPS for this element is a combination
of requirements including patient access and
interoperability. Bonus points will be awarded
to reporting to multiple sources and increasing
patient access.
Summary
Stay tuned for the final rule, and be prepared to
participate in or consider an alternative to par-
ticipating in Medicare. There is a lot of money
at stake.
A few issues that were identified by the AMA
as problematic include limited measures for
some specialties, including urology; retention
of current flawed methods for VBM; costs to
providers for certified EHR technology; lack
of ability of providers to perform true security
risk assessments; reliance on hospital-based
programs for clinical services; continuation of
policies that physicians already fail; and a complexity that makes MIPS difficult to understand
and implement, among other issues.
MIPS, as noted by many, is going to impact
The Bottom Line
Robert A. Dowling, MD
Dr. Dowling is vice president of
medical affairs and policy for IntrinsiQ
Specialty Solutions (an AmerisourceBergen Specialty Group company), a
board-certified clinical informaticist,
and the former medical director of a
large metropolitan urology practice. He
resides in Ft. Worth, TX.
by CMS) that most physicians will be starting
in MIPS in 2019. CMS will make this determination each year based upon the law and the
criteria for “qualifying participant in an APM”
when those criteria are finalized.
Changes in reimbursement
How will Medicare professionals be reimbursed under MIPS? Physicians will continue to be paid according to the Physician Fee
Schedule with the adjustments outlined above.
In addition, MACRA retires and replaces three
federal programs and their associated payment
adjustments at the end of 2018: the Physician
Quality Reporting System, the Value-Based
Payment Modifier, and the EHR Incentive
Program (meaningful use). MIPS will instead
adjust Medicare payments to professionals
based on a composite score (on a scale of 0-100)
of weighted performance in four areas: Quality, Cost, Advancing Care Information, and
Clinical Practice Improvement Activities. (The
proposed details for scoring performance, measurement periods, data submission, exceptions,
and more are outlined in the CMS proposed
rule and will be the subject of a future article.)
A threshold of median or mean performance
will be determined for the collective provider
population in MIPS, and MIPS providers will
Please see MACRA MODELS, page 28
the smaller practice more harshly than the
larger group. Clearly, CMS has much work to
do. Equally as obvious, physician groups have
their work cut out for them.
This rule is not final, but history tells us that a
proposed rule is the foundation for any final rule
set. MACRA requires change, and the changes outlined in the proposed rule comply. We
encourage you to watch for your AMA, AUA,
and state publications, read the summaries, and
react to them or in concert with them as you
see fit. This change is not going to be easy, but
change never is.
For our part, we will continue to watch for
updates and attempt to develop recommendations and actions to meet the requirements of
the “new Medicare” regardless of their final
form. UT
Actor portrayals.
INDICATION
XIAFLEX® is indicated for the treatment of adult men with Peyronie’s disease
with a palpable plaque and curvature deformity of at least 30 degrees at the
start of therapy.
IMPORTANT SAFETY INFORMATION FOR XIAFLEX®
WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS
PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE
Corporal rupture (penile fracture) was reported as an adverse reaction in
5 of 1044 (0.5%) XIAFLEX®-treated patients in clinical studies. In other
XIAFLEX®-treated patients (9 of 1044; 0.9%), a combination of penile
ecchymoses or hematoma, sudden penile detumescence, and/or
a penile “popping” sound or sensation was reported, and in these cases,
a diagnosis of corporal rupture cannot be excluded. Severe penile
hematoma was also reported as an adverse reaction in 39 of 1044
(3.7%) XIAFLEX®-treated patients.
Signs or symptoms that may reflect serious penile injury should be
promptly evaluated to assess for corporal rupture or severe penile
hematoma which may require surgical intervention.
Because of the risks of corporal rupture or other serious penile injury,
XIAFLEX® is available for the treatment of Peyronie’s disease only
through a restricted program under a Risk Evaluation and Mitigation
Strategy (REMS) called the XIAFLEX® REMS Program.
• XIAFLEX® is contraindicated in the treatment of Peyronie’s
plaques that involve the penile urethra due to potential
risk to this structure and in patients with a history of
hypersensitivity to XIAFLEX® or to collagenase used in any
other therapeutic application or application method
• Injection of XIAFLEX® into collagen-containing structures
such as the corpora cavernosa of the penis may result in
damage to those structures and possible injury such as
corporal rupture (penile fracture). Therefore, XIAFLEX®
should be injected only into the Peyronie’s plaque and
care should be taken to avoid injecting into the urethra,
nerves, blood vessels, corpora cavernosa or other
collagen-containing structures of the penis
• In the double-blind, placebo-controlled portions of
the clinical trials in Peyronie’s disease, a greater
proportion of XIAFLEX®-treated patients (4%) compared
to placebo-treated patients (1%) had localized
pruritus after up to 4 treatment cycles (involving up
to 8 XIAFLEX® injection procedures). The incidence
of XIAFLEX®-associated pruritus was similar after
each injection regardless of the number of injections
administered
When Peyronie’s disease is on his mind
THINK XIAFLEX
®
FOR YOUR APPROPRIATE PATIENTS
The only FDA-approved nonsurgical treatment option for adult men with
Peyronie’s disease with a palpable plaque and curvature deformity of at
least 30 degrees at the start of therapy
XIAFLEX® should be administered by a
healthcare provider experienced in the
treatment of male urological diseases.
Your patients may find it difficult to start a
discussion about their erectile curvature,
which could be Peyronie’s disease.1 You
play an integral role in making sure they
get help. Upon assessment, be sure to
clarify with your patients, “Do you have a
curved erection?”
Get started
Become a trained injector or refer your patients
to trained injectors nearest them.
Visit XIAFLEX.com /urot to find trained injectors.
• Because XIAFLEX® contains foreign proteins, severe allergic reactions
to XIAFLEX® can occur. Anaphylaxis was reported in a post-marketing
clinical trial in one patient who had previous exposure to XIAFLEX® for
the treatment of Dupuytren’s contracture. Healthcare providers should
be prepared to address severe allergic reactions following XIAFLEX®
injections. The safety of more than one treatment course of XIAFLEX®
is not known
• In the XIAFLEX® controlled trials in Peyronie’s disease, 65.5% of
XIAFLEX®-treated patients developed penile hematoma, and 14.5%
developed penile ecchymosis. Patients with abnormal coagulation
(except for patients taking low-dose aspirin, eg, up to 150 mg per
day) were excluded from participating in these studies. Therefore, the
efficacy and safety of XIAFLEX® in patients receiving anticoagulant
medications (other than low-dose aspirin, e.g., up to 150 mg per
day) within 7 days prior to XIAFLEX® administration is not known.
In addition, it is recommended to avoid use of XIAFLEX® in
patients with coagulation disorders, including patients receiving
concomitant anticoagulants (except for low-dose aspirin)
• In the XIAFLEX® clinical trials for Peyronie’s disease, the most
frequently reported adverse drug reactions (≥25%) and at an
incidence greater than placebo included: penile hematoma, penile
swelling, and penile pain
Please see Brief Summary of full Prescribing Information,
including Boxed Warning, on following pages.
Reference: 1. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie’s disease: AUA guideline. J Urol. 2015;194(3):745-753.
Rx Only
XIAFLEX® is a registered trademark of Endo International plc or one of its affiliates.
© 2016 Endo Pharmaceuticals Inc. All rights reserved. Malvern, PA 19355
XP-04473b/April 2016 www.xiaflex.com 1-800-462-ENDO (3636)
XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use
Brief Summary of Prescribing Information
For complete information, see the full prescribing information for XIAFLEX.
WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE
TREATMENT OF PEYRONIE’S DISEASE
Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%)
XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%),
a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile
“popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture
cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of
1044 (3.7%) XIAFLEX-treated patients [see Warnings and Precautions].
Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess
for corporal rupture or severe penile hematoma which may require surgical intervention [see
Warnings and Precautions].
Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the
treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS) called the XIAFLEX REMS Program [see Warnings and Precautions].
INDICATIONS AND USAGE
XIAFLEX is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and
curvature deformity of at least 30 degrees at the start of therapy.
DOSAGE AND ADMINISTRATION
Dosing Overview for Peyronie’s Disease
XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological
diseases, who has completed required training for use of XIAFLEX in the treatment of Peyronie’s disease.
XIAFLEX, supplied as lyophilized powder, must be reconstituted with the provided diluent prior to use
[see Dosage and Administration (2.2)]. The dose of XIAFLEX is 0.58 mg per injection administered into a
Peyronie’s plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity.
A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of
two XIAFLEX injection procedures [see Dosage and Administration (2.2)] and one penile modeling
procedure [see Dosage and Administration (2.2)]. The second XIAFLEX injection procedure is performed
1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second
injection of the treatment cycle. The interval between treatment cycles is approximately six weeks. The
treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures.
If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle,
or if the healthcare provider determines that further treatment is not clinically indicated, then the
subsequent treatment cycles should not be administered.
The safety of more than one treatment course of XIAFLEX is not known.
The table below displays an overview of the volume of sterile diluent for reconstitution and the reconstituted
XIAFLEX solution to be used in the intralesional injection [see Dosage and Administration (2.2)].
Volumes Needed for Reconstitution and Administration
Sterile Diluent for Reconstitution
Volume
0.39 mL
Reconstituted XIAFLEX Solution to be Injected1
Volume
1
0.25 mL
The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX.
Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX
solution remaining in the vial after the injection should be discarded.
Reconstitution of the Lyophilized Powder for Peyronie’s Disease
a) Before use, remove the vial containing the lyophilized powder of XIAFLEX and the vial containing the
diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for
at least 15 minutes and no longer than 60 minutes. Visually inspect the vial containing XIAFLEX. The
cake of lyophilized powder should be intact and white in color.
b) After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and
surrounding surface of the vial containing XIAFLEX and the vial containing the diluent for reconstitution
with sterile alcohol (no other antiseptics should be used).
c) Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for
the activity of XIAFLEX.
d) Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied),
withdraw a volume of 0.39 mL of the diluent supplied.
e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do
not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized
powder has gone into solution.
f) The reconstituted XIAFLEX solution can be kept at room temperature (20º to 25ºC/68º to 77ºF) for up
to one hour or refrigerated at 2º to 8°C (36º to 46°F) for up to 4 hours prior to administration. If the
reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for
approximately 15 minutes before use.
g) Discard the syringe and needle used for reconstitution and the diluent vial.
Identification of Treatment Area for Peyronie’s Disease
a) Prior to each treatment cycle, identify the treatment area as follows:
• Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil
may be used for this purpose. Apply antiseptic at the site of the injection and allow the skin to dry
prior to the intracavernosal injection.
• Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis.
• Mark the point with a surgical marker. This indicates the target area in the plaque for XIAFLEX deposition.
Injection Procedure for Peyronie’s Disease
a) The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate
matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is
discolored, do not inject the reconstituted solution.
b) Apply antiseptic at the site of the injection and allow the skin to dry.
c) Administer suitable local anesthetic, if desired.
d) Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge
½-inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing
0.58 mg of XIAFLEX).
e) The penis should be in a flaccid state before XIAFLEX is injected. Place the needle tip on the side of the
target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the
edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the
needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
f) Insert and advance the needle transversely through the width of the plaque, towards the opposite side
of the plaque without passing completely through it. Proper needle position is tested and confirmed by
carefully noting resistance to minimal depression of the syringe plunger.
g) With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly
inject XIAFLEX into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle
track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of
the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
h) Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a
dressing as necessary.
i) Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store,
pool, or use any vials containing unused reconstituted solution or diluent.
j) The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from
the first injection.
Penile Modeling Procedure for Peyronie’s Disease
Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1
to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as
described below) on the flaccid penis to stretch and elongate the treated plaque:
• Administer suitable local anesthetic, if desired.
• Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and
distal to the injection site. Avoid direct pressure on the injection site.
• Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate
and stretch the plaque. The goal is to gradually create bending opposite to the patient’s penile curvature,
with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
• After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts
at 30 seconds for each attempt.
In addition to the in-office penile modeling procedure, patients should be instructed to self-perform
penile modeling activities at home each day for the 6-week period following the investigator penile
plaque modeling visit of each treatment cycle as follows:
• During spontaneous erections, gently attempt to straighten the penis without producing pain and hold
the penis in a straightened position for 30 seconds.
• The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used
without producing pain.
CONTRAINDICATIONS
XIAFLEX is contraindicated in:
• the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure.
• patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic
application or application method [see Warnings and Precautions].
WARNINGS AND PRECAUTIONS
Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of
Peyronie’s Disease
Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX
treated patients in the controlled and uncontrolled clinical trials in Peyronie’s disease.
In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma,
sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these
cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical
intervention, but the long-term consequences are unknown.
Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the
controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions].
Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to
assess for corporal rupture or severe penile hematoma, which may require surgical intervention.
Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may
result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore,
XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into
the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.
XIAFLEX REMS Program
Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie’s
disease, XIAFLEX is available only through the XIAFLEX REMS Program [see Warnings and Precautions].
Required components of the XIAFLEX REMS Program include the following:
• Prescribers must be certified with the program by enrolling and completing training in the
administration of XIAFLEX treatment for Peyronie’s disease.
• Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for
use by certified prescribers.
Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235.
Hypersensitivity Reactions, including Anaphylaxis
In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease (Studies 1 and
2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%)
had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The
incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of
injections administered.
Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was
reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for
the treatment of Dupuytren’s contracture. Some patients with Dupuytren’s contracture developed IgE-anti-drug
antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers
should be prepared to address severe allergic reactions following XIAFLEX injections.
Risk of Bleeding in Patients with Abnormal Coagulation
In the XIAFLEX controlled trials in Peyronie’s disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients
developed penile hematoma, and 14.5% developed penile ecchymosis (see Adverse Reaction Table).
Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per
day) were excluded from participating in these studies.
Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than
low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known.
In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders, including
patients receiving concomitant anticoagulants (except for low-dose aspirin).
ADVERSE REACTIONS
The following serious adverse reactions in patients with Peyronie’s disease are discussed in greater
detail elsewhere in the labeling:
Corporal rupture (penile fracture) and severe penile hematoma [see Warnings and Precautions].
In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden penile
detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis
of corporal rupture cannot be excluded [see Warnings and Precautions].
Clinical Studies Experience in Patients with Peyronie’s Disease
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of
another drug and may not reflect the rates observed in practice.
In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie’s disease, 1044 patients
received a total of 7466 XIAFLEX injections.
Corporal Rupture and Other Serious Penile Injury
Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%)
XIAFLEX treated patients.
In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma,
sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these
cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical
intervention, but the long-term consequences are unknown.
Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the
controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions].
The data described below are based on two identical, pooled, randomized, double-blind, placebo-controlled,
multi-center trials through Day 365 in patients with Peyronie’s disease (Studies 1 and 2). These trials
included 832 patients of whom 551 and 281 received XIAFLEX and placebo, respectively. In these trials,
patients were given up to 4 treatment cycles of XIAFLEX or placebo. In each cycle, two injections of XIAFLEX
or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was
performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment
cycle was repeated at approximately 6-week intervals up to three additional times, for a maximum of 8 total
injection procedures and 4 total modeling procedures [see Clinical Studies in the full Prescribing Information].
The majority of Peyronie’s patients experienced at least one adverse reaction (92% XIAFLEX-treated patients,
61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of
these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The
adverse reaction profile was similar after each injection, regardless of the number of injections administered.
The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients
with Peyronie’s disease were penile hematoma, penile swelling, and penile pain. The table below shows
the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEX-treated
patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled
placebo-controlled trials through Day 365.
Adverse Reactions Occurring in ≥ 1% of XIAFLEX-Treated Patients with Peyronie’s disease and at a
Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined
Adverse Reaction
XIAFLEX N=551
Placebo N=281
84.2%
36.3%
65.5%
19.2%
Penile swelling
55.0%
3.2%
Penile painc
45.4%
9.3%
Penile ecchymoses
14.5%
6.8%
Blood blister
4.5%
0
Penile blister
3.3%
0
Pruritus genital
3.1%
0
Painful erection
2.9%
0
Erectile dysfunction
1.8%
0.4%
Skin discoloration
1.8%
0
Procedural pain
1.6%
0.7%
All Adverse Reactions
a
Penile hematoma
b
d
Injection site vesicles
1.3%
0
Localized edema
1.3%
0
Dyspareunia
1.1%
0
Injection site pruritus
1.1%
0
Nodule
1.1%
0
Suprapubic pain
1.1%
0
a
Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile
bruising or injection site bruising in 87% of subjects.
Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and
injection site edema.
c
Includes: injection site pain, penile pain, and injection site discomfort.
d
Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage.
Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEXtreated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.
Reports of penile “popping” sounds or sensations
A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and
sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%)
XIAFLEX-treated patients and 1/281 (0.3%) placebo-treated patients.
There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX
based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.
XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease.
Immunogenicity
During clinical studies in Dupuytren’s contracture and Peyronie’s disease, patients were tested at multiple
time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II).
In the Peyronie’s disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg,
approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had
antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of
XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies
were assayed for a subset of 70 samples selected to be representative of high and low titer binding
antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the
corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive.
Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.
In patients treated for these two indications, there was no apparent correlation of antibody frequency,
antibody titers, or neutralizing status to clinical response or adverse reactions.
Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with
human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with
human MMPs. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody
positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the
inhibition of endogenous MMPs have been observed.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in
detection and may be influenced by several factors, including sample handling, timing of sample collection,
concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies
to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading.
DRUG INTERACTIONS
Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant
anticoagulants (except for low-dose aspirin) [see Warnings and Precautions].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Because animal
reproduction studies are not always predictive of human response, XIAFLEX should be used during
pregnancy only if clearly needed.
Risk Summary
Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental
abnormalities in humans.
Human Data
Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic
circulation following injection into a Dupuytren’s cord. Low levels of XIAFLEX were quantifiable in the
plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX into the penile
plaque of subjects with Peyronie’s disease [see Clinical Pharmacology in the full Prescribing Information].
Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with
XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not
known [see Adverse Reactions].
Animal Data
Reproduction studies have been performed in rats with intravenous exposures up to approximately 11
times the maximum recommended human dose (MRHD) of XIAFLEX on a mg/m2 basis, and have revealed
no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.
Nursing Mothers
It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when XIAFLEX is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established.
Geriatric Use
Of the 551 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie’s
disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of
age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these
patients and younger patients.
OVERDOSAGE
The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive
doses of XIAFLEX may cause more severe local effects than the recommended doses including serious
adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the
injection site). Supportive care and symptomatic treatment are recommended in these circumstances.
Manufactured and Distributed by:
Auxilium Pharmaceuticals, Inc.
Malvern, PA 19355
This Brief Summary is based on PL-0108-001.g
Revised 05/2015
b
XP-03921
28
❳Business of Urology❲
JUNE 2016
∣
Urology Times
How physicians can prepare now before CMS removes the ICD-10 safety net
By Mark Rowh
On October 1, the Centers for Medicare & Medicaid Services’ (CMS) grace period for denials of claims under
ICD-10 will end. Physicians will do well to recognize that
while the updated and expanded standards for coding
specificity offer a new level of accuracy, they may also
affect the bottom line.
Prior to the ICD-10 rollout out last year, CMS
announced that Medicare claims would neither be denied
nor audited based on their coding as long as practices
submitted an ICD-10 code from the appropriate family
of codes. But that doesn’t mean a permanent free pass.
“Physicians need to ensure they are up-to-date with
the added specificity in ICD-10,” said David McCann, of
Berkeley Research Group in Hunt Valley, MD, and a trained
coder. Especially with high-volume diagnoses, he says,
close review of coding options should become the norm.
The months leading up to the October deadline will
be vital for staff training and reinforcing correct ICD10 coding, says Mary Jean Sage, CMA-AC, of The Sage
Associates, a consulting firm in Pismo Beach, CA. “It’s
important that when the grace period is lifted, practices
are thoroughly prepared and not just preparing.”
Every practice needs to plan for decreased staff
productivity and prepare for the possibilities of other
financial challenges during the remainder of the ICD-10
grace period.
“The last thing a practice wants to do is begin training when the claims are finally being denied,” Sage said.
Lisa Thomsen, MD, a family practitioner in Glendora,
CA, says her practice has not experienced any denials or
claims adjustment post-ICD-10 because payers are only
requiring a three-digit placeholder with each code. Come
October 1, however, that will expand to five to seven
digits, “which will impact the coding accuracy, thus the
financial consequences” for incorrectly coded claims.
Dr. Thomsen says even seasoned physicians with
years of ICD-9 experience routinely have a small percentage of denied claims. “In addition, the clearinghouses for these claims have their electronic glitches
and server capacity issues,” she said. “You can always
count on the unexpected to occur, so all practices should
brace themselves.”
MIPS: More winners than losers in urology
continued from page 23
be compared to that threshold. Providers with
a lower MIPS composite score during the measurement period will receive negative adjustments for a payment year, and those with higher
scores will receive positive adjustments to their
fee schedule payments. The maximum negative
adjustment starts at –4% in 2019 and increases
each year until it reaches –9% in 2026. There
❳t Practice Pointers ❲
The Medicare Access and CHIP Reauthorization
Act of 2015 replaced the sustainable growth rate
formula with a flat 0.5% annual fee increase
until 2019; no further increases will occur until
2026.
t According to MACRA, all eligible professionals
will be subject to the Merit-Based Incentive
Payment System unless they meet one of three
exceptions: They are in their first year of participation in Medicare; do not exceed a low volume
threshold of Medicare payments or patients; or
participate in an Advanced Alternative Payment
Model.
t CMS estimates that in 2019, 8,814 urologists
will be subject to MIPS.
are allowances for superior performance and
additional payments, but in aggregate the law
requires that total negative adjustments equal
total positive adjustments.
That is, MIPS will redistribute payments in
a budget-neutral fashion. Beginning in 2026,
MIPS physicians will see an annual fee schedule increase of 0.25% in addition to any payment adjustments described above.
How will Medicare professionals be reimbursed if they are excluded from MIPS by successfully participating in Advanced APMS?
APMs and Advanced APMs are strictly
defined in the proposed rule (the subject of
a future article), and qualifying participation
includes a minimum threshold of Medicare
payments or patients passing through the
Advanced APM. APMs will have quality
metrics also.
If professionals become “qualifying participants” in this manner, they will receive a
5% Medicare bonus payment on their Part B
professional services in the respective payment year. They will receive no other payment
adjustments until 2026, when qualifying participants will see an annual 0.75% annual fee
schedule increase (larger than MIPS). Finally,
these bonus payments and fee schedules are
Even without mistakes, navigating the new standards is likely to slow down processing. “The biggest
complaint I hear from practices is that it now takes more
time to select an appropriate code,” Sage said. “Finding
the correct code comes with practice.”
The key is adopting a new mindset. “Start using the
ICD-10 lingo,” Dr. Thomsen said. “This means changing
your old thinking.”
Use nomenclature that aids in triggering the necessary codes. This might mean with a diagnosis of
chronic kidney disease, for example, specifying stage
1-5, also noting that it is due to diabetes or hypertension.
“This mindset forces you to think more specifically,”
Dr. Thomsen said. “Your biller and coder now know the
complete diagnosis. They don’t have to waste time
reading through your notes.”
Ongoing education is critical, McCann says. Review
publications and sources of guidance continually. He
advises doing an audit to identify documentation gaps
and provide ongoing monitoring of high-volume diagnoses and those that can be further specified.
in addition to any other financial benefits or
risks incurred by participating in the advanced
payment model (such as receiving a portion of
shared savings) itself.
In the proposed rule, CMS estimates that in
2019, 8,814 urologists will be subject to MIPS.
Based on existing data and a midpoint sensitivity analysis, 40.5% of those will receive negative payment adjustments totaling $13 million,
and 59.2% will receive positive payment adjustments totaling $31 million. Note that there are
more winners than losers in MIPS by this estimate in urology and most specialties; notable
exceptions include chiropractic, dentistry, plastic surgery, podiatry, and psychiatry. Finally,
CMS estimates that in 2019, 1,754 urologists
will be excluded from MIPS for one of the reasons mentioned above—including qualifying
participation in an APM.
Bottom line: Medicare fee for service is not
dead, but instead now virtually all physician
fees in Medicare will be directly tied to participation in a quality-based reimbursement
model through the popular law called MACRA.
In the beginning, most physicians will probably
be measured and their fees adjusted downward
or upward in MIPS; as time goes on, CMS
expects more participation in APMs and exclusion from MIPS. In subsequent articles, I will
discuss the details of MIPS and APMs that you
will need to understand to traverse the landscape of reimbursement reform. UT
UrologyTimes.com
∣
29
JUNE 2016
Health savings account
provides triple tax benefit
Tax-free withdrawals for eligible medical expenses among
HSA’s advantages
Q What are the benefits of a health
savings account?
A
One of the greatest benefits of being
covered under a high-deductible health plan
(HDHP) is generally the ability to open a
health savings account (HSA) and receive taxpreferred treatment on money saved for medical expenses. Specifically, HSAs provide a
triple tax benefit: tax-deductible contributions,
tax-free earnings, and tax-free withdrawals.
Being aware of the tax-saving opportunities of
an HSA will give you a better understanding
of how to take full advantage.
An HSA is used to save money to cover outof-pocket medical expenses not covered by
your health insurance plan. Many banks and
brokerage firms offer HSA plans with various
interest- and dividend-earning options.
One benefit of having an HSA is that your
contributions are tax deductible. Although
there are annual limits to the amount that can
be contributed, your HSA contributions can be
claimed as a deduction on your tax return even
if you do not itemize your deductions.
For 2016, if you have individual health coverage, the maximum tax-deductible contribution remains the same as last year at $3,350,
and for family coverage the contribution limit
increased to $6,750. For those 55 and older, the
additional contribution limit remains at $1,000.
❳t Financial Tips ❲
A health savings account is used to save money
to cover out-of-pocket medical expenses not
covered by your health insurance plan.
t HSAs provide a triple tax benefit: tax-deductible
contributions, tax-free earnings, and tax-free
withdrawals.
t If you make a withdrawal from an HSA for noneligible medical expenses before age 65, you
will have to pay tax on the amount withdrawn
plus a 20% penalty.
t Money in an individual retirement account can
be used to purchase a home without incurring
a tax penalty, but only if it’s a withdrawal for a
first-time home purchase.
Many employers offset a portion of your health
care costs by making contributions to your HSA.
Although you may not deduct any contributions
made by your employer, those amounts are generally excluded from your gross income, meaning they are tax free. In addition, the contribution
limits remain the same whether the contributions
are made by you or your employer.
Although there are annual limits to
the amount that can be contributed,
HSA contributions can be claimed as
a deduction on your tax return even
if you do not itemize.
For example, if you had individual coverage
the entire year and are under the age of 55, your
contribution limit is $3,350. If your employer
contributed $1,000 to your HSA, the amount you
may contribute, and deduct, is limited to $2,350.
Contributions to your HSA can be made
throughout the year or in one lump sum. To
encourage you to maximize your HSA contribution benefit, if the annual contribution limit
is not reached by year-end, you may continue
to make contributions to your HSA through the
tax return filing deadline the following year
(without extensions) until the limit is reached.
A second tax advantage of owning an HSA is
that withdrawals for eligible medical expenses
are tax free. Eligible medical expenses are
those that would generally qualify as an itemized medical expense deduction.
A third great tax benefit of HSAs is that any
interest or dividends earned on them are tax
free. Since HSAs do not have a mandatory distribution requirement, the contributions made
to your HSA can stay there and continue to grow
tax free until you need to make a withdrawal.
If you make a withdrawal for non-eligible
medical expenses before age 65, you will have
to pay tax on the amount withdrawn plus a 20%
penalty. If you are 65 or older, there is no penalty, but you will still have to pay tax.
Finally, another benefit of owning an HSA is
that you may keep your HSA open and continue
to enjoy tax-free growth and tax-free withdrawals even if you are no longer eligible to make
Money Matters
Joel M. Blau, CFP,
Ronald J. Paprocki, JD,
CFP, CHBC
Joel M. Blau, CFP, (top) is president
and Ronald J. Paprocki, JD, CFP,
CHBC, is chief executive officer of
MEDIQUS Asset Advisors, Inc. in Chicago. They can be reached at
800-883-8555 or [email protected]
or [email protected].
tax-deductible contributions. This means that
when you are no longer enrolled in an HDHP,
or if you change employers or leave the work
force, your HSA can remain open.
With a better understanding of how HSAs
work and their benefits, it is easier to appreciate their value. As the owner of an HSA, you
will get not only the triple tax benefit of taxdeductible contributions, tax-free earnings, and
tax-free withdrawals, but also the opportunity
to build a healthy medical nest egg to cover
current and future health care expenses.
Q Can you use money in an individual
retirement account to purchase a home
without incurring a tax penalty?
A
Yes, but only if it’s a withdrawal for a firsttime home purchase. This exception allows
penalty-free IRA withdrawals to the extent the
money is spent by the IRA owner within 120
days to pay for qualified acquisition costs for a
principal residence. However, there’s a lifetime
$10,000 limit on this exception. The principal
residence can be acquired by:
the IRA owner or the IRA owner’s spouse
the IRA owner’s child, grandchild, or
grandparent, or
the spouse’s child, grandchild, or grandparent.
The buyer of the principal residence (and the
spouse if the buyer is married) must not have
owned a present interest in a principal residence
within the 2-year period that ends on the acquisition date.
r
r
r
Send us your questions
Send your questions about estate planning,
retirement, and investing to Joel M. Blau, CFP,
c/o Urology Times, at [email protected].
Questions of general interest will be chosen for publication.
The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal, investment, or tax advice.
30
❳Business of Urology❲
JUNE 2016
Tips to improve cyber
security, protect finances
Small practices often have the weakest security,
leaving physicians vulnerable to threats
A
fter more than $27,000 goes missing from his business account, a
Texas physician learns that cyber
criminals initiated a wire transfer
using a fake domain name and an
email almost identical to his own. Another physician returns from an international trip to find
that criminals hacked his email and used it to
transfer more than $30,000 from his medical
group’s account to an unknown bank in Hong
Kong.
In both cases—taken from the files of a
cyber liability insurance underwriter associated
with Austin, TX-based Texas Medical Liability Trust (TMLT)—the victims’ banks were
not liable for the losses because an authorized
account holder approved the transfers, says
John Southrey, CIC, CRM, manager of consulting services at TMLT, which provides medical
professional liability insurance to Texas Medical Association members.
“Cyber fraud is the most underestimated
and underappreciated risk faced by small
businesses, particularly in health care,” said
Southrey. “Most physicians are not budgeting
enough for computer data security because
they think their practices are too small to
attract the attention of cyber criminals. However, losses incurred as a result of a data breach
can be worse than a direct tangible property
loss such as from a fire or tornado. Many cybercriminals consider physician practices to be
low-hanging fruit because they have not kept
up with technology.”
Sara Hempfling, vice president of treasury
management at St. Peters, MO-based Enterprise Bank and Trust, recommends that all of
her clients purchase cyber liability insurance.
Large companies may pay about $2,500 per
month for $1 million in coverage, but smaller
business often pay much less and some coverage is often included in standard professional
liability policies, says Hempfling, who works
with the bank’s medical clients.
TMLT added cyber liability coverage in
2011. Since then it has handled more than 250
incidents, with more coming in nearly every
week, Southrey says. The majority of cases
involve data breaches of personal health information (PHI), which can take a financial toll
CYBER SECURITY CHECKLIST
The Texas Medical Liability Trust created the following checklist to help medical practice administrators assess their readiness to combat cyber crime:
… Is there a cyber risk management plan in
force?
procedures that address the HIPAA privacy,
security, and breach notification rules?
… Are all mobile devices that contain electronic personal health information (ePHI)
encrypted? And is your network monitored
for intrusion attempts?
… Are new employees receiving privacy and
security awareness training to comply with
federal and state medical privacy and security laws?
… Are risk assessments conducted annually,
including HIPAA privacy, security, and
breach notification assessments?
… Have you vetted the cyber security of your
third-party vendors/business associates
who have access to your PHI?
… Have all previously identified vulnerabilities
been addressed?
… Have you purchased suitable cyber liability
insurance to cover potential first party and
third party data breach claims?
… Do you have up-to-date written policies and
∣
Urology Times
Health Law & Policy
Janet Colwell
Ms. Colwell is a contributing author for Medical
Economics, where this article was first published.
on a practice, exceeding the base cyber liability
coverage limit.
Lax security leaves practices vulnerable
Criminal attacks are the leading cause of health
care data breaches, ahead of employee negligence and lost or stolen devices, according to the
Ponemon Institute, a nonprofit research group
based in Traverse City, MI. Criminal attacks
“Many cyber-criminals consider
physician practices to be lowhanging fruit because they have not
kept up with technology.”
JOHN SOUTHREY, CIC, CRM
Texas Medical Liability Trust
have risen by 125% over the past 5 years as
cyber criminals increasingly recognize the vulnerability of medical organizations that store
a trove of potentially lucrative personal data,
according to the institute’s 2015 Fifth Annual
Benchmark Study on Privacy and Security of
Healthcare Data.
More than 90% of the health care organizations included in the study reported experiencing a data breach, with 40% reporting more
than five over the past 2 years, the report says.
At the same time, only half of survey respondents reported feeling confident that they had
the resources or processes and technology in
place to detect loss or theft of patient data.
Theft of electronic PHI (ePHI) has substantial financial implications, because victims are
responsible for the costs of investigating the
breach, notifying customers, paying any government fines, and other crisis-management
activities.
It can take months or years to recover from
the financial damage of a data breach, Southrey
says. Under the Health Insurance Portability
and Accountability Act (HIPAA), for example,
practices can be fined for failing to conduct a
comprehensive risk analysis of their policies
and procedures and not having appropriate
safeguards in place to protect ePHI.
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32
❳Business of Urology❲
C Y BE R SECURI T Y
continued from page 30
ment of Health and Human Services (HHS)
$100,000 and implement new security measures in 2012 after an Office of Civil Rights
(OCR) investigation found that it had violated
HIPAA rules, according to HHS. In the OCR
investigation, which lasted more than 3 years,
“In smaller offices, one office
manager might have full control
over online banking and there is
no system set up to have a second
person authorize big transactions.
That’s a risk.”
SARA HEMPFLING
Enterprise Bank and Trust
investigators found that the practice had been
posting surgical appointments on a publicly
accessible web-based calendar and had not
taken appropriate measures to protect the
information.
In addition to potential fines under federal
and state privacy laws, practices must take steps
to mitigate the effects of the breach, Southrey
says. These can include notifying patients,
providing credit-monitoring services, hiring a
public relations firm, working with an attorney, and contracting with a forensics specialist
to trace the source of the breach and recover
unduplicated data.
“That’s not to mention the potential lost revenue due to an interruption in business or staff
overtime to reconstruct files and recover data,”
he said. “And you may lose patients if they come
to view your practice as a security risk.”
Many of those costs are covered by cyber
insurance up to certain limits (see “What cyber
insurance covers,” below), he says. For example, one physician insured with TMLT filed
a cyber extortion claim involving more than
6,000 patient records after a hacker demanded
several thousand dollars to decrypt his files.
After reporting the breach to HHS, the physician received notice of an OCR investigation
and a request to provide extensive documentation on his security practices.
“He blew through his $50,000 limit in cyber
liability coverage in less than 2 months,” Southrey said, noting that TMLT now offers up to $1
million or higher in coverage limits. “And he
had to continue to pay other out-of-pocket costs,
such as installing a new server.”
Staff training is key
In many cases, small practices are particularly
vulnerable to fraud because they do not
implement procedures that might prevent
errors, says Hempfling. In addition, they
lack the resources to dedicate one computer exclusively to banking.
“In smaller offices, one office manHealth care providers can transfer some of their cyberager might have full control over online
related risks by purchasing cyber liability insurance,
banking and there is no system set up
according to John Southrey, CIC, CRM, manager of
to have a second person authorize big
consulting services at Austin, TX-based Texas Medical
transactions,” she said. “From a bankLiability Trust (TMLT). TMLT includes cyber liability coving standpoint, that’s a risk.”
erage limits of $100,000 per claim subject to a $500,000
While your employees might be fully
aggregate if the entity is also insured per policy period,
deserving of that trust, mistakes can hapwith the option to purchase increased limits up $1 milpen, she adds. For example, many cyber
lion or higher on a stand-alone basis.
crimes involve tricking someone into
disclosing financial information.
The coverage also includes:
One of her manufacturing clients fell
privacy regulatory defense and penalty coverage
victim
to a fraudulent wire transfer. The
security and privacy liability coverage
client
received
a phone call from somemultimedia liability coverage
one
they
believed
to be an employee of
network asset protection coverage (including
a
vendor
notifying
the client that the
business interruption)
vendor’s
bank
account
had changed.
privacy breach response costs, patient notification
Hempfling’s
client
requested
a bank veriexpenses, and patient support and credit monification
letter,
which
was
immediately
toring expenses coverage
provided and looked legitimate. Trusting
cyber extortion coverage
that the contact was who they said they
cyber terrorism coverage (including business
were, the finance manager then changed
interruption).
the vendor’s bank account information on
the company’s computer system.
WHAT CYBER
INSURANCE COVERS
r
r
r
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r
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r
JUNE 2016
∣
Urology Times
“Our bank called the owner and warned him
to double check the transaction before verifying
it because it might be fraud,” Hempfling said.
“But he was in a hurry and OK’d it anyway,
trusting that his staff had already done their
due diligence.”
Employee training is a critical part of protecting your practice from cyber fraud, says Rebecca Busch, RN, president and CEO of Westmont,
IL-based Medical Business Associates and a
faculty member of the Association of Certified
Fraud Examiners. Employees should learn how
to recognize spam emails that appear to be from
a payroll company, for example, and not to open
or download programs from unknown sources
that could be malicious software giving criminals access to the practice’s records.
Cyber criminals might also install “ransomware” on your computer, which prevents you
from accessing your data unless you pay a fee
to unlock it. Such incidents led TMLT to add
cyber extortion coverage to its medical malpractice policies.
“Your inventory should include any
data that has a connection to your
banking accounts.”
REBECCA BUSCH, RN
Medical Business Associates
“Cyber extortion can be devastating from
a revenue perspective,” Southrey said. “If you
can’t access your data, how do you do your billing or conduct your patient exams?”
Notifications about changes to your bank
account should be verified “100% of the time,”
Hempfling said. Remember, as soon as the
business owner verifies a wire transaction, the
money is sent and it is very difficult to reverse
the process.
“Consumers always get reimbursed but
banks have discretion over whether or not to
cover business losses,” she said. Banks are
governed by very specific rules relating to
check fraud, she adds. For example, the bank
is exempt from liability if the business uses a
signature stamp to sign a check instead of the
account holder’s actual signature.
Mitigation and awareness are critical to protecting your practice from fraud, Busch says.
Physicians should inventory where their financial information is stored and have constant
access to their financial accounts.
“Your inventory should include any data that
has a connection to your banking accounts,”
she said. “You need to know when those
accounts are accessed and how, and constantly
monitor those channels.”
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34
❳Voices in Urology❲
Commentary from residents, non-physician providers,
and other voices in the field
JUNE 2016
∣
Urology Times
Does this protocol represent the
future of post-cystectomy care?
Enhanced Recovery After Surgery can improve patient care and reduce morbidity
R
ecently my partner and I were performing a cystectomy, and as is
common during most long cases,
our discussion became a bit philosophical. Both of us were trained
in the era of open cystectomy, but as this case
was being done robotically, the conversation
turned toward the future of surgical treatment
of muscle-invasive bladder cancer.
Surgical treatment of bladder cancer has a
long and storied history dating back to 1852.
Detubularization to create a low-pressure reservoir was a milestone by Kock in the mid1960s, and Mitrofanoff described the transappendicular continent cystostomy in 1980. In
1992, the first pure laparoscopic simple cystectomy was reported, and by 2003, case series of
robot-assisted cystectomy and diversion were
reported. (For a more detailed account, see
“Bladder cancer and diversion: A historical
perspective” below.)
Now, completely intracorporeal robotic procedures have been reported and are common.
Henry Rosevear, MD
Dr. Rosevear, a member of the
Urology Times Clinical Practice Board,
is in private practice in Colorado
Springs, CO.
So where do we go from here? Unless someone is able to grow a new bladder using the
patient’s own tissue, the surgical technique we
have maintains good oncologic principles while
providing an outcome that mimics the patient’s
original bladder and can be done in a minimally
invasive manner. Are we done advancing the
field? Absolutely not. While the technique
works, radical cystectomy still carries an unacceptably high complication rate likely secondary to a combination of patient-specific issues
(patients tend to be older and sicker) and disease- and procedure- specific issues (the operation still exposes patients to major abdominal
surgery combined with the metabolic changes
that go along with exposing urine to the bowel).
Bladder cancer and diversion: A historical perspective
Even though the Ebers’ Papyrus (a collection of ancient
Egyptian manuscripts dating from 2600-1200 BC found
in a tomb at Thebes in 1862) describe in great detail
hematuria and the presence of parasites in the bladder
(schistosomiasis anyone?), the earliest cystoprostatectomy and urinary diversion didn’t happen until 1852
when J. Simon performed a ureteroproctostomy for
exstrophy. The patients didn’t do very well, and it
wasn’t until 1911 when Coffey modified the technique
of ureteral implantation that ureterosigmoidostomy
became standard. That same year, Zaayer introduced
the ileal conduit and by 1950 with modifications by
Bricker, ileal conduits were now standard due in no
small part to the more manageable metabolic changes
associated with them.
The concept of a true continent diversion was the
subject of work by Tizzoni and Foggi as far back as
1888. By the turn of the century, others such as Verhoogen (1908), Makkas (1910), and Laengemann
(1912) had explored the idea of using an ileocecal
segment with the appendix as the continent mechanism. By the 1950s, Gilchrist and Merricks modified the
procedure to use the terminal aperistaltic segment of
ileum as the continent mechanism.
The concept of detubularization to create a lowpressure reservoir was introduced by Kock in the mid1960s and led to significant improvement in results.
Using these principles, new techniques combining
different bowel segments with various continence
mechanisms were proposed (the Kock pouch using
ileum and a nipple valve for continence, the Indiana
pouch using an ileocecal segment with a tapered
ileal segment for continence, and finally the Mainz
pouch using ileum and an intussucepted ileal nipple).
Mitrofanoff described the trans-appendicular continent cystostomy in 1980 that finally allowed for an
easily reproducible continence mechanism.
In the late 1980s, Studer and Hautmann described
the orthotopic neobladder and after almost 150 years
of work, we finally had a continent diversion that
closely duplicated the original bladder. In 1992, with
the advent of the laparoscopic era, the first pure laparoscopic simple cystectomy was reported and by 2003,
case series of robot-assisted cystectomy and diversion
were being reported. (Drs. Hautmann [Eur Urol 2006;
50:1139–50] and Studer [Probl Urol 1991; 5:197–202]
provide excellent historical reviews for those interested in more details.)
What is the future? The future is Enhanced
Recovery After Surgery, or ERAS.
The beauty of ERAS is that is allows
those of us in the trenches of
urology who don’t work at a major
academic center to provide the same
excellent perioperative care, just
without residents.
Quoting Dr. Urbach, “The immediate challenge to improving the quality of surgical care
is not discovering new knowledge, but rather
how to integrate what we already know into
practice.” Fast-track recovery protocols were
introduced in the 1990s, and I’m sure most of
us had some in-house developed protocol for
patients after cystectomy. The ERAS society is
dedicated to standardizing perioperative care
by maintaining a constantly updated, peerreviewed, evidence based protocol which is
free to access and has been shown in numerous
papers to decrease the post operative morbidity
of the procedure.
ERAS in the peer-reviewed literature
European Urology recently published a review
of this protocol that concludes, “ERAS pathways clearly improve patient care, reduce morbidity, and shorten LOS. All studies evaluating
elements of the ERAS care pathways in radical
cystectomy have found benefits in postoperative morbidity, return to bowel function, or
LOS.” (Eur Urol 2014; 65:263-66). In addition, Clinical Nutrition published the current
ERAS protocol for perioperative care after
radical cystectomy (Clin Nutr 2013; 32:87987).
The beauty of this protocol is that is allows
those of us in the trenches of urology who don’t
work at a major academic center to provide the
same excellent perioperative care, just without
residents. And that is not necessarily a disadvantage!
If anyone else is transitioning their hospital
to an ERAS protocol and has had either good
or bad experiences with such a protocol, please
write and let me know. UT
UrologyTimes.com
∣
JUNE 2016
Phase III trial to evaluate magnetic
resonance imaging for prostate Ca
The Movember Foundation, the Ontario
Institute for Cancer Research, and Prostate
Cancer Canada recently announced $3 million in funding for a new phase III clinical
trial to evaluate whether magnetic resonance
imaging (MRI) can replace the current standard of care to diagnose prostate cancer.
The primary objective of the multicenter trial,
called PRECISE, is to determine whether
MRI can spare some men from undergoing
a biopsy and avoid the possible associated
side effects. The trial will be led by Laurence
Klotz, MD, of the Sunnybrook Research
Institute in Toronto, according to a press
release from the Ontario Institute for Cancer
Research.
Collaboration, license agreement
reached for prostate Ca compound
Janssen Biotech, Inc. has entered a worldwide collaboration and license agreement
with TESARO, Inc., for exclusive rights to
the investigational compound niraparib in
prostate cancer. Niraparib is an orally administered poly polymerase inhibitor currently
in late-stage development for patients with
metastatic breast cancer and ovarian cancer.
According to terms of the license agreement
and collaboration arrangement, Janssen
will have global rights and be responsible
for all development and commercialization
activities for niraparib for use in prostate
cancer, except in Japan. TESARO will maintain global development, manufacturing, and
commercial rights for all other indications. In
addition to an upfront payment, TESARO will
be eligible to receive milestone payments,
based upon the achievement of specified
development, regulatory, and commercial
milestones, as well as royalties on future
worldwide sales.
Nocturia nasal spray shows efficacy
in phase III clinical study
At the AUA annual meeting in San Diego,
researchers reported results from a phase III
clinical study of SER120, a nasal spray with a
novel formulation of low-dose desmopressin,
in patients with nocturia. As part of the study,
researchers from multiple institutions across
the United States sought to determine whether two doses of SER120 is an effective and
safe option for treating adults age 50 years
and older with nocturia. Results showed that
individuals taking SER120 urinated at night
significantly less compared to those taking the placebo and that individuals taking
SER120 reported a statistically significant
improvement in quality of life versus those
DRUGS AND DEVICES IN DEVELOPMENT
taking the placebo, according to a press
release from the AUA.
Positive results announced
for urothelial carcinoma test
Pacific Edge Ltd. recently announced the presentation of positive results from a prospective multicenter, blinded study of Cxbladder
Monitor, the company’s new urine-based
gene expression test for the investigation of
urothelial carcinoma in patients presenting
for monitoring of recurrent disease. Results
presented at the AUA annual meeting in San
Diego demonstrated that Cxbladder Monitor
is an effective rule out test with a sensitivity of 93% and a negative predictive value
of 97%, significantly outperforming all other
existing urine-based tests evaluated across
all stages and grades of tumor, according to
Pacific Edge. The test is currently available in
New Zealand, and Pacific Edge says it plans
to begin marketing it in the United States
later this year.
Novel prostate cancer vaccine
will proceed to phase II trials
OncBioMune Pharmaceuticals, Inc. recently
provided an update on the clinical advancement of ProscaVax, the company’s novel
cancer vaccine in development for prostate
cancer. In the United States, a phase Ia/Ib
trial of ProscaVax is ongoing at the Veterans’
Administration Medical Center and the University of California, San Diego Medical School,
both in La Jolla, CA. Data to date show ProscaVax to have a meaningful impact in reducing the rise in PSA levels in 60% of patients
(six out of 10) receiving six vaccinations and
an increased immune response in 89% (eight
out of nine) patients at 31 weeks after administration of the vaccine, according to OncBioMune Pharmaceuticals. The company says
the data are compelling enough that it has
elected to forego the phase Ib component
and advance ProscaVax into two separate
phase II studies.
First patient dosed in phase II study
of androgen receptor modulator
Transition Therapeutics Inc. announced the
dosing of the first patient of a phase II study
of selective androgen receptor modulator drug
candidate TT701. The phase II study will evaluate the efficacy and safety of TT701 in improving the symptoms of androgen deficiency (sexual symptoms, fatigue/low vitality, and physical dysfunction) in men with prostate cancer
who have undergone radical prostatectomy for
organ-localized prostate cancer. Brigham and
Women’s Hospital in Boston is conducting the
Uro Pipeline
35
investigator-led phase II clinical study, which
is expected to enroll up to 125 subjects at
selected specialized clinical sites.
Patents granted for implantable
neuromodulation technology
Axonics Modulation Technologies, Inc., developer of a rechargeable implantable sacral
neuromodulation system for the treatment of
urinary and fecal dysfunction, said the U.S.
Patent and Trademark Office has granted Axonics six U.S. patents relating to implantable
neuromodulation technology and recharging
systems. The company’s neuromodulation
platform includes a miniaturized rechargeable
implantable neuromodulation stimulator (IPG)
that is approximately one-fourth the size of
the smallest currently marketed rechargeable
IPGs and can be directed toward numerous
clinical applications, according to Axonics.
Pre-clinical studies show
feasibility of stent system
Three recently completed pre-clinical model
studies of the ConvertX Nephroureteral Stent
System were presented at the Society of
Interventional Radiology annual scientific
meeting in Vancouver, BC. The studies demonstrated the feasibility of the ConvertX System in converting from an internal-external
nephroureteral (NU) catheter into an internal
NU stent without an invasive procedure,
according to developer BrightWater Medical,
Inc. The company says it will submit applications for the ConvertX System in the near
future to the FDA for 510(k) clearance as a
Class II device.
Lab services agreement reached for
trial of immunosuppressive agents
Transplant Genomics reported that it has
signed a laboratory services agreement with
Astellas Pharma Global Development, Inc.
Under terms of the agreement, Astellas will
provide Transplant Genomics with funding
and blood samples from renal transplant
patients collected as part of a 2-year, prospective, randomized, multicenter clinical trial
examining surrogate markers for long-term
kidney transplant outcomes while comparing
two immunosuppressive agents. The primary
outcome measure is a composite endpoint
combining the incidence of de novo donorspecific antibodies and molecular phenotyping using Transplant Genomics’ TruGraf test.
Transplant Genomics will provide real-time
molecular analysis of blood samples collected during the trial using TruGraf, which
will measure molecular signatures of immune
activation in renal transplant patients.
36
❳ Cover Feature ❲
JUNE 2016
∣
Urology Times
‘APOLOGY’ DILEMMA
Apology legislation: 38 states have laws
continued from page 1
to do much more than just say they’re sorry
when mistakes happen.
Meanwhile, two new studies—including one
presented at the 2016 AUA annual meeting—offer
conflicting perspectives on whether the laws are
working, at least in terms of reducing litigation.
All this makes for a complex apology landscape, one that continues to divide attorneys,
doctors, and patient advocates. Are apology laws
really “traps for the unwary physician,” as Dr.
Cotton describes them? Should they be replaced
by communication-and-resolution programs,
seen by some as a kind of apology law-plus? Or
perhaps the laws are serving a purpose by promoting openness, honesty, and accountability.
Whatever the case, “Few physicians are
familiar with apology law and even fewer
understand the significance,” said Patrick
McKenna, MD, chief of the division of pediatric urology at American Family Children’s
Hospital and professor of urology at the University of Wisconsin, Madison.
Judging by Dr. McKenna’s new research
supporting the value of apologies, what physicians don’t know could hurt them after they
hurt patients.
“A doctor who
gives his or her
best effort does
not owe the
patient an apology
for anything.”
“Apologies
decrease patients’
anger toward their
doctor and increase
patients’ trust.”
PATRICK MCKENNA, MD
VICTOR COTTON, MD, JD
“The profession was
embarrassed to be open
about the aspects of care
that weren’t going well.”
History lesson: No apologies here
Apologies and medicine are not bosom buddies. Throughout much of history, physicians
simply didn’t say they were sorry, says Thomas
H. Gallagher, MD, professor and associate chair
of the department of medicine and professor in
the department of bioethics and humanities at
the University of Washington in Seattle.
“There was a sense that we can talk with our
peers about things that have gone wrong, but
it’s not good to air our dirty laundry outside
of the profession,” he said. “Some of this was
couched in terms of trying to promote trust.
Sharing information about an error might
diminish that trust.”
Self-protection played a role too. “The profession was embarrassed to be open about the
aspects of care that weren’t going well,” Dr.
Gallagher said.
And then there’s the matter of money. Malpractice law has its roots in the middle of the
19th century, not the 20th, Dr. Gallagher says.
So there’s long been a real threat that openness—“I made a mistake, I hurt you, and I’m
sorry”—could have real consequences.
Apology laws run the gamut
In 1986, Massachusetts adopted the first law
designed to encourage physicians to apologize
without having to worry that their words would
be used against them. A total of 38 states now
have apology laws on the books.
But the laws are anything but standard, meaning that your state’s apology law mileage may
vary. Thirty-two states have so-called “partial”
apology laws and six have “full” apology laws.
“Partial and full apology laws differ in the
type of communication protected, the sentiments protected, the types of providers that are
protected, to whom the protected communication may be made, and the context in which a
communication will be protected,” Dr. McKenna explained.
The six states with full apology laws—Wisconsin, South Carolina, Georgia, Connecticut,
Colorado, and Arizona—provide the most protection to physicians.
Wisconsin’s 2014 apology law, for example,
allows statements of “apology, benevolence,
Getty Images/iStock/Getty Images Plus/26ISO
THOMAS H. GALLAGHER, MD
UrologyTimes.com
∣
❳ Cover Feature ❲
JUNE 2016
compassion, condolence, fault, liability, remorse,
responsibility, or sympathy.” The statements, however, must be made “before the commencement of
the civil action, administrative hearing, disciplinary proceeding, mediation, or arbitration.”
What you can (and shouldn’t) say
The Wisconsin law seems clear and easy to
understand. But apology laws can be maddeningly complex and vague too.
“Partial and full apology
laws differ in the type of
communication protected,
the sentiments protected,
the types of providers that
are protected, to whom the
protected communication may
be made, and the context in
which a communication will be
protected.”
PATRICK MCKENNA, MD
For example, Florida’s partial apology law
says “the portion of statements, writings, or
benevolent gestures expressing sympathy or
a general sense of benevolence relating to the
pain, suffering, or death of a person involved
in an accident and made to that person or to the
family of that person shall be inadmissible as
evidence in a civil action.”
Clear as mud, it seems. Do medical mishaps
count as “accidents”? It’s not clear. If they do
count, can a urologist, for example, apologize
and go on to admit responsibility for missing
obvious signs of cancer? No: The law says a
statement of fault is admissible.
How well do apology laws work?
Researchers have been trying to understand the
effects of apology laws, but their findings have
been mixed.
In an October 2011 study published in the
Journal of Risk and Uncertainty (2011; 43:141),
researchers reported that apology laws seemed
to reduce average malpractice payments and
settlement time, especially in cases involving
the worst harm.
However, a 2016 Vanderbilt University study
that has been presented to several academic
audiences found that, “In general, apology
laws increase the probability of malpractice
lawsuits... Overall, the evidence suggests that
apology laws do not effectively limit medical
malpractice liability risk.”
Now, a new study co-authored by a urologist,
37
Dr. McKenna, offers a contrasting opinion. The
study analyzed malpractice cases from 1991
to 2014. In states with apology laws, litigation
length was 4.4±3.3 years before the laws were
enacted (N=165,556) and 3.3±2.0 years afterwards (N=38,940) (p<.001). Litigation length
was shorter (2.6±1.4 years, N=2,281) in states
Please see APOLOGY, on page 38
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38
❳ Cover Feature ❲
JUNE 2016
∣
Urology Times
‘APOLOGY’ DILEMMA
Confirm mistake before apologizing to patient
continued from page 37
with full apology laws than in states with partial
laws (3.3±2.0, N=36,659; p<.001).
Why might there be a connection? According to other research, patients and their relatives
say “an explanation and apology would prevent them from litigating,” Dr. McKenna said.
“Additionally, apologies decrease patients’ anger
toward their doctor and increase patients’ trust,
strengthening the doctor-patient relationship.”
Not so fast, says Dr. Cotton, the anti-apology attorney. Yes, he practices law in a state—
Pennsylvania—that has a partial apology law.
But he doesn’t think it’s worth anything.
Empathy, compassion, and caring are part of
doctoring, he believes. However, he said, “The
idea that a doctor who inadvertently injures
a nerve during a complex, 6-hour surgery
has committed a moral wrong that violates
the trust of the doctor-patient relationship is
insulting.”
“The idea that a doctor who
inadvertently injures a nerve
during a complex, 6-hour
surgery has committed a
moral wrong that violates the
trust of the doctor-patient
relationship is insulting.”
VICTOR COTTON, MD, JD
As for apologizing, he said, “It is very hard to
find a real physician who has tried this approach.
They value their licenses and careers.”
Steps before you apologize
What if a doctor does actually want to apologize
and wants to do it right?
“Don’t apologize unless you know a mistake
has been made,” Dr. McKenna advised. “Wait
until the evidence clearly indicates a medical
mistake before giving an apology.”
But keep in mind that “a patient deserves to
know what happened in the event of a medical
error,” Dr. McKenna said. “At the least, the doctor should disclose the error, as this is ethical.”
Then check your state’s law.
Going beyond the apology
“I’ve found that patients really
appreciate an open and honest
conversation and, when the
harm was caused by an error, a
really frank apology.”
THOMAS H. GALLAGHER, MD
“In states with partial apology laws, physicians should be cognizant that giving an apology without admitting fault is still better than
giving no apology at all,” he said. “In states
with full apology laws, it is important to know
that patients want to understand what happened,
why it happened, how the error could impact
their health, and plans for preventing future
errors. All of this information should be offered
in the apology.”
You may also wish to look at relevant codes
of ethics. An opinion from the American Medical Association says “physicians must offer professional and compassionate concern toward
patients who have been harmed” and offer a
“general explanation” regarding what happened
and how future errors will be prevented.
The ethics code of the AUA tells urologists to
“render services to humanity with full respect
for human dignity.”
But expressions of condolence, sympathy, and
responsibility aren’t enough. “The majority of
them want to know that this error will never
happen again to anyone else,” Armstrong said.
But too often, she said, “patients are left to wonder how an error happened and whether it will
happen again.”
Indeed, apologies focus on resolving a
problem from the past, not fixing the future.
That’s one reason why some health systems are
embracing communication-and-resolution programs, which encourage medical professionals
to do more than say they’re sorry. These programs promote apologies, explanations, and—
in some cases—compensation.
In May 2016, the federal Agency for Healthcare Research and Quality introduced the
CANDOR (Communication and Optimal
Resolution) tool kit, which encourages hospitals to be open to patients about errors. The kit
is based in part on policies at the University of
Michigan Health System in Ann Arbor, which
“In all cases, [patients]
want empathy and
understanding. They
want someone to care.”
SARAH ARMSTRONG, RN, MSN, JD
‘I’m sorry’: How to apologize
Dr. Gallagher, the University of Washington
professor who is a general internist, says he
frequently apologizes to patients and uses the
words “I’m sorry,” often repeatedly.
“I’ve found that patients really appreciate an
open and honest conversation and, when the
harm was caused by an error, a really frank
apology,” he said.
But be aware, he says, that just because
patients appreciate an apology doesn’t mean
they’re happy. Also understand that acknowledging an error could bring it to a patient’s
attention and potentially prompt legal action.
So what do patients want? “In all cases, they
want empathy and understanding. They want
someone to care,” said Sarah Armstrong, RN,
MSN, JD, a health care communication and
conflict resolution consultant at the University
of Washington.
says it’s seen reductions in lawsuits, malpractice cases that reach court, and settlement payments.
Critics question whether these programs
intend to divert patients with valid cases from
suing. But others believe they not only prevent
lawsuits but also lead to change because they
emphasize preventing future errors.
“No liability reform holds as much promise
for improving safety,” Armstrong said.
So which approach is best: No apologies,
apologies, or apologies-plus?
Dr. Cotton points to words attributed variously to Hippocrates and tuberculosis pioneer
Edward Livingston Trudeau, MD: “To cure
sometimes, to relieve often, to comfort always.”
Comfort, as always, will be the hardest of those
three verbs to define. UT
UrologyTimes.com
∣
❳ Cover Feature ❲
JUNE 2016
HIF U
continued from page 1
The new study findings are being released
as urologists continue to debate the value of
HIFU in light of the FDA rulings. It’s not a new
controversy: In January 2014, a Urology Times
online poll found that 46% of respondents didn’t
believe HIFU for prostate cancer had a future in
the United States. The other 54% thought it did.
The 24-month, prospective, non-randomized
study enrolled 135 patients aged 50 years and
over with low-risk, localized prostate cancer
(stage T1-T2a, PSA <10.0 ng/mL, Gleason score
<6) and prostate AP diameter <25 mm. The
patients were treated with HIFU via Ablatherm and analyzed via prostate biopsy for cause,
24-month post-HIFU biopsy, and serum PSA.
The biopsies are unusual, Dr. Robertson said,
since surgeons typically rely on PSA results
after procedures.
inflammatory changes on urinalysis since
you’ll get some shedding of some cells,” Dr.
Robertson told Urology Times. “Most of the
patients didn’t really have any real issues. They
had their treatments and a temporary indwelling catheter, and they had that taken out.”
What should urologists take from the
research? The relevance is limited due to the
patient population. According to Dr. Robertson, patients with low-risk, low-grade prostate
cancer are “not considered a great treatment
category” for HIFU.
EDAP TMS says HIFU “is generally recommended for patients with localized prostate
cancer (stages T1-T2) who are not candidates
for surgery or who prefer an alternative option,
or for patients who failed radiotherapy treatment.”
Dr. Robertson is a consultant and principal
investigator for EDAP TMS. UT
Reduction in positive cores observed
The results: Of 1,251 baseline pre-HIFU biopsy
cores, 365 (29.2%) were positive for prostate
cancer. After the procedure, 87 (7.7%) of 1,127
biopsy cores were positive.
Before the procedure, mean PSA was 4.60
ng/mL. At 6 months after the procedure, the
mean PSA nadir was 0.53 ng/mL.
As for side effects, “Some patients had
❳ UT Figure ❲
HIFU: Change in positive Bx cores
30
29.2%
#BLOODEQUALITY
Positive biopsy cores
20
10
7.7%
0
Baseline
pre-HIFU
Source: Cary Robertson, MD
24 months
post-HIFU
39
When I tried to donate blood, they turned me away because
I’m a gay man. The FDA’s latest policy says that gay and bisexual
men can’t be blood donors unless they remain celibate for a year.
Yet the blood supply is always tested to ensure safety. So why are
they typecasting my blood? Blood is blood. And discrimination
is discrimination. That’s why it’s time for science, not stigma.
BloodEquality.com
In partnership with
40
JUNE 2016
Speak Out
What should the
AUA’s legislative
priorities be?
“A
s a private practice urologist coming up
on my 29th year of doing this, there have
been a lot of changes. What the AUA can do
for those of us in the trenches, so to speak, is to
lessen some of the regulatory
burdens that have been put
on us, specifically the [Physician Quality Reporting System]
and jumping through all these
additional hoops.
We’ve been forced into elecDr. Piser
tronic medical records, which
have increased our clerical time tremendously.
Some people just kind of give up and do poor,
cookie-cutter notes, and that goes against the
grain of a lot of docs who take pride in taking
care of patients—which means good documentation. But this adds things that are really
who are doing the screenings, and I think we’re
going to see cases of people presenting with
late metastatic disease.
The other two things that
apply to all of medicine are
access to medication, especially generics that we use but
that frequently go on shortage
because manufacturers stop
Dr. Broghammer producing it because there’s
no oversight or regulation in terms of drugs.
There’s less access and periods where some
drugs aren’t available at all. The issue is, if we
want to give guideline-directed care, we’re not
able because the medication is not there. We
need some sort of regulation.
The other issue is the Affordable Care Act.
Although I support the idea in principle of providing coverage, it hasn’t really accomplished
that. There needs to be some kind of alternative
solution.”
Joel Piser, MD
Kansas City, KS
’ve been here for 21 years in a 15-mangroup, with several of us in our 50s and
very busy. We try to be politically active. One
thing that really worries me is that we’re all
about ‘quality’ work—and paying for quality
is kind of a misnomer for me.
How are you going to pay urologists to do quality work when
much of what we do is episodic
interventions for people with
bladder cancer, kidney stones,
prostate cancer? We do some
Dr. Weisner
primary care, but we don’t
have a lot of preventive medicine to provide.
I’m worried you’re already seeing it with fewer
PSAs being done, with fewer people being
referred for elevated PSAs. Unfortunately, people
are getting diagnosed later with more aggressive prostate cancer. How do urologists fit into
this integrated network or an accountable care
organization when we’re such a small part of the
health care dollar and we’re not on the front lines?
But we’re important and necessary, and I would
like for the AUA to confirm our seat at the table so
we’re not excluded from any pay for performance.
I think the [U.S. Preventive Services Task
Force] is a bunch of hooey. They should have
had urologists’ input. They made a false decision that hurt urology and our patients.
Anything the AUA can do to tamp down
meaningful use—some of it’s OK, but so much
of it is not urology pertinent.
The other thing I hate is preauthorization for
imaging and medications. We spend hours on
the phone every day.
I love my job. Just the regulations drive me
bonkers.”
Berkeley, CA
ontinued access to PSA testing is something that needs to be looked at and
advocated for by the AUA. So far, it’s still being
covered by insurance, but we’ve seen kind of a
blanket decrease in the primary care physicians
“C
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Urology Times
unnecessary, so it takes a lot of unnecessary
time. I personally have given up and have a
scribe. That costs more money but makes my
personal time more available.
The AUA needs to advocate strongly against
repealing the in-office ancillary service exemption, especially ultrasonography. It’s also so
much more expensive to send out cultures
rather than doing our own. Study after study
have shown we deliver care less expensively
when it’s administered in our office as compared to the hospital or even the hospitalbased urologists.
If a patient in the office needs a catheter,
Medicare pays me a minimal fee and doesn’t
reimburse for the cost of the catheter. (We do it
for existing patients because I won’t make them
go sit in the ER for 4 hours when we’re here.) The
AUA can do a lot to support the independent
private practitioner that would be good for
patient care, would be most cost effective to do,
and really be the right thing to do for patients.”
Advertisers Index
Advertiser Name
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Joshua Broghammer, MD
“I
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Matthews, NC
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JUNE 2016
Careers
K ANSAS
THE UNIVERSITY OF KANSAS
MEDICAL CENTER
DEPARTMENT OF UROLOGY
CONNECT
with qualified leads
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The Department of Urology at the University of Kansas is seeking a board certified
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NEW JERSEY
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Seeking General Urologist and Pediatric Urologist
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❳Washington and You❲
JUNE 2016
MACRA proposed rule
brings new decisions
Details provided on meaningful use program replacement
Washington—Urologists and other physicians
who serve Medicare patients face some new
decisions now that the Centers for Medicare &
Medicaid Services (CMS) has proposed new
regulations implementing last year’s fee schedule reform law, while also replacing the existing
meaningful use program with a more flexible
approach to technology and electronic health
records.
“We have more work to do, but we are committed to implementing this important legislation and creating a health care system that works
better for doctors, patients, and taxpayers alike,”
said Health and Human Services Secretary
Sylvia M. Burwell, referring to the Medicare
Access and CHIP Reauthorization Act of 2015
(MACRA), which reforms the Medicare physician payment system and ends the troubling pay
cut crises that occurred year after year.
single framework to help physicians transition
from volume-based payments to those based on
value. The new rule, for which CMS is accepting comments until June 27, 2016, implements
those changes by establishing the Quality Payment Program, giving physicians two options
for Medicare reimbursement. They can participate either in the merit-based incentive payment
system (MIPS) or Advanced APMs.
“Our goal with Advancing Care
Information is to support the vision
of a simpler, more connected, less
burdensome technology.”
ANDY SLAVITT
Rule streamlines payment programs
The proposed rule, issued April 27, streamlines
a patchwork of programs that are designed to
measure the value and quality of care provided
by doctors and other clinicians. Some physicians participate in alternative payment models
(APMs) such as accountable care organizations,
the Comprehensive Primary Care Initiative, and
the Medicare Shared Savings Program, and
most participate in such programs as the Physician Quality Reporting System, the Value-Based
Payment Modifier Program, and the Medicare
Electronic Health Record Incentive Program.
MACRA streamlined these programs into a
Fast Facts
A proposed rule implementing the
Medicare Access and CHIP Reauthorization Act of 2015 would:
❯❯ establish the Quality Payment Program,
giving physicians two options for Medicare
reimbursement: the merit-based incentive
payment system (MIPS) or Advanced Alternative Payment Models
❯❯ increase clinician flexibility by allowing them
to choose MIPS measures and activities
appropriate to the type of care they provide
❯❯ replace the Medicare Electronic Health Record
Incentive Program with a MIPS measure
called Advancing Care Information
Acting CMS Administrator
In its announcement of the rule, CMS said
most Medicare clinicians will initially participate through MIPS. The agency said the proposed rule would increase clinician flexibility
by allowing them to choose measures and activities appropriate to the type of care they provide.
MIPS provides for payment through these performance categories: Quality, Advancing Care
Information, Clinical Practice Improvement
Activities, and Cost.
Those categories break down as follows:
Quality (50% of total score in year 1). Clinicians
would choose to report six measures from a
range of options that accommodate differences
among specialties and practices.
Advancing Care Information (25% of total score in
year 1). Clinicians would choose to report cus-
tomizable measures that reflect how they use
technology in their day-to-day practice, with
emphasis on interoperability and information
exchange.
Clinical Practice Improvement Activities (15%
of total score in year 1). This category rewards
clinical practice improvements, such as care
coordination, beneficiary engagement, and
patient safety. Clinicians may select activities
that match their practices’ goals from a list of
more than 90 options.
Cost (10% of total score in year 1). The score
would be based on Medicare claims, so there
would be no reporting requirements for clinicians. The category would use 40 episode-spe-
43
Bob Gatty
UT Washington
Correspondent
Bob Gatty, a former
congressional aide, covers
news from Washington
for Urology Times.
cific measures to account for differences among
specialties.
Meaningful use replacement ‘simpler’
CMS’s action to replace the meaningful use
program was based on comments from more
than 6,000 physicians and patients about their
experience with health information technology,
according to Andy Slavitt, acting administrator
at CMS.
“Our goal with Advancing Care Information is to support the vision of a simpler, more
connected, less burdensome technology,” said
Slavitt.
The new regulation would:
allow physicians and other clinicians to
choose to select the measures that reflect how
technology best suits their day-to-day practice
simplify the process for achievement and
provide multiple paths for success
align with the Office of the National Coordinator for Health Information Technology’s
2015 Edition Health IT Certification Criteria
emphasize interoperability, information
exchange, and security measures and require
that patients have online access to their health
information
simplify reporting by no longer requiring
all-or-nothing EHR measurement or quality
reporting
reduce the number of measures to 11 from
18, and no longer require reporting on the Clinical Decision Support and Computerized Provider Order Entry measures
exempt certain physicians from reporting when EHR technology is less applicable to
their practice and allow physicians to report as
a group.
CMS would begin measuring performance
through MIPS in 2017, with payments based on
those measures beginning in 2019.
Medicare physicians who participate to a sufficient extent in Advanced APMs would be
exempt from MIPS reporting requirements and
qualify for financial bonuses. CMS said it
expects the number of clinicians who qualify
as participating in Advanced APMs to grow as
the program matures.
r
r
r
r
r
r
r
Feedback
Send your comments to
Bob Gatty c/o Urology Times, at [email protected]
44
❳Malpractice Consult❲
JUNE 2016
∣
Urology Times
Could necrotizing fasciitis have
been diagnosed sooner?
Defendant claims consult, reliance on MRI scan compliant with standard of care
A
57-year-old Tennessee man presented to an emergency room in
2006 with complaints of severe
groin pain. Testing indicated a
high white blood cell count, but a
magnetic resonance imaging scan was negative
for infection.
Two days later, a surgeon was called to consult. She reviewed the medical records, ruled
out infection, and left for the weekend.
Four days later, the patient’s condition
worsened and he was then diagnosed with
necrotizing fasciitis of his groin and penis.
The surgeon was called in to perform an operation to excise the area, including removal
of skin from the penis and removal of the
scrotum with the testicles implanted in the
upper thigh. The result of the infection and
surgery was described as a horrendous and
deforming injury.
In medical malpractice cases, the
caregivers are held to the “standard
of care” expected in the particular
situation and are judged as to
whether that standard was met.
The man sued the consulting surgeon and
alleged she failed to make a timely diagnosis
of the infection or perform a biopsy; rather, she
relied on the MRI and ignored the clear clinical
signs of infection. He argued that if the infection were caught earlier, an effective treatment
would have prevented the subsequent injury.
He also claimed the surgeon failed to communicate with other medical team members before
leaving for the weekend. The man died a year
after filing the lawsuit, and his estate pursued
the case to trial.
The surgeon contended that her consult and
reliance on the MRI and communication were
all compliant with the standard of care and that
at the time of her consult, the patient did not
yet have the infection. A defense judgment was
entered.
LEGAL PERSPECTIVE: In medical malpractice
cases, the caregivers are held to the “standard
of care” expected in the particular situation
and are judged as to whether that standard
Malpractice Consult
pletely without any scarring. The jury returned
a defense verdict.
Dawn Collins, JD
Failure to diagnose torsion alleged
Ms. Collins is an attorney specializing in
medical malpractice in Long Beach, CA. She
welcomes your feedback on this column at
[email protected].
was met. In our legal system, a “reasonable
person” standard is used, meaning would a
reasonable physician with the same or similar
training, in a same or similar situation, have
performed similarly as the defendants in the
particular lawsuit?
In this case, the plaintiff introduced what
he called the “gold standard” for diagnosing
this particular infection, claiming that the gold
standard was to perform a biopsy at the time
of consult instead of relying on the MRI findings. The physician prevailed in showing that
her care was compliant with the required standard of care.
Allergic reaction to antiseptic solution
A New Jersey man in his 40s was admitted
to a hospital for a cystoscopy to examine his
bladder lining and urethra. After the procedure,
the patient had complaints of inflammation and
pain to his penis and was seen by several urologists, but with no treatments performed. As a
result, he developed scarring to his penis and
complained of tenderness and some functional
deficit.
The man sued the urologist, his nurse, and
his medical group, claiming that the antiseptic solution on the equipment used for the
cystoscopy caused a severe allergic reaction,
with severe inflammation and pain to his
penis.
The man alleged the urologist and a nurse
who assisted in the procedure negligently
failed to provide appropriate medical care and
failed to properly clean the equipment prior to
the procedure, which resulted in the allergic
reaction and injuries.
The defense denied any negligence, contending that any negative reaction the patient experienced to the antiseptic material was one that
could not have been anticipated. They argued
that the inflammation and related conditions
were temporary and had since resolved com-
A 14-year-old male from Illinois presented to
an emergency room in 2008 with complaints of
lower left abdominal pain and was examined
and treated by a pediatric ER physician.
A subsequent lawsuit alleged that those
involved with his care failed to diagnose leftsided testicular torsion, failed to perform a
testicular examination to rule out torsion, and
failed to surgically fix the right testicle to prevent a right-sided torsion. As a result, the patient
developed a right-sided torsion 6 months later
that was treated at a second hospital. There, the
medical personnel surgically removed the right
testicle, discovered an atrophied left testicle,
and surgically fixed that testicle to the scrotum
in an attempt to salvage hormone production.
The teen is now sterile and requires testosterone replacement therapy for the rest of his life.
The lawsuit alleged that those
involved with the patient’s care failed
to diagnose left-sided testicular
torsion, failed to perform a testicular
examination to rule out torsion,
and failed to surgically fix the right
testicle to prevent a right-sided
torsion.
The defense maintained that the patient did
not suffer from testicular torsion at the time of
the first ER visit, that he had none of the classic
symptoms such as painful/swollen testicles, and
that the physician found no reproducible symptoms when he examined the testicles.
The plaintiff further asserted that presenting
complaints for testicular torsion in an adolescent can be limited to lower quadrant pain without testicular pain, so the defense should have
investigated further, especially after other diagnostic tests came back normal and the source
of the abdominal pain was not found. The jury
found in favor of the patient and awarded
$351,000. UT
XTANDI® (enzalutamide) capsules for oral use
Initial U.S. Approval: 2012
BRIEF SUMMARY OF PRESCRIBING INFORMATION
The following is a brief summary. Please see the package
insert for full prescribing information.
INDICATIONS AND USAGE
XTANDI is indicated for the treatment of patients with
metastatic castration-resistant prostate cancer (CRPC).
CONTRAINDICATIONS
Pregnancy
XTANDI can cause fetal harm when administered
to a pregnant woman based on its mechanism of
action and findings in animals. XTANDI is not indicated
for use in women. XTANDI is contraindicated in women
who are or may become pregnant. If this drug is
used during pregnancy, or if the patient becomes
pregnant while taking this drug, apprise the patient of
the potential hazard to the fetus and the potential risk for
pregnancy loss.
WARNINGS AND PRECAUTIONS
Seizure
In Study 1, which enrolled patients who previously
received docetaxel, 7 of 800 (0.9%) patients treated with
XTANDI experienced a seizure and no patients treated
with placebo experienced a seizure. Seizure occurred
from 31 to 603 days after initiation of XTANDI. In Study
2, 1 of 871 (0.1%) chemotherapy-naive patients treated
with XTANDI and 1 of 844 (0.1%) patients treated with
placebo experienced a seizure. Patients experiencing
seizure were permanently discontinued from therapy
and all seizure events resolved. There is no clinical trial
experience re-administering XTANDI to patients who
experienced seizure.
Limited safety data are available in patients with
predisposing factors for seizure because these patients
were generally excluded from the trials. These exclusion
criteria included a history of seizure, underlying brain
injury with loss of consciousness, transient ischemic
attack within the past 12 months, cerebral vascular
accident, brain metastases, and brain arteriovenous
malformation. Study 1 excluded the use of concomitant
medications that may lower the seizure threshold,
whereas Study 2 permitted the use of these medications.
Because of the risk of seizure associated with XTANDI
use, patients should be advised of the risk of engaging
in any activity where sudden loss of consciousness could
cause serious harm to themselves or others. Permanently
discontinue XTANDI in patients who develop a seizure
during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES)
There have been reports of posterior reversible
encephalopathy syndrome (PRES) in patients receiving
XTANDI. PRES is a neurological disorder which can present
with rapidly evolving symptoms including seizure,
headache, lethargy, confusion, blindness, and other
visual and neurological disturbances, with or without
associated hypertension. A diagnosis of PRES requires
confirmation by brain imaging, preferably magnetic
resonance imaging (MRI). Discontinue XTANDI in
patients who develop PRES.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates
observed in practice.
Two randomized clinical trials enrolled patients with
metastatic prostate cancer that has progressed on
androgen deprivation therapy (GnRH therapy or bilateral
orchiectomy), a disease setting that is also defined as
metastatic CRPC. In both studies, patients received
XTANDI 160 mg orally once daily in the active treatment
arm or placebo in the control arm. All patients continued
androgen deprivation therapy. Patients were allowed, but
not required, to take glucocorticoids.
The most common adverse reactions (≥ 10%) that
occurred more commonly (≥ 2% over placebo) in the
XTANDI-treated patients from the two randomized
clinical trials were asthenia/fatigue, back pain, decreased
appetite, constipation, arthralgia, diarrhea, hot flush,
upper respiratory tract infection, peripheral edema,
dyspnea, musculoskeletal pain, weight decreased,
headache, hypertension, and dizziness/vertigo.
Study 1: Metastatic Castration-Resistant Prostate
Cancer Following Chemotherapy
Study 1 enrolled 1199 patients with metastatic CRPC
who had previously received docetaxel. The median
duration of treatment was 8.3 months with XTANDI and
3.0 months with placebo. During the trial, 48% of patients
on the XTANDI arm and 46% of patients on the placebo
arm received glucocorticoids.
Grade 3 and higher adverse reactions were reported
among 47% of XTANDI-treated patients and 53% of
placebo-treated patients. Discontinuations due to adverse
events were reported for 16% of XTANDI-treated patients
and 18% of placebo-treated patients. The most common
adverse reaction leading to treatment discontinuation was
seizure, which occurred in 0.9% of the XTANDI-treated
patients compared to none (0%) of the placebo-treated
patients. Table 1 shows adverse reactions reported in
Study 1 that occurred at a ≥ 2% higher frequency in the
XTANDI arm compared to the placebo arm.
Table 1. Adverse Reactions in Study 1
XTANDI
Placebo
N = 800
N = 399
Grade Grade Grade Grade
a
3-4
1-4
3-4
1-4
(%)
(%)
(%)
(%)
General Disorders
Asthenic
50.6
9.0
44.4
9.3
Conditionsb
Peripheral
15.4
1.0
13.3
0.8
Edema
Musculoskeletal And Connective Tissue Disorders
Back Pain
26.4
5.3
24.3
4.0
Arthralgia
20.5
2.5
17.3
1.8
Musculoskeletal 15.0
1.3
11.5
0.3
Pain
Muscular
9.8
1.5
6.8
1.8
Weakness
Musculoskeletal
2.6
0.3
0.3
0.0
Stiffness
Gastrointestinal Disorders
Diarrhea
21.8
1.1
17.5
0.3
Vascular Disorders
Hot Flush
20.3
0.0
10.3
0.0
Hypertension
6.4
2.1
2.8
1.3
Nervous System Disorders
Headache
12.1
0.9
5.5
0.0
9.5
0.5
7.5
0.5
Dizzinessc
Spinal Cord
Compression
and Cauda
7.4
6.6
4.5
3.8
Equina
Syndrome
Paresthesia
6.6
0.0
4.5
0.0
Mental
Impairment
4.3
0.3
1.8
0.0
Disordersd
Hypoesthesia
4.0
0.3
1.8
0.0
Infections And Infestations
Upper
Respiratory
10.9
0.0
6.5
0.3
Tract Infectione
Lower
Respiratory
8.5
2.4
4.8
1.3
Tract And Lung
Infectionf
Psychiatric Disorders
Insomnia
8.8
0.0
6.0
0.5
Anxiety
6.5
0.3
4.0
0.0
Renal And Urinary Disorders
Hematuria
6.9
1.8
4.5
1.0
Pollakiuria
4.8
0.0
2.5
0.0
Injury, Poisoning And Procedural Complications
Fall
4.6
0.3
1.3
0.0
Non-pathologic
4.0
1.4
0.8
0.3
Fractures
Skin And Subcutaneous Tissue Disorders
Pruritus
3.8
0.0
1.3
0.0
Dry Skin
3.5
0.0
1.3
0.0
Table 1. Adverse Reactions in Study 1 (cont.)
Respiratory Disorders
Epistaxis
3.3
0.1
1.3
0.3
a
b
c
d
CTCAE v4
Includes asthenia and fatigue.
Includes dizziness and vertigo.
Includes amnesia, memory impairment, cognitive disorder,
and disturbance in attention.
e Includes nasopharyngitis, upper respiratory tract infection,
sinusitis, rhinitis, pharyngitis, and laryngitis.
f Includes pneumonia, lower respiratory tract infection,
bronchitis, and lung infection.
Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer
Study 2 enrolled 1717 patients with metastatic CRPC who
had not received prior cytotoxic chemotherapy, of whom
1715 received at least one dose of study drug. The median
duration of treatment was 17.5 months with XTANDI and
4.6 months with placebo. Grade 3-4 adverse reactions
were reported in 44% of XTANDI-treated patients and
37% of placebo-treated patients. Discontinuations due to
adverse events were reported for 6% of XTANDI-treated
patients and 6% of placebo-treated patients. The
most common adverse reaction leading to treatment
discontinuation was fatigue/asthenia, which occurred in
1% of patients on each treatment arm. Table 2 includes
adverse reactions reported in Study 2 that occurred at a
≥ 2% higher frequency in the XTANDI arm compared to
the placebo arm.
Table 2. Adverse Reactions in Study 2
Placebo
XTANDI
N = 844
N = 871
Grade Grade Grade Grade
a
1-4
3-4
3-4
1-4
(%)
(%)
(%)
(%)
General Disorders
Asthenic
46.9
3.4
33.0
2.8
Conditionsb
Peripheral
11.5
0.2
8.2
0.4
Edema
Musculoskeletal And Connective Tissue Disorders
Back Pain
28.6
2.5
22.4
3.0
Arthralgia
21.4
1.6
16.1
1.1
Gastrointestinal Disorders
Constipation
23.2
0.7
17.3
0.4
Diarrhea
16.8
0.3
14.3
0.4
Vascular Disorders
Hot Flush
18.0
0.1
7.8
0.0
Hypertension
14.2
7.2
4.1
2.3
Nervous System Disorders
11.3
0.3
7.1
0.0
Dizzinessc
Headache
11.0
0.2
7.0
0.4
Dysgeusia
7.6
0.1
3.7
0.0
Mental
5.7
0.0
1.3
0.1
Impairment
Disordersd
Restless Legs
2.1
0.1
0.4
0.0
Syndrome
Respiratory Disorders
11.0
0.6
8.5
0.6
Dyspneae
Infections And Infestations
Upper
16.4
0.0
10.5
0.0
Respiratory
Tract Infectionf
Lower
Respiratory
7.9
1.5
4.7
1.1
Tract And Lung
Infectiong
Psychiatric Disorders
Insomnia
8.2
0.1
5.7
0.0
Renal And Urinary Disorders
Hematuria
8.8
1.3
5.8
1.3
Injury, Poisoning And Procedural Complications
Fall
12.7
1.6
5.3
0.7
Non-Pathological
8.8
2.1
3.0
1.1
Fracture
Metabolism and Nutrition Disorders
Decreased
18.9
0.3
16.4
0.7
Appetite
Investigations
Weight
12.4
0.8
8.5
0.2
Decreased
Reproductive System and Breast Disorders
1.4
3.4
0.0
0.0
Gynecomastia
Table 2. Adverse Reactions in Study 2 (cont.)
a
b
c
d
CTCAE v4
Includes asthenia and fatigue.
Includes dizziness and vertigo.
Includes amnesia, memory impairment, cognitive disorder,
and disturbance in attention.
e Includes dyspnea, exertional dyspnea, and dyspnea at rest.
f Includes nasopharyngitis, upper respiratory tract infection,
sinusitis, rhinitis, pharyngitis, and laryngitis.
g Includes pneumonia, lower respiratory tract infection,
bronchitis, and lung infection.
Laboratory Abnormalities
In the two randomized clinical trials, Grade 1-4
neutropenia occurred in 15% of patients treated with
XTANDI (1% Grade 3-4) and in 6% of patients treated
with placebo (0.5% Grade 3-4). The incidence of Grade
1-4 thrombocytopenia was 6% of patients treated with
XTANDI (0.3% Grade 3-4) and 5% of patients treated
with placebo (0.5% Grade 3-4). Grade 1-4 elevations in
ALT occurred in 10% of patients treated with XTANDI
(0.2% Grade 3-4) and 16% of patients treated with
placebo (0.2% Grade 3-4). Grade 1-4 elevations in
bilirubin occurred in 3% of patients treated with XTANDI
(0.1% Grade 3-4) and 2% of patients treated with placebo
(no Grade 3-4).
Infections
In Study 1, 1% of patients treated with XTANDI compared
to 0.3% of patients treated with placebo died from
infections or sepsis. In Study 2, 1 patient in each treatment
group (0.1%) had an infection resulting in death.
Falls and Fall-related Injuries
In the two randomized clinical trials, falls including fallrelated injuries, occurred in 9% of patients treated with
XTANDI compared to 4% of patients treated with placebo.
Falls were not associated with loss of consciousness or
seizure. Fall-related injuries were more severe in patients
treated with XTANDI and included non-pathologic
fractures, joint injuries, and hematomas.
Hypertension
In the two randomized trials, hypertension was reported
in 11% of patients receiving XTANDI and 4% of patients
receiving placebo. No patients experienced hypertensive
crisis. Medical history of hypertension was balanced
between arms. Hypertension led to study discontinuation
in < 1% of patients in each arm.
Post-Marketing Experience
The following additional adverse reactions have been
identified during post approval use of XTANDI. Because
these reactions were reported voluntarily from a
population of uncertain size, it is not always possible
to reliably estimate the frequency or establish a causal
relationship to drug exposure.
Neurological Disorders: posterior reversible encephalopathy
syndrome (PRES)
DRUG INTERACTIONS
Drugs that Inhibit CYP2C8
Co-administration of a strong CYP2C8 inhibitor
(gemfibrozil) increased the composite area under the
plasma concentration-time curve (AUC) of enzalutamide
plus N-desmethyl enzalutamide by 2.2-fold. Coadministration of XTANDI with strong CYP2C8 inhibitors
should be avoided if possible. If co-administration
of XTANDI with a strong CYP2C8 inhibitor cannot be
avoided, reduce the dose of XTANDI.
Drugs that Induce CYP3A4
Co-administration of rifampin (strong CYP3A4 inducer
and moderate CYP2C8 inducer) decreased the composite
AUC of enzalutamide plus N-desmethyl enzalutamide
by 37%. Co-administration of strong CYP3A4 inducers
(e.g., carbamazepine, phenobarbital, phenytoin, rifabutin,
rifampin, rifapentine) with XTANDI should be avoided
if possible. St John’s wort may decrease enzalutamide
exposure and should be avoided. If co-administration of a
strong CYP3A4 inducer with XTANDI cannot be avoided,
increase the dose of XTANDI.
Effect of XTANDI on Drug Metabolizing Enzymes
Enzalutamide is a strong CYP3A4 inducer and a moderate
CYP2C9 and CYP2C19 inducer in humans. At steady
state, XTANDI reduced the plasma exposure to midazolam
(CYP3A4 substrate), warfarin (CYP2C9 substrate), and
omeprazole (CYP2C19 substrate). Concomitant use of
XTANDI with narrow therapeutic index drugs that are
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine,
dihydroergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus and tacrolimus), CYP2C9 (e.g.,
phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin)
should be avoided, as enzalutamide may decrease their
exposure. If co-administration with warfarin cannot be
avoided, conduct additional INR monitoring.
USE IN SPECIFIC POPULATIONS
Pregnancy– Pregnancy Category X.
Risk Summary
XTANDI can cause fetal harm when administered to a
pregnant woman based on its mechanism of action and
findings in animals. While there are no human data on the
use of XTANDI in pregnancy and XTANDI is not indicated
for use in women, it is important to know that maternal
use of an androgen receptor inhibitor could affect
development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than
in patients receiving the recommended dose. XTANDI
is contraindicated in women who are or may become
pregnant while receiving the drug. If this drug is used
during pregnancy, or if the patient becomes pregnant
while taking this drug, apprise the patient of the potential
hazard to the fetus and the potential risk for pregnancy
loss. Advise females of reproductive potential to avoid
becoming pregnant during treatment with XTANDI.
Animal Data
In an embryo-fetal developmental toxicity study in
mice, enzalutamide caused developmental toxicity
when administered at oral doses of 10 or 30 mg/kg/day
throughout the period of organogenesis (gestational days
6-15). Findings included embryo-fetal lethality (increased
post-implantation loss and resorptions) and decreased
anogenital distance at ≥ 10 mg/kg/day, and cleft palate
and absent palatine bone at 30 mg/kg/day. Doses of
30 mg/kg/day caused maternal toxicity. The doses tested
in mice (1, 10 and 30 mg/kg/day) resulted in systemic
exposures (AUC) approximately 0.04, 0.4 and 1.1 times,
respectively, the exposures in patients. Enzalutamide
did not cause developmental toxicity in rabbits when
administered throughout the period of organogenesis
(gestational days 6-18) at dose levels up to 10 mg/kg/day
(approximately 0.4 times the exposures in patients based
on AUC).
Nursing Mothers
XTANDI is not indicated for use in women. It is not known
if enzalutamide is excreted in human milk. Because
many drugs are excreted in human milk, and because
of the potential for serious adverse reactions in nursing
infants from XTANDI, a decision should be made to either
discontinue nursing, or discontinue the drug taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of XTANDI in pediatric patients
have not been established.
Geriatric Use
Of 1671 patients who received XTANDI in the two
randomized clinical trials, 75% were 65 and over, while
31% were 75 and over. No overall differences in safety
or effectiveness were observed between these patients
and younger patients. Other reported clinical experience
has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of
some older individuals cannot be ruled out.
Patients with Renal Impairment
A dedicated renal impairment trial for XTANDI has not
been conducted. Based on the population pharmacokinetic
analysis using data from clinical trials in patients with
metastatic CRPC and healthy volunteers, no significant
difference in enzalutamide clearance was observed
in patients with pre-existing mild to moderate renal
impairment (30 mL/min ≤ creatinine clearance [CrCL]
≤ 89 mL/min) compared to patients and volunteers with
baseline normal renal function (CrCL ≥ 90 mL/min).
No initial dosage adjustment is necessary for patients
with mild to moderate renal impairment. Severe renal
impairment (CrCL < 30 mL/min) and end-stage renal
disease have not been assessed.
Patients with Hepatic Impairment
Dedicated hepatic impairment trials compared the
composite systemic exposure of enzalutamide plus
N-desmethyl enzalutamide in volunteers with baseline
mild, moderate, or severe hepatic impairment (ChildPugh Class A, B, or C, respectively) versus healthy
controls with normal hepatic function. The composite
AUC of enzalutamide plus N-desmethyl enzalutamide
was similar in volunteers with mild, moderate, or severe
baseline hepatic impairment compared to volunteers with
normal hepatic function. No initial dosage adjustment is
necessary for patients with baseline mild, moderate, or
severe hepatic impairment.
OVERDOSAGE
In the event of an overdose, stop treatment with XTANDI
and initiate general supportive measures taking into
consideration the half-life of 5.8 days. In a dose escalation
study, no seizures were reported at ≤ 240 mg daily,
whereas 3 seizures were reported, 1 each at 360 mg,
480 mg, and 600 mg daily. Patients may be at increased
risk of seizure following an overdose.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been conducted to
evaluate the carcinogenic potential of enzalutamide.
Enzalutamide did not induce mutations in the bacterial
reverse mutation (Ames) assay and was not genotoxic
in either the in vitro mouse lymphoma thymidine
kinase (Tk) gene mutation assay or the in vivo mouse
micronucleus assay.
Based on nonclinical findings in repeat-dose toxicology
studies, which were consistent with the pharmacological
activity of enzalutamide, male fertility may be impaired
by treatment with XTANDI. In a 26-week study in rats,
atrophy of the prostate and seminal vesicles was observed
at ≥ 30 mg/kg/day (equal to the human exposure based
on AUC). In 4-, 13-, and 39-week studies in dogs,
hypospermatogenesis and atrophy of the prostate and
epididymides were observed at ≥ 4 mg/kg/day (0.3 times
the human exposure based on AUC).
Manufactured by: Catalent Pharma Solutions, LLC,
St. Petersburg, FL 33716
Manufactured for and Distributed by: Astellas Pharma
US, Inc., Northbrook, IL 60062
Marketed by:
Astellas Pharma US, Inc., Northbrook, IL 60062
Medivation, Inc., San Francisco, CA 94105
Revised: October 2015
15C018-XTA
Rx Only
© 2015 Astellas Pharma US, Inc.
XTANDI® is a registered trademark of Astellas Pharma Inc.
076-1200-PM
XTANDI (enzalutamide) capsules is indicated for the treatment of
patients with metastatic castration-resistant prostate cancer (CRPC).
Important Safety Information
Contraindications XTANDI is not indicated for
women and is contraindicated in women who are or may
become pregnant. XTANDI can cause fetal harm when
administered to a pregnant woman.
Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic
castration-resistant prostate cancer (CRPC) who previously
received docetaxel, seizure occurred in 0.9% of XTANDI
patients and 0% of placebo patients. In Study 2, conducted
in patients with chemotherapy-naive metastatic CRPC,
seizure occurred in 0.1% of XTANDI patients and 0.1%
of placebo patients. There is no clinical trial experience
re-administering XTANDI to patients who experienced a
seizure, and limited safety data are available in patients with
predisposing factors for seizure. Study 1 excluded the use of
concomitant medications that may lower threshold; Study 2
permitted the use of these medications. Because of the risk
of seizure associated with XTANDI use, patients should be
advised of the risk of engaging in any activity during which
sudden loss of consciousness could cause serious harm to
themselves or others. Permanently discontinue XTANDI in
patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES)
In post approval use, there have been reports of PRES in
patients receiving XTANDI. PRES is a neurological disorder
which can present with rapidly evolving symptoms including
seizure, headache, lethargy, confusion, blindness, and
other visual and neurological disturbances, with or without
associated hypertension. A diagnosis of PRES requires
confirmation by brain imaging, preferably MRI. Discontinue
XTANDI in patients who develop PRES.
Adverse Reactions
The most common adverse reactions (≥ 10%) reported from
two combined clinical studies that occurred more commonly
(≥ 2% over placebo) in XTANDI patients were asthenia/
fatigue, back pain, decreased appetite, constipation, arthralgia,
diarrhea, hot flush, upper respiratory tract infection, peripheral
edema, dyspnea, musculoskeletal pain, weight decreased,
headache, hypertension, and dizziness/vertigo.
In Study 1, Grade 3 and higher adverse reactions were
reported among 47% of XTANDI patients and 53% of
placebo patients. Discontinuations due to adverse events
were reported for 16% of XTANDI patients and 18% of
placebo patients. In Study 2, Grade 3-4 adverse reactions
were reported in 44% of XTANDI patients and 37% of
placebo patients. Discontinuations due to adverse events
were reported for 6% of both study groups.
• Lab Abnormalities: Grade 1-4 neutropenia occurred in 15%
of XTANDI patients (1% Grade 3-4) and 6% of placebo
patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia
occurred in 6% of XTANDI patients (0.3% Grade 3-4)
and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4
elevations in ALT occurred in 10% of XTANDI patients
(0.2% Grade 3-4) and 16% of placebo patients (0.2%
Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3%
of XTANDI patients (0.1% Grade 3-4) and 2% of placebo
patients (no Grade 3-4).
• Infections: In Study 1, 1% of XTANDI patients compared to
0.3% of placebo patients died from infections or sepsis. In
Study 2, 1 patient in each treatment group (0.1%) had an
infection resulting in death.
• Falls (including fall-related injuries), occurred in 9% of
XTANDI patients and 4% of placebo patients. Falls were not
associated with loss of consciousness or seizure. Fall-related
injuries were more severe in XTANDI patients, and included
non-pathologic fractures, joint injuries, and hematomas.
• Hypertension occurred in 11% of XTANDI patients and 4%
of placebo patients. No patients experienced hypertensive
crisis. Medical history of hypertension was balanced
between arms. Hypertension led to study discontinuation in
< 1% of all patients.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8
inhibitors, as they can increase the plasma exposure to XTANDI.
If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the
plasma exposure to XTANDI. If co-administration is
necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9,
and CYP2C19 substrates with a narrow therapeutic index,
as XTANDI may decrease the plasma exposures of these
drugs. If XTANDI is co-administered with warfarin (CYP2C9
substrate), conduct additional INR monitoring.
Please see adjacent pages for Brief Summary of
Full Prescribing Information.
© 2016 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-1306-PM 1/16
XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.
patient lives
94% ofareinsured
covered for XTANDI*
2
*As of February 2015. A product’s placement on a plan formulary involves
a variety of factors known only to the plan and is subject to eligibility.
To learn more, please visit XtandiHCP.com
XTANDI (enzalutamide) capsules is indicated for the treatment of
patients with metastatic castration-resistant prostate cancer (CRPC).
bilatera
*Or after
l orchiecto
1
my.
patient lives
94% ofareinsured
covered for XTANDI
†2
†As of February 2015. A product’s placement on a plan formulary involves
a variety of factors known only to the plan and is subject to eligibility.
Select Safety Information
To learn more, please visit XtandiHCP.com
XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may
become pregnant.
Seizure occurred in 0.9% of patients receiving XTANDI who previously received docetaxel and in 0.1%
of patients who were chemotherapy-naive. Permanently discontinue XTANDI in patients who develop a
seizure during treatment.
There have been post approval reports of posterior reversible encephalopathy syndrome (PRES), a
neurological disorder which can present with rapidly evolving symptoms and requires confirmation by
brain imaging. Discontinue XTANDI in patients who develop PRES.
References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Data on file, Medivation, Inc.
Please see inside page for additional Important Safety Information.
Please see adjacent pages for Brief Summary of Full Prescribing Information.