January 2013 Clinical Advisor

THE CLINICAL ADVISOR • JANUARY 2013

A F O R U M F O R P H Y S I C I A N A S S I S TA N T S

NEWSLINE

■ Assess CVD risk with ABI ■ Steroid shots for sciatica ■ Boomers ripe for advice ADVISOR FORUM

■ Vitamin overdose ■ Onychomycosis diagnosis ■ Fun with rehydration LEGAL ADVISOR

A nurse practitioner gets tangled up in Medicare fraud

✶ FREE CME COURSES!

■ Dermatology Clinic

HYPERPIGMENTED SHIN MACULES PAGE 53

■ Dermatologic Look-Alikes VOLUME 16, NUMBER 1

PAINFUL TONGUE ULCERS PAGE 63 Take the Scavenger Hunt Challenge and Win an iPad! Turn to p. 13 for details

| J A N U A RY 2 013 | www.ClinicalAdvisor.com

CME: MANAGING CHRONIC

KIDNEY DISEASE Hypertension is present in most patients with CKD and causes renal atrophy and scarring.

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Group production director Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6075.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 1

CONTENTS JANUARY 2013

NEWS AND COMMENT

■ Erosions develop on a the hands and

neck of a man with chronic hepatitis C. 8

71

Newsline ■ Ankle-brachial index guidance available ■ Kidney decline linked with cognitive decline ■ Sciatica relief from epidural steroids is brief ■ Use upper endoscopy wisely ■ Stress counseling lacking ■ People ready to talk health at age 51 years

Corticosteroid shots for sciatica pain 11

58

Alternative Meds Update Practitioners of iridology assess organ function simply by inspecting the iris.

63

CME/CE Dermatologic Look-Alikes Can you differentiate between these ulcerations in the oral cavity?

67

CME/CE Posttest

Commentary

ADVISOR FORUM FEATURES 18

CME/CE New paradigms in managing chronic kidney disease Primary-care clinicians must be able to identify, screen, treat, and educate at-risk individuals.

24

Vasomotor rhinitis and allergic conjunctivitis Several therapies are available for these common conditions, so learn how to choose the right one.

36

Consultations ■ How common is vitamin overdose?

■ Chronic use of OTC topical corticosteroids ■ Treating a paranoiac for dementia ■ Onychomycosis diagnosis

37

Clinical Pearls ■ Can I get your number?

■ A fun way to rehydrate children

Treatment of allergic conjunctivitis 24

38

Your Comments ■ More skin-saving shaving advice ■ Palliative care too often overlooked

DEPARTMENTS 40

Legal Advisor A clinician learns that patient charts and medication doses have been falsified.

53

CME/CE Dermatology Clinic ■ For years, a man with diabetes has had asymptomatic lesions on his shins.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

Spontaneously healing oral ulcerations 63

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives ClinicalAdvisor.com/WebExclusives FDA approves quadrivalent flu vaccine The new flu vaccine will protect against two influenza A strains and two influenza B strains to limit the likelihood of a mismatch between the vaccine and circulating viruses.

Rates of chlamydia and gonorrhea increasing in the United States Cases of chlamydia and gonorrhea went up in 2011, the CDC reports.

Long-term aspirin use may damage eyes Regular aspirin use over a 10-year period significantly increased the incidence of late age-related macular degeneration.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Zachary Leonard, PA-C The health care we’ve inherited: perspectives from a new graduate As the health-care crisis unfolds, make keeping a positive outlook a priority for the future.

Robyn Carlisle, MSN, CNM, WHNP Making sense of mass shootings In the wake of the tragedy at Sandy Hook Elementary School, we must address our culture of violence.

Lauren Gorence, MPAP, PA-C Avoiding the self-diagnosis epidemic Information from online health websites often results in unnecessary anxiety and expensive testing.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments.

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Cartoon Archive

The Clinical Advisor’s monthly cartoons are now available online as well.

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MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

© Roy Delgado

A child with sweaty hands and feet Several years ago, a girl noted excessive sweating of her palms and soles—just like her father. What is your diagnosis?

Like us on Facebook facebook.com/TheClinicalAdvisor

6 THE CLINICAL ADVISOR • JANUARY 2013 • www.clinicaladvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

Newsline

Best practices for use of endoscopy in GERD patients page 12

Steroid shots provide brief sciatica relief page 11

J A N U A R Y 2 0 13

More stress counseling in primary care page 12

© SCIENCE SOURCE / STUDIO MACBETH

Ankle-brachial index guidance available

The ABI can be used to detect atherosclerosis (shown).

method. While noninvasive and safe, ABI measurement by pressure cuff should be interrupted if it is painful for the patient. Cuff inflation should be avoided over a recently placed bypass due to the risk of graft thrombosis, and the ankle cuff should not be placed over open wounds or ulcers.

The AHA also was involved in issuing a clinical guideline focusing on the diagnosis of ischemic heart disease (IHD). With the American College of Physicians, the Society of Thoracic Surgeons, and three other organizations, the AHA coauthored 28 recommendations that address the initial diagnosis of the patient who might have stable IHD, cardiac stress testing to assess the risk for death or MI in patients diagnosed with stable IHD, and use of coronary angiography for risk assessment (Ann Intern Med. 2012;157:729-734).

Prevalence of current depression by age group and sex The CDC finds that females have higher rates of depression than males in every age group.

Source: National Health and Nutrition Examination Survey data, 2007–2010

Male

12

Female

10

Percentage

AS ONE OF the least expensive and most available markers of atherosclerosis, the ankle-brachial index (ABI) is a highly appropriate measurement for cardiovascular disease risk assessment in the primary-care setting, according to the American Heart Association (AHA) (Circulation.

2012;126:2890-2909).

Originally proposed as a noninvasive means of diagnosing lowerextremity peripheral artery disease (PAD), the ABI now also serves as an indicator of atherosclerosis at other vascular sites. The measure can serve as a prognostic marker for cardiovascular events and functional impairment even in the absence of PAD symptoms.

The AHA statement points out that the ABI—the ratio of the systolic BP measured at the ankle to that measured at the brachial artery—can be determined in about 15 minutes, despite earlier

research citing time constraints as a barrier to ABI measurement in primary care. Another obstacle in the broader use of ABI measurement in general practice is the lack of reimbursement; however, “The standardized ABI measurement proposed in this document has very good test characteristics for the diagnosis of PAD and should be considered for appropriate reimbursement,” wrote the guideline authors.

Patients should be lying flat for an accurate measurement, with head and heels fully supported and not hanging off of the exam table.

The AHA also recommends that the Doppler method be used to measure the systolic BP in each arm and each ankle to obtain the ABI, that cuff size be at least 40% of the limb circumference, and that the cuff be placed just above the malleoli with the straight wrapping

8 6 4 2 0

⬎12 ⫺

8 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

12-17

18-39

Age group (years)

40-59

⬎60 ⫺

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Newsline EARLY DETECTION of mild to moderate kidney disease is an important public-health concern with regard to cognitive decline, concluded researchers who found that reductions in estimated glomerular fi ltration rate (eGFR) values were associated with declines in cognitive function in a five-year longitudinal study of 590 community-living individuals.

Previous research has shown decreased eGFR and higher serum creatinine levels to be associated with longitudinal decline in global mental-status measures. A team led by Adam Davey, of Temple University’s College of Health Professions and Social Work, launched the current study (published online ahead of print in Nephrology

Dialysis Transplantation) to determine which specific abilities are most affected in persons with impaired renal function.

The study subjects (mean age 62.1 years; mean eGFR 78.4 mL/ min/1.73m2) were free of dementia, acute stroke, and end-stage renal disease at baseline. Changes in the participants’ renal functioning over time were related to changes observed in global cognitive ability, verbal episodic memory, and abstract reasoning.

The relationship between declines in kidney function and in cognitive function persisted even after statistical adjustments were made for demographic variables and cardiovascular disease risk factors, and after persons who developed dementia or experienced an acute stroke were excluded.

© PHOTO RESEARCHERS, INC. / BIO PHOTO

Kidney decline linked with cognitive decline

In kidney disease, the glomerular membrane (white) thickens.

“The brain and kidney are both organs affected by the cardiovascular systems,” pointed out Davey.

“They are both affected by things like blood pressure and hypertension, so it’s natural to expect that changes in one organ are going to be linked with changes in another.”

EPIDU R A L cor ticosteroid injections may offer only shortterm relief of leg pain and disability for patients with sciatica, suggests a recent review of published studies.

Existing guidelines and systematic review provide inconsistent recommendations for epidural corticosteroid injections for individuals with sciatica. Rafael Zambelli Pinto, MSc, and colleagues pooled data from 25 reports, including 23 trials. As the investigators described in Annals of Internal Medicine (published online ahead of print), the

Long-term effects were smaller and not statistically significant.

pooled results showed a significant—although small—effect of epidural corticosteroid injections compared with placebo for leg pain in the short term and for disability in the short term. The long-term pooled effects were found to be smaller and not statistically significant.

Specifically, at short-term follow-up—between two weeks and three months—14 studies involving a total of 1,316 patients showed that the injections offered significant relief from leg pain compared with placebo. Ten of the trials, involving a total of

1,154 participants, revealed a significant effect of injections for reducing disability, and six trials involving a total of 723 patients showed that the injections had no effect on back pain. One year or longer later, no difference was seen in leg pain, back pain, or disability between the patients given epidural corticosteroid injections and those receiving placebo.

“The small size of the treatment effects…raises questions about the clinical utility of this procedure in the target population,” the authors noted.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 11

© PHOTO RESEARCHERS, INC. / DAVID GIFFORD

Sciatica relief from epidural steroids is brief

Newsline ALTHOUGH upper endoscopy is commonly used in the diagnosis and management of gastroesophageal reflux disease (GERD), new best-practice advice from the American College of Physicians cautions that this procedure is indicated only in certain situations, and inappropriate use generates unnecessary costs and exposes patients to harms without improving outcomes.

The evidence-based clinical policy paper (Ann Intern Med. 2012;157:808-816) offers three pieces of best-practice advice regarding the appropriate use of upper endoscopy in GERD: (1) upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting); (2) upper endoscopy is indicated in men and women with typical GERD symptoms that persist despite four to eight weeks of b.i.d. protonpump inhibitor (PPI) therapy, severe erosive esophagitis after a

Upper endoscopy is indicated only in certain situations.

two-month course of PPI therapy to assess healing and to rule out Barrett esophagus (in the absence of Barrett esophagus, recurrent endoscopy after this follow-up exam is not indicated), or history of esophageal stricture who have recurrent symptoms of dysphagia; and (3) upper endoscopy may be indicated in men older than age 50 years with chronic GERD symptoms and additional risk factors (nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intraabdominal distribution of fat) to detect esophageal adenocarcinoma and Barrett esophagus.

Upper endoscopy may also be indicated for surveillance evaluation in men and women with a history of Barrett esophagus.

In patients with Barrett esophagus and no dysplasia, surveillance exams should be performed no more often than every three to five years. For patients with Barrett esophagus and dysplasia, more frequent intervals are indicated.

People ready to talk health at age 51 years Clinicians trying to counsel patients on taking proactive health measures may find their most receptive audience to be patients aged 51 years.

A nationwide survey of 477 persons aged 45 to 65 years revealed that individuals in their late 40s had the lowest levels of interest in health issues, but that interest rose quickly and hit its highest point among persons in their early 50s. Interest then dropped slightly and plateaued during a

person’s 50s and early 60s, with another rise in interest occurring near age 65 years.

“The early 50s would be a great time to reach boomers with messages about how to improve and protect their health,” affirmed Katey Price, a doctoral candidate in communication at Ohio State University and one of the study investigators.

Price presented her group’s findings at the annual convention of the National Communication Association in November.

12 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

STR ESS-M ANAGEM ENT counseling was identified in a recent study as the least common type of counseling provided by primary-care clinicians.

In a letter published online ahead of print by Archives of Internal Medicine, Aditi Nerurkar, MD, MPH, and colleagues noted that 60% to 80% of primary-care visits may have a stress-related component. The investigators described the results of what they believe is the first study to examine factors associated with the provision of stress-management counseling by primary-care clinicians using a nationally representative sample.

The researchers obtained data from 2006 through 2009. They sought evidence of clinicians who provided such stress-management help as engaging in counseling during the office visit; offering information to help patients reduce stress through exercise, biofeedback, yoga, or other means; or referring the patient to other health professionals for the purpose of coping with stress.

Only 3% of office visits included stress-management counseling.

This was the least common type of counseling provided, compared with nutrition counseling (included in 16.8% of office visits), physical-activity counseling (12.3%), weight-reduction counseling (6.3%), and tobaccocessation counseling (3.7%). ■

© PHOTO RESEARCHERS, INC. / GÉRARD VILLARÉAL

Use upper endoscopy wisely Stress counseling lacking

Take the Scavenger Hunt Challenge January edition

Correctly answer the questions below— all of which can be found within this issue of The Clinical Advisor—and you’ll be entered into a random drawing to win an Apple iPad mini.

To submit your responses, simply go to CliniAd.com/UJrBmF. QUESTIONS 1. What condition was the ankle-brachial index originally proposed to diagnose? (p. 8) 2. According to a nationwide survey, at what age are 45-to-65-year-olds least interested in discussing health issues? (p. 12) 3. What are the three ways to evaluate the presence of proteinuria? (p. 20) 4. What is the single most important factor in slowing the progression of chronic kidney disease? (p. 22) 5. What is the sixth most prevalent chronic illness in the United States, affecting as many as 40 million adults and children every year? (p. 24) 6. What percentage of all cases of ocular allergy do seasonal and perennial allergic conjunctivitis comprise? (p. 26) 7. What vitamins are most likely to cause problems with overdose and may even lead to liver damage? (p. 36) 8. In 2010, approximately how many new cases of diabetes mellitus were diagnosed? (p. 54) 9. In iridology, what color iris is associated with biliary disease? (p. 58) 10. What year was the term Behçet’s disease first used? (p. 64)

WHO MAY ENTER All nurse practitioners and physician assistants 21 and over who are on The Clinical Advisor’s subscriber list. Employees and families of employees of Haymarket Media Inc., its affiliates, printer, agencies, mailers, and advertisers are not eligible.

RULES: No purchase necessary. Entries are limited to one per person. Void where prohibited.

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COMMENTARY Rachael Buitrago, CPNP, DNP, is an ANCC board-certified pediatric nurse practitioner in a private office in South Florida, and is teaching as adjunct nursing faculty at local universities.

Deconditioning as a special condition Medical diagnoses change quite frequently to meet the health-care needs of today’s society. New diseases are diagnosed, named, and stamped with an ICD-9 code so frequently that a new coding set with more than 2,000 codes is under way. Health-care providers can choose from a plethora of diagnoses and ailments.

Nevertheless, a new ailment is beckoning to be labeled and called upon by health-care providers, as explained by Mayo Clinic physiologist Michael J. Joyner in The Journal of Physiology (2012;590:34133414; available at jp.physoc.org/content/590/15/3413.full, accessed December 15, 2012).

Would elevating this to the status of a legitimate, stand-alone diagnosis create havoc?

However, I’m not so sure this one condition— that of deconditioning —should be allotted its own prestigious new title.

Joyner brings to light a type of orthostatic intolerance known as postural orthostatic tachycardia syndrome, or POTS. Affl icted patients experience an excessive heart rate upon standing, an increased heart rate at certain levels of exercise, and a reduction in physical-exercise abilities. This deconditioning, whether primary or secondary, is one of the most common causes of morbidity and mortality in many preventable diseases, such as obesity.

This is where it gets tricky. In a statement issued on July 27, 2009, the CDC estimated that the annual medical costs of obesity were as high as $147 billion (available at www .cdc.gov/media/pressrel/2009/r090727.htm; accessed December 15, 2012). Deconditioning could be a secondary cause of obesity, with the overweight individual being unable to exercise properly. The creation of a new deconditioning diagnosis could help health-care providers recognize a gap in a patient’s health status that could greatly benefit from specially designed therapies and exercise regimens. Along with this treatment plan there would be an increase in health-care dollars spent for these therapeutic modalities.

But there are always two sides to a coin.

Deconditioning is not actually a condition,

but more of a complication of POTS. Would elevating deconditioning to the status of a legitimate, stand-alone diagnosis create havoc, allowing people who are obese to use this to their benefit? Americans cannot afford an increase in health-care spending, especially when a large sum is already allocated to obesity.

If a person has a true medical condition, such as POTS, then by all means he or she meets the criteria to claim deconditioning as an illness. But if a person is simply sedentary in life, he or she should take responsibility for his or her health, including the need to exercise to prevent deconditioning.

This brings us to the realization that creating a new diagnosis for deconditioning might be a slippery slope. Clear-cut diagnoses are not always the answer; some patients may require a more in-depth approach to achieve certain health goals.

Clinicians must weigh diagnoses carefully for each person and encourage all patients to be active participants in their own health. Labels or diagnoses may not always be accessible, but providing optimal care to meet the patient’s needs should not be overlooked.

Bottom line: Let’s not create an easy scapegoat diagnosis for some, but instead bring awareness to what deconditioning is and how we as clinicians can help our patients prevent or manage it. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 71

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PROGRAM OUTLINE JANUARY 2013

0.5 CREDITS

Page 18 FEATURE New paradigms in managing chronic kidney disease Denise Keller Link, MPAS, PA-C Denise Keller Link, MPAS, PA-C, has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Describe risk factors associated with chronic kidney disease (CKD).

• Name the preferred method to determine kidney function in the outpatient setting.

• Define the BP target to treat all types of kidney disease and to reduce cardiovascular risk.

• Identify the first-line therapy if a CKD patient does not have diabetes or proteinuria 0.5 CREDITS

Page 53 DERMATOLOGY CLINIC Small brown spots on the lower shins Anthony Trace, PhD, and Julia R. Nunley, MD Anthony Trace, PhD, and Julia R. Nunley, MD, have no relationships to disclose relating to the content of this article.

Erosions on the hands and elevated iron levels Adam Rees, MD Adam Rees, MD, has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 63 DERMATOLOGIC LOOK-ALIKES Ulcerations in the oral cavity Kerri Robbins, MD, and Damjan Jutric Kerri Robbins, MD, and Damjan Jutric have no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVE: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 67 POSTTEST This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of January 2013. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 17

■ LEARNING OBJECTIVES :

CME CE FEATURE

• Describe risk factors associated with chronic kidney disease (CKD).

• Name the preferred method used to determine kidney function in the outpatient setting.

• Define the BP target to treat all types of kidney disease and to reduce cardiovascular risk.

• Identify the first-line therapy if a CKD patient does not have diabetes or proteinuria ■ COMPLETE THE POSTTEST: Page 67 ■ ADDITIONAL CME/CE: Pages 53, 63 Turn to page 17 for additional information on this month’s CME/CE courses.

DENISE KELLER LINK, MPAS, PA-C

New paradigms in managing chronic kidney disease To slow the progression to end-stage renal disease, primary-care clinicians must be able to identify, screen, treat, and educate at-risk individuals.

© CMSP / SPL

D

Hypertension reduces blood flow and causes chronic renal failure and shrunken end-stage kidneys (shown).

18 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

o the words nephrology or kidney evoke terrible memories of the renal section that you never completely understood?

This article provides a step-by-step process for evaluating kidney function and offers information on early management of chronic kidney disease (CKD) in a primary-care setting. Identifying CKD facilitates appropriate treatment of this very destructive disease.

The clinical scenario of Mr. H will be used throughout the article to illustrate this step-by-step process.

• Aged 55 years • The patient’s status one year post-coronary stenting included a history of obesity, type 2 diabetes mellitus, hypertension, and cardiovascular disease (CV D).

• Mr. H is a current tobacco user with a 30-pack year smoking history.

• Present medications include insulin, metoprolol (Lopressor, Toprol), and hydrochlorothiazide (HCTZ) (HydroDIURIL, Microzide).

• Mr. H has retinopathy, a fourth heart sound, +2 lower extremity edema, and peripheral neuropathy.

• Serum creatinine (sCr) 2.4 mg/dL (up from 2.0 mg/dL one year ago), blood urea nitrogen (BUN) 30 mg/dL, potassium 4.8 mEq/L, hemoglobin (Hb) 10.4 g/dL, HbA1c 9.8%, and spot urine albumin/creatinine 2,500 mg/g.

When Mr. H returns for a four-month follow-up visit, should the focus be on weight management or on treating his diabetes? Do you provide advice on smoking cessation? Do you attempt to evaluate kidney function?

Most clinicians have likely seen an increase in abdominal girth and obesity among the patient population. The rates of type 2 diabetes continue to increase as well, leading to a rise in the prevalence of CKD. Diabetes is the foremost cause of CKD and end-stage renal disease (ESRD) in the United States, followed closely by hypertension.1 Given this knowledge, it is unethical not to evaluate each at-risk patient for the potential development of CKD. Dialysis has made tremendous advances in prolonging patients’ lives once ESRD is reached, but it is not an ideal way to live. Dialysis strongly affects the physical, financial, and emotional aspects of a patient’s life. Evaluating renal function, especially in people with CKD risk factors, is of paramount importance.

Step 1: Identify patients at increased risk for CKD

Individuals who are older than age 60 years, have diabetes, hypertension, CVD, family history of CKD, history of autoimmune disease, recurrent urinary tract infections, nephrolithiasis, systemic infections, neoplasms, or history of acute kidney injury are at increased risk for CKD and must be screened (Table 1).

Clinical scenario 1: Based on his medical history, Mr. H should definitely be screened for CKD. Diabetes, hypertension, and CVD (not to mention elevated sCr and albuminuria) place Mr. H at increased risk for developing CKD. Step 2: Screen patients at increased risk for CKD

Based on the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines, the diagnosis of CKD is determined by the presence of kidney damage and/ TABLE 1. Risk factors for chronic kidney disease Age older than 60 years Family history of CKD Hypertension CVD Type 2 diabetes mellitus History of autoimmune disease, recurrent urinary tract infections, nephrolithiasis, systemic infections, neoplasms, or acute kidney injury

or the level of kidney function, irrespective of diagnosis.2 In clinical terms, CKD is defi ned as: (1) the persistent and usually progressive reduction in glomerular fi ltration rate (GFR) (i.e., GFR <60 mL/minute/1.73 m 2 for three months or longer, with or without kidney damage); and/ or (2) albuminuria (>30 mg of urinary albumin per gram of urinary creatinine) based on spot urine collection.2 In the outpatient setting, kidney function is determined by calculating the estimated GFR (eGFR), which is done using the patient’s age, race, sex and sCr concentration. Most labs report the eGFR with the metabolic panel. A normal eGFR is approximately 100 mL/min/1.73 m2. The eGFR gives a percentage of kidney function. For example, if the eGFR is 40, the patient has approximately 40% of kidney function remaining, meaning that approximately 60% of kidney function has been lost.

Clinical scenario 2: Mr. H’s sCr, age, race, and sex produce an eGFR of 36. Last year, his sCr was 2.0 mg/dL with an eGFR of 42. Since he has had an eGFR of <60 for at least three months, we can conclude that Mr. H has CKD. Mr. H should be informed that he has approximately 36% of his kidney function remaining.

The eGFR is critical to calculate, and clinicians should be cautioned against using sCr alone to establish kidney function. Serum creatinine concentration is determined mainly by muscle mass and dietary animal-protein intake, independent of renal function. If a patient has extremes in muscle mass and/or dietary animal-protein intake, sCr will not accurately determine renal function.

For example, a black male bodybuilder, aged 25 years, may have an sCr of 1.5 mg/dL with a normal eGFR, while a thin, white woman aged 80 years with a history of hypertension with the identical sCr may have an eGFR of 30. The young bodybuilder is on the extreme side in both muscle mass and dietary intake of animal protein, so his sCr is more reflective of these factors than of his true level of kidney function. The elderly thin woman has very little muscle mass and a poor diet. An eGFR of 30 classifies her as stage 4 CKD, with advanced renal disease. Her sCr alone would not accurately depict the severity of her kidney disease because of her dietary intake and lack of muscle mass. It is important to calculate eGFR every time you order sCr, while also closely observing your patient to determine whether his or her sCr accurately describes level of kidney function vs. muscle mass or dietary animal-protein intake.

The eGFR is not always accurate, however. As a general rule of thumb, consider an eGFR >60 as unreliable. In fact, many labs do not even report values >60. The eGFR is a product of the Modification of Diet in Renal Disease (MDRD) study.

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TABLE 2. Stages of chronic kidney disease Stage

Description

Estimated glomerular filtration rate (GFR)

1

Kidney damage with normal or elevated GFR

>90

2

Kidney damage with mild decrease in GFR

60-89

3

Moderate decrease in GFR

30-59

4

Severe decrease in GFR

15-29

5

Kidney failure

<15

Adapted from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.

The patient population in the MDRD study had kidney disease (mean eGFR 39.4). This means that eGFR was not validated in patients without kidney disease. Since it was developed and validated in patients with moderate kidney disease, the formula cannot be used in patients with mild CKD (i.e., eGFR >60).

Nevertheless, the eGFR is vital because it helps determine the stage of CKD (Table 2). Kidney disease is progressive, and many patients will move from stage 1 to stage 5 through the course of a lifetime.3 The time frame of progression is based on factors that can be influenced by treatments. The stage of CKD helps indicate when the patient will develop renal comorbidities attributable to kidney dysfunction.

The job functions of the kidneys include removal of toxins from the blood; acid/base regulation; BP control; fluid balance; maintenance of normal hemoglobin through production of erythropoietin; and regulation of vitamin D and the balance of minerals, including calcium, phosphorus, and potassium. As the patient advances from stage 1 to stage 5 CKD, comorbid conditions will begin to develop due to the loss of the kidneys’ ability to perform various tasks.

Patients in early stage 1 or 2 CKD may develop hypertension. In stages 2 and 3, bone and mineral abnormalities develop. Anemia related to CKD develops in stage 4, at which time patients will need aggressive management of these comorbid conditions. Most CKD patients should be referred to a nephrologist, who can work alongside the primary-care team to treat the disease and its comorbidities and slow the progression to ESRD. Electronic medical records make it easy to graphically display trends of any lab value, and this is especially vital for the eGFR. With this in mind, plot the patient’s eGFR and/ or sCr to view the trend of kidney function over a period of time. This visual will help illustrate to you whether the kidney disease is stable or progressing. Do not compare only

one value to the previous value. Instead, look at all of the values over a period of time.

The first qualifier for decreased kidney function is an eGFR <60 for at least three months. The second qualifier is based on the level of kidney function and/or the presence of kidney damage. To determine whether a patient has kidney damage, look for albuminuria.

Clinical scenario 3: If Mr. H had a sCr of 0.9 mg/dL and eGFR >60 yet continued to have spot urine albumin/creatinine of 2,500 mg/g, he would still meet the criteria for CKD. Even with normal kidney function (eGFR >60), he has the presence of kidney damage based on his level of albuminuria or proteinuria. This can be seen early on in the development of diabetic nephropathy.

Renal function can be normal, but the presence of microalbuminuria (30-300 mg/g) would demonstrate that kidney damage is occurring even though it has not yet resulted in a decline in kidney function. An albumin/creatinine ratio >30 mg/g for at least three months is an indication of CKD. Because there are different types of urinary protein, the term albuminuria is used interchangeably with proteinuria. However, urine albumin makes up the majority of urinary protein.

The three ways of evaluating the presence of proteinuria are by urine dipstick, 24-hour urine collection, and spot urine albumin/creatinine. Urine dipstick is a relatively crude quantification of urinary albumin and does not accurately determine the presence of microalbuminuria. Additionally, urine dipstick does not detect urinary protein other than albumin and can be affected by the overall state of urine concentration or dilution.4 A 24-hour urine collection allows the clinician to establish renal function by determining the level of protein excreted in the patient’s urine over a 24-hour period, total salt consumption, and creatinine clearance (CrCl). The CrCl and eGFR are both used to determine renal function: The CrCl determines renal function based on results from a 24-hour urine collection, and the eGFR calculates renal function from a blood collection (as described above). However, the CrCl is not the most accurate method for estimating GFR.5 The accuracy of any 24-hour urine collection to determine an individual’s level of proteinuria, daily salt consumption, or level of kidney function depends on adherence to proper collection. Therefore, the results are susceptible to inaccuracy caused by over- or under-collection. If the patient collected for only 20 hours, then the CrCl, level of proteinuria, and salt consumption would be underestimated. A proper 24-hour urine collection can be challenging. The patient must not miss a collection. The urine specimen must also be kept on ice for the entire 24-hour period. Although not always inaccurate,

20 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

TABLE 3. Evaluation of proteinuria Morning urine for albumin/creatinine ratio 30-300 mg/g creatinine Microalbuminuria

>300 mg/g creatinine Macroalbuminuria

Unconfirmed

Confirmed within three months

Intervention (e.g., ACE inhibitor)

Monitor annually

Monitor every three to six months

the 24-hour urine collection is not the preferred method for routine screening for proteinuria.

A random or spot urine sample is the preferred method of screening for proteinuria, especially microalbuminuria, which is the only early clue to the development of kidney disease in patients with diabetes.6 Order a spot urine albumin and creatinine and calculate the ratio of urinary albumin to urinary creatinine. The result is expressed in mg/g and will approximate the amount of albumin excreted into the urine in a 24-hour period. The urine albumin-to-creatinine ratio corrects for the amount of dietary creatinine intake and standardizes the collection. Table 3 depicts an algorithm to follow when screening for proteinuria. Vigorous exercise or infections can result in transient proteinuria, so testing must be repeated within three months.

Step 3: Treatment of CKD

After determining the level of kidney function (based on eGFR) and/or the presence of kidney damage (based on albuminuria) and staging the level of CKD, it is time to start treatment. As previously discussed, CKD is progressive, and most patients will advance to kidney failure, ESRD, and eventually death. CKD also puts patients at increased risk for developing cardiovascular events independent of medical history.6 Clinical scenario 4: What if Mr. H did not have hypertension, CVD, or diabetes? What if he was not a smoker? If Mr. H only had CKD, would he be at risk for developing CVD? The answer is, “yes.”

A 2004 study investigated the rate of cardiovascular events, hospitalization, and death in patients who had CKD.6 Prior to this study, the data showed that patients with ESRD had mortality rates higher than 20% per year with the use of dialysis, and more than half of these deaths were related to CVD. The study followed approximately 1.1 million adults in whom sCr had been measured and who had not undergone dialysis or kidney transplantation. Median follow-up was 2.84 years, mean age was 52 years, and 55% of the participants were women. The cohort was examined for a multivariable association between the eGFR and the risks of death, cardiovascular events, and hospitalization.

The results were astonishing: • A reduced eGFR was associated with increased risks of death, cardiovascular events, and hospitalization, independent of such known risk factors as history of CVD or proteinuria.

• Risk of death from any cause increased sharply as the eGFR declined—from a 17% increase in risk with an eGFR of 45-49 to a nearly 600% increase with an eGFR of <15.

• Risk of cardiovascular events increased as the eGFR declined—from a 43% increase in risk with an eGFR of 45-49 to a 343% increase with an eGFR of <15.

• Risk of hospitalization increased as the eGFR declined— from a 14% increase in risk with an eGFR of 45-49 to a 315% increase with an eGFR of <15.

These findings highlight the clinical and public-health importance of CKD. As early as stage 3 CKD (eGFR 45-49),

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CME CE

CHRONIC KIDNEY DISEASE

patients are at increased risk of developing cardiovascular events independent of medical history.

The goals of CKD treatment are to slow the progression to ESRD and decrease risk of cardiovascular events. Halting the disease progression is based on two treatment modalities: (1) lowering BP to <130/80 mm Hg; and (2) inhibiting the renin-angiotensin-aldosterone system (RAAS) and to limit proteinuria.

Current guidelines recommend a BP target of <130/80 to treat all types of kidney disease and to reduce cardiovascular risk.2 BP control can make a significant difference in the rate of kidney decline. Controlling BP is the single most important factor in slowing the progression of CKD and is the most predictive value for determining time to ESRD. For example, Mr. H has a BP of 150/100 and will progress to ESRD in five years. Lowering his BP to <130/80 will lengthen his time to ESRD to 20 years.

As most clinicians know from experience, reducing BP is not easy, especially if the patient is not motivated, which is where patient education comes in.

Step 4: Education, education, and more education

Educating individuals with CKD regarding their role in the treatment of the disease is essential. Each patient must understand the importance of BP control in preserving his or her remaining level of kidney function. Begin by explaining that the BP goal is <130/80. Second, emphasize that if the BP goal is not met, progression to ESRD will occur at a more rapid rate. Third, encourage consistent home BP monitoring, which is more accurate than intermittent office readings. Each CKD patient should be taught to accurately monitor and record BP daily (Table 4). These BP readings should be brought to every clinic visit. Finally, discuss treatment options, including medications and such lifestyle changes as low-sodium diet (<2,000 mg/day), modest weight loss, smoking cessation, limiting alcohol, and exercise. Explain that multiple therapeutic agents will be necessary to reach the BP goal.7

TABLE 4. Accurate BP monitoring Measure twice daily (AM and PM) for one week.

Before measuring, sit for five minutes with the arm at the height of the heart.

If no difference between AM and PM is noted, measure daily.

Sit with the legs uncrossed.

Measure at the same time every day.

An arm cuff is more accurate than a wrist cuff.

Use the same arm for each measurement.

Home measurement is more accurate than office measurement.

ACE inhibitors or angiotensin-receptor blockers (ARBs) are indicated for individuals who have diabetes with or without hypertension and for CKD patients with proteinuria (Table 5).7 In patients with CKD with proteinuria (>200 mg/g), inhibition of the RAAS axis is superior to conventional antihypertensive drug therapy in slowing the decline of renal function.8 If a CKD patient does not have diabetes or proteinuria, a thiazide diuretic would be indicated as first-line therapy. ACE inhibitors/ARBs should be used at moderate to high doses, and patients should be monitored carefully for hypotension, decrease in eGFR, and hyperkalemia.2 Clinical scenario 5: Mr. H has a BP of 150/100 and a heart rate of 89 beats per minute while on metoprolol and HCTZ. His urine albumin/creatinine is 2,500 mg/g. What medication changes would be needed to achieve optimal BP (i.e., <130/80)? a) Start ACE inhibitor or ARB. b) Discontinue HCTZ and start furosemide (Lasix). c) Increase metoprolol based on heart rate. d) All of the above The answer is “all of the above.” An individual with diabetes and proteinuria needs an ACE inhibitor/ARB. HCTZ is not an effective diuretic once eGFR is <50. Loop diuretics help mitigate the hyperkalemia commonly seen in CKD patients taking ACE inhibitors/ARBs. Another treatment option would be to up-titrate metoprolol based on heart rate.

Mr. H is already on two agents, and the BP is suboptimal.

Most CKD patients will require at least two and as many as

TABLE 5. BP-lowering medications Type of kidney disease

BP target (mm Hg)

Recommended agents for CKD with or without hypertension

Other agents to reduce cardiovascular risk and reach BP target

Diabetic

<130/80

ACE inhibitor or angiotensinreceptor blocker (ARB)

Diuretics preferred, followed by beta blocker (BB) or calcium channel blocker (CCB)

Nondiabetic with proteinuria

<130/80

ACE inhibitor

Diuretics preferred, followed by BB or CCB

Nondiabetic without proteinuria

<130/80

No preference

Diuretics preferred, followed by ACE inhibitor, ARB, BB, or CCB

22 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

Among patients with chronic kidney disease, proteinuria is an important and independent risk factor for cardiovascular disease and mortality. five antihypertensive medications. Educate patients to know which BP-lowering medications they are taking and stress the importance of taking the medications at the same time every day. Consistency is the key. Encourage medication compliance by prescribing once-daily dosing or combination drugs whenever possible. Education will motivate patients and must be a component of every office visit. Increase emphasis on education when BP-lowering strategies are unsuccessful.

The next component of treating CKD is to limit the amount of proteinuria through inhibition of RAAS. RAAS inhibition provides nephroprotection independent of BP lowering and is mainly achieved through the use of ACE inhibitors and ARBs. Higher levels of proteinuria are associated with faster progression of CKD and increased risk of CVD.2,9-12 Decline in the eGFR varies by disease state from patient to patient but is accelerated in individuals with proteinuria. Focal segmental glomerulosclerosis (FSGS) is a glomerulopathy that can lead to nephritic-range proteinuria (>3.0 g of proteinuria in 24 hours). Diabetic nephropathy can lead to microalbuminuria (30-300 mg), followed by macroalbuminuria (>300 mg), and then on to nephrotic ranges. Autosomal dominant polycystic kidney disease (ADPKD) does not lead to significant proteinuria. FSGS progresses to ESRD at a much more rapid rate compared with diabetic nephropathy, and diabetic nephropathy progresses to ESRD at a more rapid rate compared with ADPKD. It is thought that the different rates of progression to ESRD are partially attributable to the amount of proteinuria.10-12 Among patients with CKD, proteinuria is an important and independent risk factor for CVD and mortality.9 Treating proteinuria with medications that hinder the RAAS blockade slow progression to ESRD and limit cardiovascular events.9,12

References 1. U.S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012. Available at www.usrds.org/adr.aspx.

2. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.

3. Jaber BL, Madias NE. Progression of chronic kidney disease: can it be prevented or arrested? Am J Med. 2005;118:1323-1330.

4. Jayne AD. Hematuria and proteinuria. In: Greenburg A. Primer on Kidney Diseases: Expert Consult, 5th ed. Philadelphia, Pa.: Saunders Elsevier; 2009:33-42.

5. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470. Available at annals.org/article.aspx?articleid=712617.

6. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. Available at www.nejm.org/doi/full/10.1056/ NEJMoa041031.

7. National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Available at www.nhlbi.nih.gov/guidelines/hypertension/.

8. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-1462. Available at www.nejm. org/doi/full/10.1056/NEJM199311113292004.

9. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.

The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. Available at www.nejm.org/doi/full/10.1056/ NEJM200001203420301.

Conclusion

10. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, pro-

Primary-care clinicians must screen all individuals who are at risk for CKD and then aggressively treat with multiple antihypertensive agents BPs that are not at goal of <130/80.

Initiate RAAS-blockade agents in CKD patients who are diabetic or have proteinuria. Refer early to nephrology for education on transplant or dialysis and for treatment of the associated comorbidities (e.g., anemia of CKD, bone/mineral disorder, electrolyte abnormalities, and fluid balance). ■

teinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754-762.

11. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:20192032. Available at www.nejm.org/doi/full/10.1056/NEJMoa0907845.

12. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421-2431. Available at jama.jamanetwork.com/article.aspx?articleid=195530.

Ms. Keller Link is a nephrology physician assistant at The University of Texas Southwestern Medical School in Dallas.

All electronic documents accessed December 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 23

FEATURE: GABRIEL ORTIZ, MPAS, PA-C, DFAAPA

Vasomotor rhinitis and allergic conjunctivitis The ability to differentiate between the allergic and nonallergic form of these conditions is crucial when determining treatment.

R

hinitis—the infl ammation of mucous membranes lining the nasal passages—is characterized by one or more of the following symptoms: nasal congestion, nasal pruritus, postnasal drip, rhinorrhea, and sneezing.

These symptoms are frequently accompanied by itchy eyes, ears, and/or throat.1

Burden of disease

Allergic rhinitis is the sixth most prevalent chronic illness in the United States, affecting as many as 40 million adults and children every year.2 Worldwide, an estimated 10% to 30% of adults and up to 40% of children are diagnosed with allergic rhinitis, making it the most prevalent chronic pediatric condition.3 The prevalence of allergic rhinitis has increased substantially in recent decades in developed countries.4 However, only about 43% of affected patients have a pure allergic component to their rhinitis.

Approximately 23 % have a nonallergic (vasomotor) rhinitis component, and 34% have a mixed component (both allergic and nonallergic).5

© CMSP

Differential diagnosis

FIGURE 1. Perennial conjunctivitis (shown) features no tissue destruction and does not affect vision.

24 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

Because the therapy can be different for allergic and nonallergic rhinitis, providers must differentiate between the two. Nonallergic rhinitis is a broad classification of diseases that may be acute or chronic. Nonallergic rhinitis usually has an onset after age 20 years, unlike allergic rhinitis, which usually has an onset before age 20 years. Common symptoms of nonallergic rhinitis include nasal congestion, postnasal drip,

rhinorrhea, and sneezing, with no allergic etiology. The differential diagnosis of rhinitis can include allergic, nonallergic and mixed rhinitis. These different forms of rhinitis can have symptoms in common.

Screening for rhinitis leads to a more precise diagnosis.

To help differentiate between the various forms, include a comprehensive history and physical exam along with information about patterns of disease, chronicitiy, seasonality, and magnitude of symptoms. Obtain detailed information about the presence of triggers or allergens in the home, school, workplace, or environment. Examples of potential irritants include paint fumes, tobacco smoke, perfume, car exhaust, cold or damp weather, alcoholic beverages, and spicy foods.

Finally, ask when the symptoms first appeared.

Nonallergic rhinitis is the most common type and can be induced by a range of triggers, including changes in weather, ingestants, strong odors, and other environmental factors. Nonallergic rhinitis is a diagnosis of exclusion. The classification of nonallergic rhinitis syndromes includes several different types of disease (Table 1). These types can be divided into known etiology and unknown etiology.

The unknown-etiology group can be further differentiated into eosinophilic and noneosinophilic groups. The known-etiology group can be subdivided into hormonal, medication, cholinergic, and anatomical types.

There are several ways to determine whether an individualâ&#x20AC;&#x2122;s rhinitis is allergic or nonallergic, including a skin-prick test or a simple blood test.6 Many laboratories still use allergenspecific immunoglobulin E testing, commonly known as a radioallergosorbent test (RAST). However, the RAST has been replaced by the more sensitive fluorescent enzyme-labeled assays, of which the ImmunoCAP is most common.7 All of these tests will help identify possible allergic triggers.

A simple questionnaire called a Patient Rhinitis Screen may be useful. This tool asks the patient about symptoms and what time of the year they occur. The questionnaire also asks about allergens and irritants that can cause rhinitis symptoms. An individual with only allergen triggers could have a pure allergic rhinitis; if only irritant triggers are noted, the condition could be nonallergic rhinitis; if both types of triggers are identified, a mixed type of rhinitis is the likely diagnosis.

Treatment

The best treatment for rhinitis is allergen and/or irritant avoidance along with environmental controls. These nonpharmacotherapeutic options will work better for known and easily avoidable triggers. This treatment choice will work for such triggers as indoor pet dander, mold, dust mites, and cockroaches. However, it is very difficult to avoid such irritants as weather changes, strong odors, and environmental triggers, especially in the workplace or in large cities.

Several pharmacotherapeutic options exist for allergic rhinitis, most commonly oral antihistamines, intranasal antihistamines, and intranasal corticosteroids. Other choices include intranasal cromolyn sodium and subcutaneous specific immunotherapy (i.e., allergy shots).8 Oral second-generation antihistamines are considered fi rst-line therapy for allergic rhinitis but are not indicated for nonallergic vasomotor rhinitis.1 Intranasal antihistamines can also be first-line therapy for allergic rhinitis and are indicated for nonallergic vasomotor rhinitis.1,9 Only intranasal antihistamines and intranasal corticosteroids have been approved for the treatment of both seasonal allergic rhinitis and nonallergic vasomotor rhinitis. The intranasal corticosteroids beclomethasone dipropionate (Beconase AQ), budesonide (Rhinocort), and fluticasone propionate (Flonase) have been approved for use against allergic and nonallergic vasomotor rhinitis. Azelastine (Astelin), a second-generation intranasal antihistamine, has been approved for the treatment of both seasonal allergic rhinitis and nonallergic vasomotor rhinitis.

ALLERGIC CONJUNCTIVITIS

Components of allergy can exist alone or in combination with others, to include allergic rhinitis, allergic conjunctivitis, allergic sinusitis, allergic dermatitis, and allergy-induced asthma.10,11 Allergic conjunctivitis has been reported in as many as 40% of the population with positive skin tests to various aeroallergens.12 Since the eye is one of the most active sites of allergic inflammation, there has been much pharmacologic development in this area.13 Continues on page 26

For more on rhinitis, conjunctivitis, and other similar conditions, visit our Allergy & Immunology Information Center at

Cliniad.com/S9dzN1. www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ JANUARY 2013 25

RHINITIS AND CONJUNCTIVITIS

Table 1. Classification of nonallergic rhinitis syndromes NARES Eosinophilic BENARES Unknown etiology

Sinusitis Noneosinophilic

Vasomoteor Mastocytosis

Perennial nonallergic rhinitis

Hormonal

Nasal polyps Pregnancy Hypothyroidism Medicamentosa

Medication Atrophic Known etiology

Gustatory Cholinergic

Skiers'/Joggers' nose Tumor Septal deviation

Anatomical Foreign body Malformation

Adapted from Feather IH, Wilson SJ. Eosinophilis in rhinitis. In Busse WW, Holgate ST, eds.

Asthma and Rhinitis, 2nd ed. Boston, Mass.: Clackwell Scientific Publications; 1995:348.

Causes

Causes of ocular allergic reactions include environmental factors, genetics, medications, cosmetics, and devices. Some of the more common environmental causes of ocular allergy are dust mites, ragweed, grass, molds, animal dander, and trees.

Symptoms

The most common ocular symptoms of allergy are itching, redness, chemosis, eyelid swelling, and tearing. When treating patients with potential ocular allergies, remember these diagnostic clues: (1) If the eye doesn’t itch, it’s probably not allergy; (2) if the eye itches, it’s allergy; (3) if the eye burns, it’s dry eye; and (4) if the eye is sticky, it’s bacterial conjunctivitis.

Several mediators of inf lammation drive the allergic response and ocular symptoms. Ocular itch is induced by histamine; hyperemia is induced by such mediators as prostaglandins, tumor necrosis factor-alpha, leukotrienes, platelet-activating factor, and tryptase as well as histamines; and chemosis, eyelid swelling, and tearing is driven by other mediators and histamine.14 The differential diagnosis of the red eye includes conjunctivitis, lid disease, foreign body, trauma, uveitis, neoplasm, and structural change.

Conjunctivitis can be caused by bacteria, viruses, inclusion,

irritants, allergy, and contact-lens use. This article only addresses allergic causes of conjunctivitis.

Subtypes of allergic conjunctivitis

The four main subtypes of allergic conjunctivitis are seasonal/ perennial allergic conjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC).

Seasonal/perennial conjunctivitis. The primary symptom of seasonal/perennial allergic conjunctivitis (Figure 1) is itching, which can range from mild and intermittent to chronic and severely debilitating. Appropriate timely treatment enhances quality of life. Seasonal and perennial allergic conjunctivitis comprise 90% or more of all cases of ocular allergy. As an early-phase allergic disease, histamine is the primary mediator involved. Because there is little cellular component to the allergic process in early-phase disease, there is no tissue destruction in seasonal and perennial disease and no effect on the visual acuity.

Vernal keratoconjunctivitis. VKC is a seasonally recurring bilateral inflammation of the conjunctiva (Figure 2) and occurs predominately in male children. More females are affected as age of onset increases. VKC tends to cease in the

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RHINITIS AND CONJUNCTIVITIS

POLL POSITION

Do you feel comfortable performing a skin-prick test on patients with symptoms of rhinitis? n=140

Yes No

35% 65%

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cataracts happen to be associated with AKC in some cases and are likely caused by eye-rubbing/chronic inflammation and steroid use/chronic inflammation, respectively.

Giant papillary conjunctivitis. The pathogenesis of GPC is not fully understood. Repeated mechanical trauma of the superior tarsus and the rough surface of a contact lens, prosthesis, or suture is thought to be the cause. Hypersensitivity reactions may also play a role. The signs of GPC are hyperemia, thickening, and abnormally large papillae (diameter >0.3 mm) on the superior tarsal conjunctiva. Soft contact lenses account for the majority of cases. Failure to follow prescribed lens-care regimens and the wearing of soft lenses overnight may increase risk of GPC. Contact-lens use must be discontinued once the diagnosis of GPC is made. Topical antihistamine/mast-cell stabilizers may be helpful for symptomatic relief once lens use has been discontinued. The goal of GPC treatment is to enable patients to return to wearing contact lenses.

early twenties. There is frequently a family history of asthma or atopy. Symptoms consist of intense itching, blepharospasm, photophobia, blurred vision, and copious mucus discharge. The two forms of vernal conjunctivitis are palpebral and limbal.

Atopic keratoconjunctivitis. AKC (Figure 3) is more common in individuals in their 20s and 30s. Subepithelial fibrosis, symblepharon, corneal ulcers, and pannus formation (neovascularization of the cornea) may occur. Patients with AKC typically have an allergic history and commonly exhibit atopic eczema. No one knows exactly why some AKC patients have keratoconus or anterior polar cataracts, but the evidence suggests that these conditions are not attributable to systemic connective tissue disease. Keratoconus and anterior polar

There are several OTC therapies available to combat allergic conjunctivitis. The topical ophthalmic H1 antihistamines have a more rapid onset of action than do oral H1 antihistamines but require more frequent dosing because of washout from the nasal mucosa or conjunctivae.15 Vasoconstrictors. The vasoconstrictors are sympathomimetic drugs (adrenergic agonists) that stimulate adrenergic receptors, causing capillary constriction and reduced blood flow, thereby reducing hyperemia, chemosis, and eyelid swelling. Combined use of xylometazoline and naphazoline has been shown to be more effective than either agent alone, but

FIGURE 2. Vernal keratoconjunctivitis (shown under the upper lid) causes inflammation of the cornea and conjunctiva.

FIGURE 3. Patients with atopic keratoconjunctivitis (shown) typically have an allergic history.

© PHOTOTAKE / BARBARA GALATI

© PHOTOTAKE / DR. ALLAN HARRIS

Treatment

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 33

RHINITIS AND CONJUNCTIVITIS

long-term use is not recommended. Rebound conjunctivitis has been reported in long-term use but was not reported in short-term use (fewer than 10 days).16 Antihistamines. Levocabastine (Livostin) has the advantage of rapid onset of action and is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. It has been shown to have a high selective binding affinity for histamine H1 receptors along with an exceptionally slow rate of dissociation from these receptors.17 Emedastine (Emadine) is another antihistamine product with no apparent effect on adrenergic, dopaminergic, or serotonin receptors.18 Nonsteroidal anti-inflammatory drugs. Ketorolac tromethamine (Acular) was one of the first products used for ocular itching attributable to allergic conjunctivitis. This treatment has also provided significant relief of conjunctival hyperemia.19 Mast-cell stabilizers. The products in this group include cromolyn (Crolom), lodoxamide (Alomide), nedocromil (Alocril), and pemirolast (Alamast). Cromolyn is indicated for chronic allergic ocular disorders, including VKC, vernal conjunctivitis, and vernal keratitis. Use of cromolyn provides symptomatic relief of itching, tearing, redness, and discharge within a few days of administration, but some patients may not achieve optimum symptom relief until up to six weeks.20 Several animal trials have shown lodoxamide to be approximately 2,500 times more potent than cromolyn in the prevention of histamine release.21,22 Nedocromil, a cromolyn derivative, was shown to provide relief in 80% of patients with a safety profi le similar to that of sodium cromoglycate but with increased potency and twice-daily administration.23 The potency of pemirolast is reported to be more than 100 times that of sodium cromoglycate. Compared with placebo, pemirolast 0.1% dosed four times daily proved significantly superior in relieving ocular itching.24 Dual-action agents. Epinastine (Elestat) is a histamine H1- and H2-receptor antagonist with mast-cell stabilizing properties as well the ability to reduce interleukins.25 Twicedaily treatment with azelastine eye drops (Optivar) resulted in significant reduction in conjunctival inflammation.26 Olopatadine (Patanol 0.1%, Pataday 0.2%) has selective histamine H1-receptor antagonist and mast-cell stabilizing properties and inhibits various cytokines.27 The original olopatadine (0.1%) was approved for all signs and symptoms of allergic conjunctivitis, but the once-a-day formulation (0.2%) is approved only for itching (as are all other dual-action agents).

Now available OTC and generically, ketotifen (Zaditor) is a mast-cell stabilizer, a strong histamine H1-receptor antagonist, and leukotriene inhibitor.28 Alcaftadine (Lastacaft) is a potent

CLINICAL SLIDESHOW For additional information regarding the various types of conjunctivitis, visit CliniAd.com/S7nyCr.

histamine H1-receptor antagonist with H2- and H4-receptor properties as well.29 Bepotastine besilate (Bepreve) is a histamine H1-receptor antagonist with mast-cell-stabilizing and eosinophil-inhibiting activity.30 Corticosteroids. As potent anti-inflammatory agents, corticosteroids should be reserved for cases of severe allergic conjunctivitis. Corticosteroids block most of the late-phase mediators of inflammation that lead to the persistent and chronic forms of ocular allergy.13 Use topical corticosteroids for short periods of up to two weeks with caution to avoid such serious side effects as cataracts, elevated intraocular pressure, and infection. An eye-care specialist should be consulted for patients who require steroid use of longer than two weeks.

Loteprednol etabonate (Alrex) 0.2% is indicated for relief of the signs and symptoms of allergic conjunctivitis.31 Loteprednol 0.5% (Lotemax) is also effective in treating GPC. Final instructions

Primary-care clinicians should be aware of the differential diagnoses of nonallergic rhinitis and allergic conjunctivitis.

The treatment for allergic rhinitis is different from nonallergic rhinitis. Allergic conjunctivitis may require a trial of several therapies. Ask the patient about ocular symptoms, and remember that topical therapy is preferred. Take care not to make the eye redder with therapy. Finally, know when to treat and when to refer to an eye-care specialist. ■ Mr. Ortiz is a physician assistant at Pediatric Pulmonary Services in El Paso, Tex. REFERENCES 1. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. American Academy of Allergy, Asthma, and Immunology. Ann Allergy Asthma Immunol. 1998;81:478-518.

2. Agency for Healthcare Research and Quality. Management of allergic and nonallergic rhinitis. Evidence Report/Technology Assessment Number 54. AHRQ Publication No. 02-E024, May 2002, Rockville Md. Available at archive.ahrq.gov/downloads/pub/evidence/pdf/rhinitis/rhinitis.pdf.

34 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

22. Johnson HG, VanHout CA, Wright JB. Inhibition of allergic reactions by

test-positive allergic rhinitis in Danish adults: two cross-sectional surveys

cromoglycate and by a new antiallergy drug U-42,585E. I. Activity in rats.

8 years apart. The Copenhagen Allergy Study. Allergy. 2000;55:767-772.

Int Arch Allergy Appl Immunol. 1978;56:416-423.

4. Sibbald B, Rink E, D'Souza M. Is the prevalence of atopy increasing?

23. Verin PH, Dicker ID, Mortemousque B. Nedocromil sodium eye drops are

Br J Gen Pract. 1990;40:338-340.

more effective than sodium cromoglycate eye drops for the long-term man-

5. Settipane RA. Demographics and epidemiology of allergic and nonaller-

agement of vernal keratoconjunctivitis. Clin Exp Allergy. 1999;29:529-536.

gic rhinitis. Allergy Asthma Proc. 2001;22:185-189.

24. Abelson MB, Berdy GJ, Mundorf T, et al. Pemirolast potassium 0.1%

6. Ortiz G, Cox L. Allergen specific-IgE blood testing for allergic diseases.

ophthalmic solution is an effective treatment for allergic conjunctivitis: a

Adv Phy Asst. 2010;18:S39.

pooled analysis of two prospective, randomized, double-masked, placebo-

7. Rachelefsky GS. Food allergy and atopic dermatitis. Infectious Diseases in

controlled, phase III studies. J Ocul Pharmacol Ther. 2002;18:475-488.

Children. 2011;4:8.

25. Galatowicz G, Ajayi Y, Stern ME, Calder VL. Ocular anti-allergic com-

8. Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group;

pounds selectively inhibit human mast cell cytokines in vitro and conjuncti-

World Health Organization. Allergic rhinitis and its impact on asthma.

val cell infiltration in vivo. Clin Exp Allergy. 2007;37:1648-1656.

J Allergy Clin Immunol. 2001;108:S147-S334.

26. Ciprandi G, Buscaglia S, Catrullo A, et al. Azelastine eye drops reduce

9. Storms WW, Pearlman DS, Chervinsky P, et al. Effectiveness of

and prevent allergic conjunctival reaction and exert anti-allergic activity.

azelastine nasal solution in seasonal allergic rhinitis. Ear Nose Throat J.

Clin Exp Allergy. 1997;27:182-191.

1994;73:382-386.

27. Yanni JM, Weimer LK, Sharif NA, et al. Inhibition of histamine-induced

10 Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc.

human conjunctival epithelial cell responses by ocular allergy drugs. Arch

2010;31:375-380.

Ophthalmol. 1999;117:643-647. Available at archopht.jamanetwork.com/

11. Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular

article.aspx?articleid=411899.

allergy. J Allergy Clin Immunol. 2000;106:1019-1032.

28. Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer antihis-

12. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal aller-

tamines in the treatment of allergic conjunctivitis. Drugs. 2005;65:215-228.

gy in the United States, 1988-1994. J Allergy Clin Immunol. 2010;126:778-783.

29. Greiner JV, Edwards-Swanson K, Ingerman A. Evaluation of alcaftadine

13. Bielory L. Allergic conjunctivitis: the evolution of therapeutic options.

0.25% ophthalmic solution in acute allergic conjunctivitis at 15 minutes

Allergy Asthma Proc. 2012;33:129-139.

and 16 hours after instillation versus placebo and olopatadine 0.1% . Clin

14. Abelson M. Allergic Diseases of the Eye. Philidelphia, Pa.: Elsevier Health

Ophthalmol. 2011;5:87-93. Available at www.ncbi.nlm.nih.gov/pmc/articles/

Sciences; 2001.

PMC3037035/.

15. Simons FE. Advances in H1-antihistamines. N Engl J Med. 2004;351

30. Hussar DA, Abbas CA. New drugs: asenapine, iloperidone, and bepo-

:2203-2217.

tastine besilate. J Am Pharm Assoc (2003). 2010;50:107-110. Available at

16. Spector SL, Raizman MB. Conjunctivitis medicamentosa. J Allergy Clin

japha.org/article.aspx?articleid=1043703.

Immunol. 1994;94:134-136.

31. Dell SJ, Lowry GM, Northcutt JA, et al. A randomized, double-masked,

17. Leysen JE, Gommeren W. Drug receptor dissociation time, new tool

placebo-controlled parallel study of 0.2% loteprednol etabonate in patients

for drug research: Receptor binding affinity and drug receptor dissociation

with seasonal allergic conjunctivitis. J Allergy Clin Immunol. 1998;102:251-255.

profiles of serotonin S2, dopamine D2, histamine H1 antagonists and opiates. Drug Develop Res. 1986;8:119-131.

All electronic documents accessed December 15, 2012.

18. Sharif NA, Xu S, Yanni J. Emedastine: pharmacological profile of a novel antihistamine for use in allergic conjunctivitis. Invest Ophthalmol Vis Sci. 1995;36:s135.

19. Ballas Z, Blumenthal M, Tinkelman DG, et al. Clinical evaluation of ketorolac tromethamine 0.5% ophthalmic solution for the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol. 1993;38 Suppl:141-148.

20. Friday GA, Biglan AW, Hiles DA, et al. Treatment of ragweed allergic conjunctivitis with cromolyn sodium 4% ophthalmic solution. Am J Ophthalmol. 1983;95:169-174.

21. Johnson HG, VanHout CA, Wright JB. Inhibition of allergic reactions by cromoglycate and by a new antiallergy drug U-42,585E. II. Activity in primates against aerosolized Ascaris suum antigen. Int Arch Allergy Appl Immunol. 1978;56:481-487.

“I know you’re angry at me—I’m angry at me, too!” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 35

© The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

3. Linneberg A, Jørgensen T, Nielsen NH, et al. The prevalence of skin-

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum JANUARY 2013

Consultations How common is vitamin overdose? . .36 Chronic use of OTC topical corticosteroids . . . . . . . . . . . . . . . . .36 Treating a paranoiac for dementia . . . .37 Onychomycosis diagnosis . . . . . . . . . .37

Clinical Pearls Can I get your number? . . . . . . . . . . .37 A fun way to rehydrate children . . . . .38

Your Comments More skin-saving shaving advice . . . . .38

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

Palliative care too often overlooked . . .38

CONSULTATIONS HOW COMMON IS VITAMIN OVERDOSE? Is it possible to overdose on vitamins? Many of the vitamins my patients take have 100% to 400% of the recommended daily allowance of B vitamins and vitamin A. My understanding is that as long as kidney function is normal, excess amounts will be flushed out.—LEIGH BEARS, ARNP, New London, N.H. The fat-soluble vitamins (i.e., A, D, E, and K) are much more likely to cause problems with overdose. Excess amounts of these vitamins can even cause liver damage. The other vitamins are watersoluble. As long as the individual’s kidney function is normal, the excess is usually eliminated in the urine. Adverse effects from some water-soluble vitamins are still possible, however. One example of dangerous overdose is that too much manganese can affect the central nervous system in a manner similar to that of Parkinson disease. As always, the best advice is to eat a balanced diet and never supplement above the tolerable upper-intake level.—Julee B. Waldrop, DNP (171-1)

CHRONIC USE OF OTC TOPICAL CORTICOSTEROIDS Topical corticosteroids are frequently prescribed for pruritic conditions (e.g., dermatitis, pruritus ani). Is there any danger

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of California San Diego.

36 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

of systemic effects from chronic use of OTC steroid creams and/or ointments?—JAMES MAY, PA-C, Macon, Ga. OTC topical corticosteroid creams and ointments typically include preparations that contain hydrocortisone acetate in concentrations ranging from 0.5% to 1.0%. Chronic use may result in cutaneous atrophy, pigment changes, or both at the site of application. Systemic adverse effects from localized application of these preparations would be unexpected. Even if the OTC corticosteroid preparation was applied over larger areas of the body, systemic effects would be unlikely since the potency of these creams and ointments is low.—Philip R. Cohen, MD (171-2)

TREATING A PARANOIAC FOR DEMENTIA All typical and atypical antipsychotic medications include an FDA black-box warning against use in individuals with dementia. What is the recommended treatment for patients diagnosed with dementia who are suffering with paranoia and/or hallucinations?—DENNIS LOVE, PA-C, Butler, Pa. The behavioral issues related to patients with dementia are complex.

There are a number of factors that can contribute to behavioral disturbances. Carefully assess the patient and consider such other causes of paranoia and hallucinations as infections, drug abuse, and dehydration. Risperidone (Risperdal) and olanzapine (Zyprexa) may be useful in reducing aggression. Risperidone can help reduce psychosis but can be associated with serious adverse cerebrovascular events and cause extrapyramidal symptoms, usually with long-term use. Neither drug should be used routinely. Close monitoring is essential during initiation and maintenance. Low dosing is generally well-tolerated and results in fewer side effects. For more specific details regarding medication management and dosing, see the 2008

report, Guidelines for Alzheimer’s Disease Management (available at www.caalz.org/PDF_files/Guideline-FullReport-CA. pdf, accessed December 15, 2012).—Deborah L. Cross, MPH, CRNP, ANP-BC (171-3)

ONYCHOMYCOSIS DIAGNOSIS What is the most sensitive test to use when trying to diagnose toenail fungus?—KERI LAZURE, PA-C, Omaha, Neb. Conventional methods for identifying fungal organisms in the nail plate of patients with onychomycosis (OM) include direct microscopy (after KOH solution incubation), fungal culture, and histopathology (using periodic acid Schiff [PAS] stain). Surgical pathology testing (of the subungual nail bed and/or the nail plate) using PAS stain is the current gold standard (approaching 100% sensitivity) for the diagnosis of OM. Newer methods for diagnosing OM include polymerase chain reaction (which has a very high specifi city), optical coherence tomography, confocal laser scan microscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and phase contrast hard x-ray microscopy. Confirmation of observations and availability and cost must be considered before these newer methods for diagnosing OM can be incorporated in clinical practice (Indian J Dermatol Venereol Leprol. 2012;78:263-270).—Philip R. Cohen, MD (171-4)

CLINICAL PEARLS CAN I GET YOUR NUMBER? Every medical-insurance representative you speak with regarding precertification has an identification number.

This knowledge will prevent you from having to repeat the

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

is associate professor at the University of Central Florida (UCF), and practices pediatrics at the UCF Health Center.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 37

Advisor Forum detailed patient information in the event that you have to call back. Simply ask to speak to the same representative using his or her identification number. The insurance companies do not regularly volunteer this information, so you have to request it.—PATRICK AUFIERO, MD, Hamilton, N.J. (171-5)

A FUN WAY TO REHYDRATE CHILDREN To help get a mildly dehydrated child to drink oral electrolyte solution (Pedialyte), mix with flavored sugar-free gelatin, substituting Pedialyte for water. The added flavor from the gelatin will help to decrease the salty flavor while avoiding the excess sugar that can worsen diarrhea and GI upset. Depending on personal preference, the child can either drink the mixed solution at room temperature or eat it like gelatin after chilling it for approximately four hours.

A third option is to freeze the solution in ice cube trays with Popsicle sticks in the center.—SHERI CARSON, NP, Tucson, Ariz. (171-6)

“It’s a rather interesting phenomenom. Every time I press this lever, that post-graduate student breathes a sigh of relief.”

YOUR COMMENTS MORE SKIN-SAVING SHAVING ADVICE To further minimize skin problems associated with shaving (Item 170-4): (1) apply warmth to area to be shaved for one to two minutes; (2) shave in the direction of the hair (e.g., downward for legs, toward midline for pubic area, and from center of the armpit out); (3) wash all soap or shaving cream off with warm—but not hot—water; and (4) avoid application of any powder, lotion, or deodorant for at least 10 minutes after shaving (to avoid folliculitis by allowing hair follicles to close). These principles have served me well with patients throughout more than 30 years of clinical practice.—WAYNE VonSEGGEN, PA-C, Winston Salem, N.C. (171-7)

“You have a lot of boring health issues, so I’m prescribing medical marijuana for myself.”

38 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

© The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

PALLIATIVE CARE TOO OFTEN OVERLOOKED I am certified in hospice and palliative medicine (Item 1702). Although cost-effective, logical, and compassionate, palliative care is tyically underutilized until the patient’s condition is quite advanced. Please encourage patients and families to consider palliative care as an option or call a specialist for a consult.—DANIEL BERGER, DO, Coral Gables, Fla. (171-8) ■

“And that’s how babies are made.”

LEGAL ADVISOR CASE

Fraudulent practices set off alarms

BY ANN W. LATNER, JD

Sometimes doing the right thing could cost you a job, and it seems—on the surface—that keeping quiet is the best option. Keeping quiet, however, poses a distinct dilemma when you are aware that your employer is doing something illegal—and especially when your employer is also endangering the lives of patients entrusted to him.

Ms. V, a veteran nurse practitioner working in private practice, encountered something she never expected to see after more than 20 years of working. She had recently begun working in Dr. D’s busy hematology/oncology practice.

Ms. V was one of three nurses working for Dr. D. If a patient were coming in for something routine, such as an injection, the patient would see Ms. V or one of the other nurses rather than the physician.

Ms. V had a good working relationship with the other nurses, all of whom were relatively new to the practice. Ms. V didn’t have as much interaction with Dr. D as she’d had with previous employers, but this did not bother her; she was confident in what she was doing.

© THNKSTOCK

What do you do when patient charts have been changed after the fact and medication doses altered?

Ms.V did not know how she would treat her next anemia patient, and the thought of dividing the epoetin alfa vial in half did not sit right with her.

40 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

The first months on the job were uneventful, aside from one oddity: Ms. V was told that the practice in the office was to bill visits at level 3 (a price structure reserved for physician-based contact), even if the patient had only been seen by the nursing staff. While that seemed strange to Ms. V, she shrugged it off.

A few weeks later, however, Ms. V was sure that she had recorded the specific medication dosage that she administered in the patient’s file, but when she went back to review the file later, the dosage was different than what she’d originally written.

Chalking it up to bad memory, she ignored it— until it happened again. At this point, she asked one of the other nurses if this had happened to her, and the nurse replied in the affirmative.

“I think Dr. D is changing the chart notes,” said the other nurse. “I’ve noticed the same thing.”

Continues on page 50

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR Ms. V was perplexed but didn’t want to confront Dr. D or ask the office manager, who happened to be the physician’s wife. She was concerned about losing her job, as the market was tough right now and finding another position might prove difficult in the short term. So she and the other nurses said nothing about the obvious chart changes, and went about their business.

Then, Dr. D called an office meeting and announced a change in policy.

“From now on,” the physician told his staff, “you are to split the 40,000-unit vials of epoetin alfa [Epogen, Procrit] between two patients—giving them each a 20,000-unit dose.”

Medicare was being billed for medication that had not been dispensed, and for services that had not been rendered.

The nurses snuck dubious looks at each other but said nothing.

“Just chart it as a single vial in each patient’s record,” Dr. D instructed.

The nurses quietly went back to caring for their patients.

But Ms. V was torn. This wasn’t right, yet she wasn’t sure what to do about it. Her coworkers felt the same way—each had the feeling that this split in dosing was not appropriate, yet each needed to keep her job.

Ms. V considered going to an attorney for advice, but decided against it. She didn’t know how she would treat her next anemia patient, and the thought of dividing the epoetin alfa vial in half did not sit right with her. Internally, she was weighing whether to not to follow the physician’s instructions.

Before she had to make that decision, however, the situation came to a head. One morning, federal subpoenas were delivered to the office, demanding all patient and office records. Dr. D flew into a panic and called an emergency staff meeting, at which he ordered an office-wide audit of records and demanded that all patient records be shredded immediately.

At this point, Ms. V refused to shred documents, insisting that the records must be preserved. Her two coworkers also refused to comply with Dr. D’s instructions.

Dr. D was eventually arrested and charged with health-care fraud. He had been billing Medicare and other insurance companies for medication that hadn’t been dispensed, and for services that hadn’t been rendered. The office shut down, and Ms. V was served with a subpoena requiring her to testify for the prosecution at the trial.

Concerned about her own liability, Ms. V sought advice from a criminal defense attorney who advised her that as long as she cooperated in full—testifying truthfully about what had transpired—she would most probably not be held liable.

At trial, Ms. V was called to the stand and asked about Dr. D’s billing practices, and whether he was actually seeing the patients that he claimed to have seen. She was asked about medication dosages and whether they had actually been administered to the patients. Although she was nervous, Ms. V testified truthfully about noticing that dosages had been changed in records, and that Dr. D had instructed them to give half the dose of epoetin alfa but record in the patient’s chart that a full dose had been given.

“Did you do that?” asked the prosecutor.

“No,” replied Ms. V. “I had not seen a patient requiring epoetin alfa after Dr. D instituted the new practice, and then he was arrested.”

Ms. V was excused. The other nurses testified similarly.

Dr. D was convicted of 28 separate counts of health-care fraud. He was sentenced to five years in jail, ordered to pay more than $1 million in restitution, and his medical license was suspended.

Legal background

Health-care fraud is considered a white-collar crime. In this case, the perpetrator filed incorrect health-care claims to make a profit. According to the Federal Bureau of Investigation, health-care fraud comes in many forms—fraudulent billings, administering medically unnecessary services or prescriptions, kickbacks, duplicate claims, and more. In this case, Dr. D billed Medicare and other insurance providers for patient care that he had not provided and for medication dosages that had not been given.

Protecting yourself

Ms. V was in a difficult position. Yet, when it became clear that Dr. D was doing something illegal, she had a duty to report it—especially since these actions could impact the health of patients. Had Ms. V actually given a patient a halfdose of epoetin alfa as the physician ordered, and recorded in the patient’s chart that the patient had received a full dose, she might have been prosecuted as well, or sued. Health-care fraud is a significant problem in the United States. If you are aware that fraud is being committed, you must report it—to protect not only yourself, but your patients, too. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

50 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

helP INTeRcePT ThRomBoTIc RISk

with the versatility of multiple indications

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The fIRST ANd oNly oRAl, SelecTIve fAcToR Xa INhIBIToR offeRING The veRSATIlITy of mulTIPle INdIcATIoNS APPRoved By The fdA Stroke riSk reduction in nonvalvular aF To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). There are limited data on the relative effectiveness of XARELTO速 and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

dvt and Pe treatment and reduction in tHe riSk oF recurrence For the treatment of deep vein thrombosis (DVT).

For the treatment of pulmonary embolism (PE).

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dvt ProPHylaxiS aFter knee or HiP rePlacement Surgery For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Please see the Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNINGS, on following pages.

Approved For multiple indicAtions

8.5

ImPoRTANT SAfeTy INfoRmATIoN WARNING: (A) dIScoNTINuING XARelTo® IN PATIeNTS WITh NoNvAlvulAR ATRIAl fIBRIllATIoN INcReASeS RISk of STRoke, (B) SPINAl/ePIduRAl hemATomA A. dIScoNTINuING XARelTo® IN PATIeNTS WITh NoNvAlvulAR ATRIAl fIBRIllATIoN discontinuing XArelto® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XArelto® discontinuation in clinical trials in atrial fibrillation patients. if anticoagulation with XArelto® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

B. SPINAl/ePIduRAl hemATomA epidural or spinal hematomas have occurred in patients treated with XArelto® who are receiving neuraxial anesthesia or undergoing spinal puncture.

contraindicationS Active pathological bleeding Severe hypersensitivity reaction to XARELTO® (e.g., anaphylactic reactions)

WarningS and PrecautionS

11

increased risk of stroke After discontinuation in nonvalvular Atrial Fibrillation: Discontinuing XARELTO® in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO® in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

• A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

these hematomas may result in long-term or permanent paralysis. consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (nsAids), platelet inhibitors, other anticoagulants, see drug interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery monitor patients frequently for signs and symptoms of neurological impairment. if neurological compromise is noted, urgent treatment is necessary. consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

• Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs. • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk. spinal/epidural Anesthesia or puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO® is to be delayed 24 hours. use in patients With renal impairment: • nonvalvular Atrial Fibrillation: Avoid the use of XARELTO® in patients with creatinine clearance (CrCl) <15 mL/min since drug exposure is increased.

Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

• treatment of dvt, pe, and reduction in the risk of recurrence of dvt and of pe: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

• prophylaxis of deep vein thrombosis Following Hip or Knee replacement surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due

8.5

XARelTo helPS INTeRcePT ThRomBoTIc RISk ®

for a wide range of patient types evidence Generated in multiple Phase 3 clinical Trials

>55,000 patients at thrombotic risk1-9

Affordable With Broad formulary coverage for >90% of your Insured Patients

>90

%

ReImBuRSed

COVERED at lowest branded co-pay for...

>70% of Medicare patients10 >65% of commercial patients10

Real-world experience

>1.7 milliOn

COmpREhEnsiVE

patients worldwide*11

support program and reimbursement assistance for patients and caregivers

>600,000 US prescriptions12

*reflects imS data from 2008-may 2012 for the 10-mg tablets (includes uS, european union, china, and latin america) and november 2011-July 2012 for 15-mg and 20-mg tablets (uS only). Standard units factored by labeled length of therapy. the majority of treated patients received 10-mg tablets for dvt prophylaxis in total knee replacement and total hip replacement.

visit www.XARelTohcp.com to learn more Please see full indications and the Important Safety Information on prior pages and Brief Summary of full Prescribing Information, including Boxed WARNINGS, on following pages.

8.5

APPROVED FOR MULTIPLE INDICATIONS

ImPoRTANT SAfeTy INfoRmATIoN WARNING: (A) dIScoNTINuING XARelTo® IN PATIeNTS WITh NoNvAlvulAR ATRIAl fIBRIllATIoN INcReASeS RISk of STRoke, (B) SPINAl/ePIduRAl hemATomA A. dIScoNTINuING XARelTo® IN PATIeNTS WITh NoNvAlvulAR ATRIAl fIBRIllATIoN discontinuing XArelto® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XArelto® discontinuation in clinical trials in atrial fibrillation patients. if anticoagulation with XArelto® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

B. SPINAl/ePIduRAl hemATomA epidural or spinal hematomas have occurred in patients treated with XArelto® who are receiving neuraxial anesthesia or undergoing spinal puncture.

contraindicationS Active pathological bleeding Severe hypersensitivity reaction to XARELTO® (e.g., anaphylactic reactions)

WarningS and PrecautionS

11

increased risk of stroke After discontinuation in nonvalvular Atrial Fibrillation: Discontinuing XARELTO® in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO® in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

• A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

these hematomas may result in long-term or permanent paralysis. consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (nsAids), platelet inhibitors, other anticoagulants, see drug interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery monitor patients frequently for signs and symptoms of neurological impairment. if neurological compromise is noted, urgent treatment is necessary. consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

• Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs. • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk. spinal/epidural Anesthesia or puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO® is to be delayed 24 hours. use in patients With renal impairment: • nonvalvular Atrial Fibrillation: Avoid the use of XARELTO® in patients with creatinine clearance (CrCl) <15 mL/min since drug exposure is increased.

Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

• treatment of dvt, pe, and reduction in the risk of recurrence of dvt and of pe: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

• prophylaxis of deep vein thrombosis Following Hip or Knee replacement surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due

8.5

XARelTo helPS INTeRcePT ThRomBoTIc RISk ®

for a wide range of patient types evidence Generated in multiple Phase 3 clinical Trials

>55,000 patients at thrombotic risk1-9

Affordable With Broad formulary coverage for >90% of your Insured Patients

>90

%

ReImBuRSed

COVERED at lowest branded co-pay for...

>70% of Medicare patients10 >65% of commercial patients10

Real-world experience

>1.7 milliOn

COmpREhEnsiVE

patients worldwide*11

support program and reimbursement assistance for patients and caregivers

>600,000 US prescriptions12

*reflects imS data from 2008-may 2012 for the 10-mg tablets (includes uS, european union, china, and latin america) and november 2011-July 2012 for 15-mg and 20-mg tablets (uS only). Standard units factored by labeled length of therapy. the majority of treated patients received 10-mg tablets for dvt prophylaxis in total knee replacement and total hip replacement.

visit www.XARelTohcp.com to learn more Please see full indications and the Important Safety Information on prior pages and Brief Summary of full Prescribing Information, including Boxed WARNINGS, on following pages.

8.5

APPROVED FOR MULTIPLE INDICATIONS

WarningS and PrecautionS (cont’d)

11

to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue the treatment. use in patients With Hepatic impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased. use With p-gp and strong cYp3A4 inhibitors or inducers: Avoid concomitant use of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO® with drugs that are P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort). risk of pregnancy-related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed.

Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

drug interactionS drugs that inhibit cYp3A4 enzymes and drug transport systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors. drugs that induce cYp3A4 enzymes and drug transport systems: Results from drug interaction studies and population pharmacokinetic (PK) analyses from clinical studies – coadministration of XARELTO® with a combined P-gp and strong CYP3A4 inducers (eg, rifampin, phenytoin) decreased rivaroxaban exposure by 27%-50%. Similar decreases in pharmacodynamic effects were also observed.

These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants and nsAids/Aspirin: Single doses of enoxaparin and XARELTO® given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO® resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO®.

Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. drug-disease interactions With drugs that inhibit cYp3A4 enzymes and drug transport systems: Patients with renal impairment receiving full dose XARELTO® in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

XARELTO® should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

uSe in SPeciFic PoPulationS pregnancy category c: There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post implantation pregnancy loss occurred in rabbits. XARELTO® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. labor and delivery: Safety and effectiveness of XARELTO® during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum exposure of the unbound drug at the human dose of 20 mg/day). nursing mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother. pediatric use: Safety and effectiveness in pediatric patients have not been established.

Geriatric use: In the EINSTEIN DVT, PE, and Extension clinical studies, approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

8.5

ImPoRTANT SAfeTy INfoRmATIoN (cont’d) uSe in SPeciFic PoPulationS (cont’d) Females of reproductive potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. renal impairment: In a pharmacokinetic study, comparing healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44% to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO® in patients with CrCl <30 mL/min.

Hepatic impairment: In a pharmacokinetic study, comparing healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (ChildPugh B). The safety and PK of XARELTO® in patients with hepatic impairment (Child-Pugh C) have not been evaluated. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

overdoSage Overdose of XARELTO® may lead to hemorrhage.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

adverSe reactionS in clinical StudieS Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications. nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were

bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. treatment of dvt, pe and to reduce the risk of recurrence of dvt and of pe: In the pooled analysis of the EINSTEIN DVT and PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO® versus enoxaparin/vitamin K antagonist (VKA) incidence rates of 1.7% versus 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO®-treated patients and 204 days for enoxaparin/VKA-treated patients. In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO® versus 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO® and placebo treatment groups. prophylaxis of deep vein thrombosis Following Hip or Knee replacement surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO®. other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

K02X121084

ImPoRTANT SAfeTy INfoRmATIoN (cont’d)

References: 1. mega Jl, Braunwald e, Wiviott Sd, et al. N Engl J Med. 2012;366(1):9-19.

2. the einStein–Pe investigators. oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 3. the einStein investigators. oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):24992510. 4. Patel mr, mahaffey kW, garg J, et al; and the rocket aF Steering committee, for the rocket aF investigators. rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

N Engl J Med. 2011;365(10):883-891. 5. lassen mr, ageno W, Borris lc, et al; for the record3 investigators. rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 6. kakkar ak, Brenner B, dahl oe, et al; for the record2 investigators. extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. 7. eriksson Bi, Borris lc, Friedman rJ, et al; for the record1 Study group. rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 8. Hori m, matsumoto m, tanahashi n, et al; on behalf of the J-rocket aF study investigators. rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-rocket aF study. Circ J. 2012;26(9):2104-2111. 9. data on file. Janssen Pharmaceuticals, inc. 10. data on file. Janssen Pharmaceuticals, inc. data as of 10/1/12. 11. data on file. Janssen Pharmaceuticals, inc. Based on imS Health midaS database, 2008-may 2012 and imS market dynamics, november 2011-July 2012. 12. data on file. Janssen Pharmaceuticals, inc.

Based on imS Health, nPa Weekly, total Prescriptions, July 2011-august 2012.

visit www.XARelTohcp.com to learn more Please see the additional Important Safety Information on prior pages and Brief Summary of full Prescribing Information, including Boxed WARNINGS, on following pages.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2012 December 2012 K02X121005

Janssen Pharmaceuticals, inc.

8.5

WarningS and PrecautionS (cont’d)

11

to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue the treatment. use in patients With Hepatic impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased. use With p-gp and strong cYp3A4 inhibitors or inducers: Avoid concomitant use of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO® with drugs that are P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort). risk of pregnancy-related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed.

Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

drug interactionS drugs that inhibit cYp3A4 enzymes and drug transport systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors. drugs that induce cYp3A4 enzymes and drug transport systems: Results from drug interaction studies and population pharmacokinetic (PK) analyses from clinical studies – coadministration of XARELTO® with a combined P-gp and strong CYP3A4 inducers (eg, rifampin, phenytoin) decreased rivaroxaban exposure by 27%-50%. Similar decreases in pharmacodynamic effects were also observed.

These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants and nsAids/Aspirin: Single doses of enoxaparin and XARELTO® given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO® resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO®.

Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. drug-disease interactions With drugs that inhibit cYp3A4 enzymes and drug transport systems: Patients with renal impairment receiving full dose XARELTO® in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

XARELTO® should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

uSe in SPeciFic PoPulationS pregnancy category c: There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post implantation pregnancy loss occurred in rabbits. XARELTO® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. labor and delivery: Safety and effectiveness of XARELTO® during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum exposure of the unbound drug at the human dose of 20 mg/day). nursing mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother. pediatric use: Safety and effectiveness in pediatric patients have not been established.

Geriatric use: In the EINSTEIN DVT, PE, and Extension clinical studies, approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

8.5

ImPoRTANT SAfeTy INfoRmATIoN (cont’d) uSe in SPeciFic PoPulationS (cont’d) Females of reproductive potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. renal impairment: In a pharmacokinetic study, comparing healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44% to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO® in patients with CrCl <30 mL/min.

Hepatic impairment: In a pharmacokinetic study, comparing healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (ChildPugh B). The safety and PK of XARELTO® in patients with hepatic impairment (Child-Pugh C) have not been evaluated. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

overdoSage Overdose of XARELTO® may lead to hemorrhage.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

adverSe reactionS in clinical StudieS Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications. nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were

bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. treatment of dvt, pe and to reduce the risk of recurrence of dvt and of pe: In the pooled analysis of the EINSTEIN DVT and PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO® versus enoxaparin/vitamin K antagonist (VKA) incidence rates of 1.7% versus 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO®-treated patients and 204 days for enoxaparin/VKA-treated patients. In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO® versus 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO® and placebo treatment groups. prophylaxis of deep vein thrombosis Following Hip or Knee replacement surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO®. other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

K02X121084

ImPoRTANT SAfeTy INfoRmATIoN (cont’d)

References: 1. mega Jl, Braunwald e, Wiviott Sd, et al. N Engl J Med. 2012;366(1):9-19.

2. the einStein–Pe investigators. oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 3. the einStein investigators. oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):24992510. 4. Patel mr, mahaffey kW, garg J, et al; and the rocket aF Steering committee, for the rocket aF investigators. rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

N Engl J Med. 2011;365(10):883-891. 5. lassen mr, ageno W, Borris lc, et al; for the record3 investigators. rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 6. kakkar ak, Brenner B, dahl oe, et al; for the record2 investigators. extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. 7. eriksson Bi, Borris lc, Friedman rJ, et al; for the record1 Study group. rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 8. Hori m, matsumoto m, tanahashi n, et al; on behalf of the J-rocket aF study investigators. rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-rocket aF study. Circ J. 2012;26(9):2104-2111. 9. data on file. Janssen Pharmaceuticals, inc. 10. data on file. Janssen Pharmaceuticals, inc. data as of 10/1/12. 11. data on file. Janssen Pharmaceuticals, inc. Based on imS Health midaS database, 2008-may 2012 and imS market dynamics, november 2011-July 2012. 12. data on file. Janssen Pharmaceuticals, inc.

Based on imS Health, nPa Weekly, total Prescriptions, July 2011-august 2012.

visit www.XARelTohcp.com to learn more Please see the additional Important Safety Information on prior pages and Brief Summary of full Prescribing Information, including Boxed WARNINGS, on following pages.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2012 December 2012 K02X121005

Janssen Pharmaceuticals, inc.

8.5

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anti­ coagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long­term or permanent paralysis.

Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non­ steroidal anti­inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

11

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

Treatment of Deep Vein Thrombosis: XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism: XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism: XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical trials.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/ epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Use in Patients with Renal Impairment: Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations] Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations].

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations].

Use in Patients with Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations].

Use with P­gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) [see Drug Interactions].

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Drug Interactions].

Risk of Pregnancy Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF*

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.

ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: • Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed Warning and Warnings and Precautions] • Bleeding risk [see Warnings and Precautions] • Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions] Clinical Trials 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.

During clinical development for the approved indications, 16326 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 patients who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

8.5

Parameter

XARELTO N = 7111 n (%)

Event Rate Warfarin (per 100 N = 7125 Pt­yrs) n (%)

Table 3: Bleeding Events* in EINSTEIN Extension Study

Event Rate (per 100 Pt­yrs)

Parameter

Major bleeding event‡

3.6

386 (5.4)

3.5

4 (0.7)

0

91 (1.3)

0.8

133 (1.9)

1.2

Decrease in Hb ≥2 g/dL

4 (0.7)

0

2 (0.3)

0

Fatal bleeding

27 (0.4)

0.2

55 (0.8)

0.5

Transfusion of ≥2 units of whole blood or packed red blood cells

Bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells

183 (2.6)

1.7

149 (2.1)

1.3

Gastrointestinal

3 (0.5)

0

Menorrhagia

1 (0.2)

0

32 (5.4)

7 (1.2)

104 (17.4)

63 (10.7)

Clinically relevant non-major bleeding 221 (3.1)

2.0

140 (2.0)

Any bleeding

1.2

* For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE: EINSTEIN DVT and EINSTEIN PE Studies: In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

*

† ‡

Parameter

Major bleeding event

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1­3) Total treated patients Major bleeding event

40 (1.0)

Enoxaparin/ VKA† N = 4116 n (%) 72 (1.7)

Fatal bleeding

3 (<0.1)

8 (0.2)

Intracranial

2 (<0.1)

4 (<0.1)

10 (0.2)

29 (0.7)

Intracranial‡

3 (<0.1)

10 (0.2)

Retroperitoneal‡

1 (<0.1)

8 (0.2)

Intraocular‡

3 (<0.1)

2 (<0.1)

Non-fatal critical organ bleeding

Intra-articular‡

0

4 (<0.1)

Non-fatal non-critical organ bleeding§

27 (0.7)

37 (0.9)

Decrease in Hb ≥ 2g/dL

28 (0.7)

42 (1.0)

Transfusion of ≥2 units of whole blood or packed red blood cells

18 (0.4)

25 (0.6)

Clinically relevant non-major bleeding Any bleeding

§

XARELTO† N = 4130 n (%)

357 (8.6)

357 (8.7)

1169 (28.3)

1153 (28.0)

Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.

Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells

EINSTEIN Extension Study: In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO and placebo treatment groups.

Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.

Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily There were no fatal or critical organ bleeding events.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies

‡

N = 590 n (%)

395 (5.6)

Gastrointestinal bleeding

†

Placebo†

Bleeding into a critical organ‡

Major bleeding†

*

XARELTO† 20 mg N = 598 n (%)

14 (0.3)

9 (0.2) 0

Bleeding into a critical organ

2 (<0.1)

3 (0.1)

Bleeding that required re-operation

7 (0.2)

5 (0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

4 (0.1)

1 (<0.1)

Major bleeding event

261 (5.8)

251 (5.6)

N = 3281 n (%)

N = 3298 n (%)

7 (0.2)

3 (0.1)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

1 (<0.1)

1 (<0.1)

Bleeding that required re-operation

2 (0.1)

1 (<0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

3 (0.1)

1 (<0.1)

Any bleeding event‡ Knee Surgery Study Major bleeding event Fatal bleeding

201 (6.1)

191 (5.8)

N = 1206 n (%)

N = 1226 n (%)

7 (0.6)

6 (0.5)

0

0

Bleeding into a critical organ

1 (0.1)

2 (0.2)

Bleeding that required re-operation

5 (0.4)

4 (0.3)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

1 (0.1)

0

60 (5.0)

60 (4.9)

Any bleeding event‡

‡

N = 4524 n (%)

1 (<0.1)

Any bleeding event‡

†

Enoxaparin†

N = 4487 n (%)

Fatal bleeding

Hip Surgery Studies

*

XARELTO 10 mg

Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event.

Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Includes major bleeding events

Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

8.5

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNING: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anti­ coagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long­term or permanent paralysis.

Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non­ steroidal anti­inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

11

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

Treatment of Deep Vein Thrombosis: XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism: XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism: XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical trials.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/ epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Use in Patients with Renal Impairment: Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations] Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations].

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations].

Use in Patients with Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations].

Use with P­gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) [see Drug Interactions].

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Drug Interactions].

Risk of Pregnancy Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF*

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.

ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: • Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed Warning and Warnings and Precautions] • Bleeding risk [see Warnings and Precautions] • Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions] Clinical Trials 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.

During clinical development for the approved indications, 16326 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 patients who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

8.5

Parameter

XARELTO N = 7111 n (%)

Event Rate Warfarin (per 100 N = 7125 Pt­yrs) n (%)

Table 3: Bleeding Events* in EINSTEIN Extension Study

Event Rate (per 100 Pt­yrs)

Parameter

Major bleeding event‡

3.6

386 (5.4)

3.5

4 (0.7)

0

91 (1.3)

0.8

133 (1.9)

1.2

Decrease in Hb ≥2 g/dL

4 (0.7)

0

2 (0.3)

0

Fatal bleeding

27 (0.4)

0.2

55 (0.8)

0.5

Transfusion of ≥2 units of whole blood or packed red blood cells

Bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells

183 (2.6)

1.7

149 (2.1)

1.3

Gastrointestinal

3 (0.5)

0

Menorrhagia

1 (0.2)

0

32 (5.4)

7 (1.2)

104 (17.4)

63 (10.7)

Clinically relevant non-major bleeding 221 (3.1)

2.0

140 (2.0)

Any bleeding

1.2

* For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE: EINSTEIN DVT and EINSTEIN PE Studies: In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

*

† ‡

Parameter

Major bleeding event

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1­3) Total treated patients Major bleeding event

40 (1.0)

Enoxaparin/ VKA† N = 4116 n (%) 72 (1.7)

Fatal bleeding

3 (<0.1)

8 (0.2)

Intracranial

2 (<0.1)

4 (<0.1)

10 (0.2)

29 (0.7)

Intracranial‡

3 (<0.1)

10 (0.2)

Retroperitoneal‡

1 (<0.1)

8 (0.2)

Intraocular‡

3 (<0.1)

2 (<0.1)

Non-fatal critical organ bleeding

Intra-articular‡

0

4 (<0.1)

Non-fatal non-critical organ bleeding§

27 (0.7)

37 (0.9)

Decrease in Hb ≥ 2g/dL

28 (0.7)

42 (1.0)

Transfusion of ≥2 units of whole blood or packed red blood cells

18 (0.4)

25 (0.6)

Clinically relevant non-major bleeding Any bleeding

§

XARELTO† N = 4130 n (%)

357 (8.6)

357 (8.7)

1169 (28.3)

1153 (28.0)

Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.

Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells

EINSTEIN Extension Study: In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO and placebo treatment groups.

Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.

Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily There were no fatal or critical organ bleeding events.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies

‡

N = 590 n (%)

395 (5.6)

Gastrointestinal bleeding

†

Placebo†

Bleeding into a critical organ‡

Major bleeding†

*

XARELTO† 20 mg N = 598 n (%)

14 (0.3)

9 (0.2) 0

Bleeding into a critical organ

2 (<0.1)

3 (0.1)

Bleeding that required re-operation

7 (0.2)

5 (0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

4 (0.1)

1 (<0.1)

Major bleeding event

261 (5.8)

251 (5.6)

N = 3281 n (%)

N = 3298 n (%)

7 (0.2)

3 (0.1)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

1 (<0.1)

1 (<0.1)

Bleeding that required re-operation

2 (0.1)

1 (<0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

3 (0.1)

1 (<0.1)

Any bleeding event‡ Knee Surgery Study Major bleeding event Fatal bleeding

201 (6.1)

191 (5.8)

N = 1206 n (%)

N = 1226 n (%)

7 (0.6)

6 (0.5)

0

0

Bleeding into a critical organ

1 (0.1)

2 (0.2)

Bleeding that required re-operation

5 (0.4)

4 (0.3)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

1 (0.1)

0

60 (5.0)

60 (4.9)

Any bleeding event‡

‡

N = 4524 n (%)

1 (<0.1)

Any bleeding event‡

†

Enoxaparin†

N = 4487 n (%)

Fatal bleeding

Hip Surgery Studies

*

XARELTO 10 mg

Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event.

Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Includes major bleeding events

Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

8.5

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Other Adverse Reactions: Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5.

DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and fluconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 30% to 160%. Significant increases in rivaroxaban exposure may increase bleeding risk [see Clinical Pharmacology (12.3) in full Prescribing Information].

When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors [see Warnings and Precautions].

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of XARELTO with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed.

These decreases in exposure to rivaroxaban may decrease efficacy [see Clinical Pharmacology (12.3) in full Prescribing Information].

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions].

Anticoagulants and NSAIDs/Aspirin: Single doses of enoxaparin and XARELTO given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Coadministration of the platelet aggregation inhibitor clopidogrel and XARELTO resulted in an increase in bleeding time for some subjects [see Clinical Pharmacology (12.3) in full Prescribing Information].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

Drug­Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

XARELTO should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.

Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious

adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in full Prescribing Information].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3) in full Prescribing Information].

Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE: In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery: The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Hepatic Impairment: In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in full Prescribing Information].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

Table 5: Other Adverse Reactions* Reported by ≥1% of XARELTO­Treated Patients in EINSTEIN Extension Study System Organ Class Preferred Term

XARELTO N = 598 n (%)

Placebo N = 590 n (%)

Gastrointestinal disorders Abdominal pain upper

10 (1.7)

1 (0.2)

Dyspepsia

8 (1.3)

4 (0.7)

Toothache

6 (1.0)

0

6 (1.0)

3 (0.5)

Sinusitis

7 (1.2)

3 (0.5)

Urinary tract infection

7 (1.2)

3 (0.5)

Back pain

22 (3.7)

7 (1.2)

Osteoarthritis

10 (1.7)

5 (0.8)

6 (1.0)

2 (0.3)

General disorders and administration site conditions Fatigue Infections and infestations

Musculoskeletal and connective tissue disorders

Respiratory, thoracic and mediastinal disorders Oropharyngeal pain

* Adverse reaction (with Relative Risk >1.5 for XARELTO versus placebo) occurred after the first dose and up to 2 days after the last dose of study drug.

Incidences are based on the number of patients, not the number of events.

Although a patient may have had 2 or more clinical adverse reactions, the patient is counted only once in a category. The same patient may appear in different categories.

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 6.

Table 6: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO­Treated Patients in RECORD 1­3 Studies System/Organ Class Adverse Reaction

11

XARELTO 10 mg (N = 4487) n (%)

Enoxaparin†

125 (2.8)

89 (2.0)

Pain in extremity

74 (1.7)

55 (1.2)

Muscle spasm

52 (1.2)

32 (0.7)

55 (1.2)

32 (0.7)

Pruritus

96 (2.1)

79 (1.8)

Blister

63 (1.4)

40 (0.9)

(N = 4524) n (%)

Injury, poisoning and procedural complications Wound secretion Musculoskeletal and connective tissue disorders

Nervous system disorders Syncope Skin and subcutaneous tissue disorders

*

†

Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication.

Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)

Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. 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.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

8.5

OVERDOSAGE: Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany © Janssen Pharmaceuticals, Inc. 2011 10185204 K02X121070BBM

8.5

XARELTO® (rivaroxaban) tablets

“Not tonight, honey, but here’s a voucher.”

“Can you recommend any wines for the middle class?”

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany © Janssen Pharmaceuticals, Inc. 2011 10185204 K02X121070BBM

“First, we discuss my percentage of any water you find, real or imagined!”

© The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment.

Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in full Prescribing Information].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3) in full Prescribing Information].

Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE: In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery: The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Hepatic Impairment: In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in full Prescribing Information].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE: Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

CME CE

Dermatology Clinic ■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 67

■ ADDITIONAL CME/CE: Pages 18, 63

Turn to page 17 for additional information on this month’s CME/CE courses.

CASE #1

Small brown spots on the lower shins ANTHONY TRACE, PHD, AND JULIA R. NUNLEY, MD

A white man, aged 55 years, presented with several discrete, welldemarcated, atrophic, hyperpigmented, nonblanching brown macules on the pretibial aspect of both lower legs. The spots appeared several years ago with no precedent trauma and are asymptomatic. Neither OTC topical 1% hydroquinone nor 1% hydrocortisone cream had improved the color or number of lesions. The man had been diagnosed with type 2 diabetes at age 35 years. Current medications included metformin (Fortamet, Glucophage, Glumetza, Riomet), exenatide (Byetta), and enalapril (Vasotec).

What is your diagnosis? Turn to page 54

CASE #2

Elevated iron levels and erosions on the hands ADAM REES, MD

A few months prior to presentation, a white man, aged 50 years, developed blisters and erosions on the back of his hands, forearms, and posterior neck. The erosions were mildly painful and healed with small scars. He had been spending most of his days outdoors managing a construction project. Medical history was significant for chronic hepatitis C. A complete metabolic panel, a complete blood count, and iron studies were significant for hemoglobin and iron levels at the upper limits of normal. The man’s urine appeared coral-red when illuminated with a Wood’s lamp.

What is your diagnosis? Turn to page 55 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 53

CME CE

CASE #1

Dermatology Clinic

Diabetic dermopathy

Diabetic dermopathy (DD), a significant cutaneous marker of diabetes mellitus (DM), can be diagnosed by close visual inspection and conf irmed by biopsy if necessary. DM affects more than 25 million Americans; in 2010, almost 2 million new cases were diagnosed. As the leading cause of blindness, kidney failure, and nontraumatic lowerlimb amputation, the direct and indirect costs of caring for patients with DM amounted to an estimated $174 billion dollars in 2007, highlighting the need for appropriate screening, early detection, and treatment of complications from this rapidly growing disease.1 Numerous cutaneous conditions are associated with DM. Acanthosis nigricans (AN)—the soft velvety hyperpigmention commonly found around the neck and in the axillae—is highly characteristic and has been closely correlated with insulin resistance for years. In rare instances, AN may instead be a manifestation of a paraneoplastic syndrome; sudden onset of AN after age 50 years should trigger a workup for

The presence of diabetic dermopathy is significant since it is a reliable marker for potentially serious vascular complications. malignancy, with adenocarcinoma of the stomach being the most common. Other cutaneous fi ndings associated with DM include diabetic scleredema, necrobiosis lipoidica diabeticorum, Kyrie disease, diabetic bullae, diabetic foot ulcers, periungual erythema, erysipelas-like erythema, rubeosis facei, pigmented purpura, and diabetic dermopathy.

Some of these changes are a result of the microangiopathic effects of DM. Although underappreciated, DD is probably the most common cutaneous manifestation of DM and considered by many to be pathognomonic for DM. The presence of DD is highly significant since it is a reliable marker for potentially serious vascular complications. First described in the 1960s, DD has gone by several names, including shin spots, pigmented pretibial patches, spotted-leg syndrome,

and brown spots of DM. The current nomenclature implies its association with the micro- and macrovascular complications of longstanding disease.2 The incidence of DD varies; the largest study of 457 patients found a rate of 13% among patients with DM.3 The longer the duration of DM, the higher the incidence of DD. DD is most common in patients older than age 50 years, with a male-to-female ratio of 2:1.4 Most important, the presence of DD directly correlates with the incidence of both large- and small-vessel complications of DM.2,4 One study showed that 52% of patients with one microvascular complication (retinopathy, nephropathy, or neuropathy) had DD; this rate rose to 81% in patients who had all three microvascular complications.5 Another study demonstrated coronary artery disease in 53% of patients with DD.3 Because of its association with vascular disease, DD may be a surrogate marker for the severity of diabetic complications.

The vascular association initially led researchers to hypothesize an ischemic vascular etiology for DD, but laser Doppler studies have revealed blood flow to be increased within these cutaneous lesions.6 Thus, the current understanding of the pathophysiology is not complete, but existing evidence suggests a combination of impaired or altered wound-healing following minor trauma possibly related to nerve degeneration.

The diagnosis of DD is based primarily on history and clinical findings; in rare instances, a biopsy may be necessary.

Histologically, DD shows atrophic rete ridges, thickened superficial blood vessels with hyalinization of arterioles in the papillary dermis, hemosiderin deposition from extravasated erythrocytes, and a mild perivascular lymphocytic infiltrate.7 The characteristic red-brown color is attributable to hemosiderin deposition. Although rarely necessary for a diagnosis of DD, a biopsy may be required to exclude the diagnosis of look-alike or comorbid conditions.

Diabetic dermopathy typically develops as multiple, discrete, well-demarcated, round or oblong, hyperpigmented, brown, nonblanching, atrophic macules asymmetrically distributed primarily on the pretibial aspect of both lower legs (lesions can also be found on the upper extremities, trunk, abdomen, and thighs).8,9 Early lesions may be mistaken for a fungal infection or stasis dermatitis. Although DD shares a similar distribution, stasis dermatitis will classically show hyperpigmentation with scale and lichenification, whereas DD is much more atrophic. Furthermore, DD is asymptomatic whereas stasis dermatitis and fungal infections are usually very pruritic. Traumatic scars and healed neurotic

54 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

excoriations may resemble DD morphologically, but the history will help differentiate these conditions as well.

Necrobiosis lipoidica diabeticorum (NLD) is another important diabetes-related cutaneous disease to distinguish from DD. Both conditions are typically asymptomatic and develop bilaterally on the shins, yet there are some distinct clinical, histologic, and biologic differences. Whereas DD tends to affect middle-aged men, NLD occurs more commonly in younger individuals, with women being affected three times more frequently then men. Although the majority of patients who develop NLD have diabetes, the disease also can occur in individuals without diabetes. DD occurs uniquely in patients with DM. Unlike DD, NLD is a granulomatous process that typically presents as an isolated, expanding yellow-brown-red waxy lesion with visible telangiectasias and an atrophic epidermal center, although multiple lesions may be present at times. As NLD lesions enlarge they may ulcerate, an uncommon event in DD. Less common diseases to consider include papulonecrotic tuberculids, pigmented purpuric lichenoid dermatitis of Gougerot-Blum, and Schamberg disease. These diseases can be differentiated clinically or histologically if necessary.

If DD is suspected clinically, the patient should be evaluated for diabetes as well as for the potential for DM-related vascular complications. Consider an ophthalmologic exam to assess for retinopathy; urinalysis, blood urea nitrogen, and creatinine to evaluate for nephropathy; cardiac exam as suggested by a thorough review of systems; and a full neurologic exam to evaluate for neuropathy.

The man in this case was educated about the nature of DD and its associated cardiovascular risks. Appointments with appropriate specialists were made. Unfortunately, there currently is no effective treatment available for the skin lesions. Lesional color may slowly fade with time, giving the lesions a more scarlike appearance, but stable persistence of lesions is more commonplace. The primary focus should be on controlling diabetes and preventing/managing the microangiopathic complications of the disease. This patient was advised to have close follow-up with his primary-care provider, to whom he should report any new symptoms.

Dr. Trace is a fourth-year medical student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is professor of dermatology.

References 1. Centers for Disease Control and Prevention. 2001 National Diabetes Fact Sheet. Available at www.cdc.gov/diabetes/pubs/factsheet11.htm.

2. Morgan AJ, Schwartz RA. Diabetic dermopathy: A subtle sign with grave implications. J Am Acad Dermatol. 2008;58:447-451.

3. Romano G, Moretti G, Di Benedetto A, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Res Clin Pract.

1998;39:101-106.

4. Shemer A, Bergman R, Linn S, et al. Diabetic dermopathy and internal complications in diabetes mellitus. Int J Dermatol. 1998;37:113-115.

5. Houck GM, Morgan MB. A reappraisal of the histologic findings of pigmented pretibial patches of diabetes mellitus. J Cutan Pathol. 2004;31:141-144.

6. Wigington G, Ngo B, Rendell M. Skin blood flow in diabetic dermopathy. Arch Dermatol. 2004;140:1248-1250. Available at archderm.jamanetwork.com/article.aspx?articleid=480832.

7. McCash S, Emanuel PO. Defining diabetic dermopathy. J Dermatol.

2011;38:988-992.

8. Sehgal VN, Srivastava G, Aggarwal AK, et al. Noninsulin-dependent, type II diabetes mellitus–related dermatoses: part II. Skinmed. 2011;9:302-308.

9. Timshina DK, Thappa DM, Agrawal A. A clinical study of dermatoses in diabetes to establish its markers. Indian J Dermatol. 2012;57:20-25.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3312650/.

All electronic documents accessed December 15, 2012.

CASE #2

Porphyria cutanea tarda

The porphyrias are metabolic diseases caused by deficiencies in enzymes involved in the heme biosynthetic pathway.

The enzymatic deficiencies lead to accumulation of precursor proteins called porphyrins.

There are eight porphyrias, which are categorized as acute or nonacute. The acute porphyrias are characterized by potentially life-threatening neurologic attacks that do not occur in the nonacute porphyrias.

The acute porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and ALAD-deficiency porphyria. The nonacute porphyrias include porphyria cutanea tarda (PCT), erythropoietic protoporphyria, congenital erythropoietic porphyria, and hepatoerythropoietic porphyria. With the exception of acquired PCT, the porphyrias are inherited diseases.1,2 The man in this case was diagnosed with PCT, the most common porphyria, associated with an average age of onset of 45 years. PCT results from decreased activity of

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CME CE

Dermatology Clinic

the enzyme uroporphyrinogen decarboxylase (UROD).

PCT can be inherited or acquired, with the acquired form being significantly more common. The decreased activity of UROD leads to the accumulation of uroporphyrins in the skin and in the urine. Uroporphyrin absorbs light intensely in the Soret band (400-410 nm, UVA wavelength). When this energy is absorbed, the porphyrins enter into an excited state, leading to reactive oxygen species that cause tissue damage. This action is manifested clinically as increased photosensitivity, skin fragility, erosions, blisters, scarring, and milia in sun-exposed skin (particularly on the dorsal hands, face, and posterior neck). Other cutaneous manifestations include hypertrichosis (most frequently seen on the temples and cheeks) and scleroderma-like skin changes.1,2

The definitive test for porphyria cutanea tarda is the demonstration of elevated urinary porphyrin levels.

Because of the excessive accumulation of porphyrins, the urine may appear reddish after exposure to natural light and may have a bright-pink fluorescence when exposed to UVA light (e.g., a Wood’s lamp). However, these urinary color changes are not sensitive or specific.1,2 Liver disease is common in individuals with PCT. Alcoholism, estrogen therapy, hepatitis, HIV, and hereditary hemochromatosis are among the factors contributing to hepatic dysfunction, which results in excess accumulation of iron stores in the liver. The excess iron leads to oxidation products that inhibit UROD. A 75% reduction in the activity of hepatic UROD as compared with normal is required for clinical disease expression.3 In the United States, 94% of PCT patients are infected with hepatitis C. Additionally, 20% of patients have hereditary hemochromatosis. Diabetes mellitus is associated with PCT in 15% to 20% of patients.1,2 PCT can be suspected on the clinical presentation, but the definitive test is the demonstration of elevated urinary porphyrin levels in a 24-hour urine collection, with a greater than 3:1 ratio of uroporphyrin to coproporphyrin. Skin biopsy of a blister demonstrates a subepidermal split with hyalinized blood vessel walls in the mid and upper dermis.1,2 The differential for PCT includes pseudoporphyria, epidermolysis bullosa acquisita, polymorphous light eruption, and hydroa vacciniforme. It is important to recognize that

porphyrin studies of urine, stool, and other body fluids will be normal in these diseases. Also included in the differential are the other porphyrias that present with blistering (congenital erythropoietic porphyria, hepatoerythropoietic porphyria, variegate porphyria, and hereditary coproporphyria).1,2 In pseudoporphyria, individuals develop blistering and skin fragility similar to that of PCT. However, porphyrin levels are normal. Hypertrichosis and sclerodermoid changes are not present. Pseudoporphyria is most commonly caused by the nonsteroidal anti-infl ammatory drug naproxen.

Ibuprofen is a safe alternative. Pseudoporphyria may occur with use of various other medications, in association with hemodialysis, and with tanning-bed use.1,2 Epidermolysis bullosa acquisita is an acquired blistering disease in which individuals develop autoantibodies to type VII collagen, which is found at the dermal-epidermal junction. Patients may develop blistering at areas of pressure or friction. Porphyrin studies are normal in cases of epidermolysis bullosa acquisita.4 Polymorphous light eruption is the most common photosensitive skin disease. Lesions present on sun-exposed areas and may be papulovesicular, eczematous, or plaquelike. Patients frequently complain of itching following sun exposure, with subsequent development of skin lesions 24 to 96 hours later. Porphyrin studies are normal.5 Hydroa vacciniforme is a rare photosensitive skin disease of childhood. Within six hours of sun exposure, a stinging sensation develops, which progresses to vesicles over the next 24 hours. Lesions heal with pockmark-like scars. The ears, cheeks, and backs of the arms and hands are the most commonly affected areas. Porphyrin studies are normal.5 Congenital erythropoietic protoporphyria is a rare, severe, mutilating autosomal recessive porphyria caused by deficiency of the enzyme uroporphyrinogen III synthase. This condition presents at birth with severe painful photosensitivity. Patients subsequently develop blistering that leads to mutilating scarring on sun-exposed areas. Porphyrin deposition causes the teeth appear red in individuals with erythropoietic protoporphyria. Increased levels of uroporphyrin and coproporphyrin are found in the patient’s urine, stool, and red blood cells, which have a red fluorescence.1,2 Hepatoerythropoietic porphyria is a rare autosomalrecessive porphyria attributable to a defect in UROD, which is the same enzyme impaired in PCT. The biochemical studies are similar to PCT, but the clinical presentation resembles congenital erythropoietic protoporphyria.1,2 Variegate porphyria, most common in South Africa, is an autosomal dominant disorder caused by decreased activity

56 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

Dr. Rees is a first-year dermatology resident at Baylor College of Medicine in Houston.

“We figured it out—you listen to me but when you get caught you listen to him. ”

“He’s got your trudge.”

References: 1. Frank J, Poblete-Gutierrez R. Porphyria. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008: 641-651.

2. James WD, Berger TG, Elston DM. Errors in metabolism. In: James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa: Elsevier; 2011:511–515.

3. Medscape Reference. Porphyria cutanea tarda. Available at emedicine. medscape.com/article/1103643-overview.

4. Borradori L, Bernard P. Pemphigoid Group. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:463-476.

5. James WD, Berger TG, Elston DM. Dermatoses resulting from physical factors. In: James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa: Elsevier; 2011:34-35.

All electronic documents accessed December 15, 2012.

“O.K., I’m going to demonstrate the proper way to lie to me about flossing.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 57

© The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

of protoporphyrinogen oxidase. Patients may have skin lesions similar to those seen in PCT and will suffer from acute neurologic and GI attacks. In contrast to PCT, urinary coproporphyrins are increased over uroporphyrins.1,2 Hereditary coproporphyria is a rare autosomal dominant porphyria that results from a deficiency of coproporphyrinogen oxidase. Patients present with photosensitivity and acute neurologic and GI attacks. The level of fecal coproporphyrin is increased.1,2 The treatment of choice for PCT is therapeutic phlebotomy, which creates iatrogenic iron-deficiency anemia to lower hepatic iron stores. This procedure consists of removing 500 mL of blood at two-week intervals until the hemoglobin level is between 10 g/dL and 11 g/dL. This process may take several months, and the patient’s cutaneous manifestations will gradually resolve. An alternative to phlebotomy is lowdose antimalarial therapy. After either treatment, remission may last many years. If the patient relapses, treatment is repeated. Removal of such precipitating factors as medications (particularly estrogens) and alcohol is also important.

Finally, sun protection in the form of physical blockers (e.g., clothing, hats, and such inorganic sunscreens as zinc oxide) is emphasized.1,2 In this case, the patient’s urinary uroporphyrin level was significantly elevated over the coproporphyrin level, thus confirming the suspected diagnosis of PCT. He underwent five months of therapeutic phlebotomy and ultimately achieved a sustained remission. ■

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Iridology © PHOTO RESEARCHERS, INC. / RALPH C. EAGLE, JR. / SCIENCE SOURCE

Often referred to as “the windows to the soul,” the eyes express joy, sadness, and fear. The iris is the most obvious feature of the external eye, with its color being a major factor in ethnic and familial identity. In fact, eye color has been the topic of many researchers’ works, most notably the geneticist Gregor Mendel. In recent years, naturopathic practitioners have exhibited renewed interest in a disease-recognition method that is based on detailing characteristics of the human iris. Iridology is the study of carefully mapped sections of the iris and the assigned organ systems represented by those areas.1

Background Iridology, also known as iridodiagnosis, is an alternativemedicine technique that uses the colors, patterns, and various other properties of the iris to assess an individual’s general health.2 The technique of iridology is based on the belief that each organ in the human body has a corresponding region in the iris. Thus, the premise is that organ functioning can be examined simply by inspecting the iris.

Iridologists generally use cameras, flashlights, and microscopes to examine the patient’s iris in order to detect tissue change, stromal irregularities, and pigment patterns. The results are then compared with an iris chart, which helps in correlating the various parts of the human body with different zones in the iris. A typical iris chart divides the iris into approximately 90 zones, each corresponding to a different part of the human body. Iridologists believe that the details reflected by the iris are generally the changes in the tissues of the corresponding body organelle.2

According to practitioners of this therapy, iridology is not meant to diagnose illness, but rather to detect impaired organ functions attributable to environmental toxins, poor nutrition, and fatigue. For iridologists, color variations in the iris (sparkles and rings) carry specific significance and can even indicate whether a suspected condition is acute/inflammatory, chronic/inflammatory, or allergic.2 Some iridologists further divide organ-system dysfunction by iris color. They believe that lymphatic-related disease is associated with a blue or blue-gray iris and that people with this eye color are prone to atopic conditions; hematogenous-related pathology is linked to brown-eyed individuals who are more prone to anemia and endocrine disorders; biliary disease is associated with both blue and brown irises and is indicative of gastric deficiencies.3 Iridology was used as early as the 17th century in Europe, but the practice gained notice in the United States only in the latter half of the 20th century.1 Despite the long history of iridology, solid scientific data supporting its utility are scarce.

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Continues on page 62

ALTERNATIVE MEDS UPDATE Science

Safety, interactions

A correlation between hypertention and iris type has been noted.

Because of the noninterventional nature of this practice, there are no contraindications for use. In the United States, there are many organizations for training and education in iridology, but the practice is not regulated by the health-care industry.

Iridology is Summary not meant to is based on intriguing possibilities, but, diagose illness, Iridology to date, evidence-based studies do not support its but rather to safety and utility. Some researchers are considering detect impaired improving the accuracy of the practice by using organ functions computer-aided diagnostics. For now, however, the study of the iris for systemic disease indications is attributable to far from being a viable clinical tool. ■ environmental References toxins, poor 1.Salles LF, Silva MJ. Iridology: a systematic review. Rev Esc nutrition, and Enferm USP. 2008;42:596-600. fatigue.

2. Buchanan T. An investigation of the relationship between

62 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

anatomical features in the iris and systematic disease with reference to iridology. Comp Ther Med. 2006;4:98-102.

3. Iridology page. Natural Standard website. Available at www.naturalstandard.com/index.asp.

4.Yoo CS, Hwang WJ, Hong SH, et al. Relationship between iris constitution analysis and TNF-alpha gene polymorphism in hypertensives. Am J Chin Med. 2007;35:621-629.

5. Um JY, Hwang CY, Hwang WJ, et al. Association between iris constitution and apolipoprotein E gene polymorphism in hypertensives. J Altern Complement Med. 2004;10:1101-1105.

6. Herber S, Rehbein M, Tepas T, et al. Looking for colorectal cancer in the patients iris? Ophthalmologe. 2008;105:570-574.

7. Münstedt K, El Safadi S, Brück F, et al. Can iridology detect susceptibility to cancer? A prospective case-controlled study.

J Altern Complement Med. 2005;11:515-519.

All electronic documents were accessed on December 15, 2012.

© THINKSTOCK

Out of the four of conditions most commonly assessed by practitioners of iridology (hypertension, cancer, gallbladder disease, and kidney disease), only hypertension earned a strengthof-evidence grade of “C,” while the remaining three conditions ended with very weak showings of “D” levels.3 In one study, researchers explored the overlapping of tumor necrosis factor-alpha (TNF-alpha), hypertension, and specific variations of iris constitution.4 Eighty-seven Korean patients with known hypertension were compared with 79 Korean participants with no known BP concerns.

Individuals were evaluated on iris characteristics, BP, and the presence or absence of the TNF-alpha genotype.4 The study results did not show a statistically significant difference in the genotype and the presence of hypertension, but there was a definite elevation in the hypertensive patients with the iris characteristic denoting cardio-renal connective-tissue weakness.

In another study of the same patient population, researchers sought to find a correlation between iris characteristics and the presence or absence of apolipoprotein-E (apoE).5 There is a wellestablished relationship between this genotype and vascular diseases, including hypertension.5 Study participants were examined by iris pattern and then tested for the apoE genotype. There was a significant correlation between iris type and hypertension, and an increased percentage of apoE presence in those same hypertensive individuals.

Neither of these studies was large enough to support the practice of iridology. Further trials with larger study populations are needed.

Studies on the practice have also typically focused on the potential utility of iridology as a screening tool for cancer. One trial examined age- and gender-matched participants for the possibility of colorectal cancer.6 Twenty-nine patients with known diagnoses of this disease were matched with 29 healthy patients.The researchers presented photographic slides of each participant’s eyes to two trained iridology practitioners. At the end of the study, the presence of cancer was

detected in only 50% to 53% of patients, proving no better than random chance.6 In another trial exploring iridology and cancer detection, 68 patients with known cancer and 42 healthy patients were examined by a single, experienced iridologist.With no other information than the visualization of the iris, the practitioner correctly detected only three cases of cancer.7

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations.

■ COMPLETE THE POSTTEST: Page 67

■ ADDITIONAL CME/CE: Pages 18, 53

Turn to page 17 for additional information on this month’s CME/CE courses.

Ulcerations in the oral cavity KERRI ROBBINS, MD, AND DAMJAN JUTRIC

CASE #1

CASE #2

An Asian woman, aged 25 years, has had recurrent oral ulcerations for three years. On average, the oral ulcerations appeared every two months and healed spontaneously within two weeks. Several 2-mm to 6-mm shallow ulcerations with a white pseudomembrane and surrounding erythematous halo were appreciated on her labial mucosa, buccal mucosa, and soft palate. The woman complained of similar lesions in the anogenital region and periorbital pain with photophobia. A review of systems was otherwise negative.

A man, aged 34 years, presented with painful ulcerations on his labial mucosa, soft palate, and lateral tongue of two weeks' duration. A history of recurrent painful ulcerations that would usually heal within two to three weeks was noted. The man had received no previous treatment and felt that the ulcerations were beginning to heal spontaneously. A review of systems was otherwise negative.

Large ulcerations with a white pseudomembrane and minimal surrounding erythema were noted on his left lateral tongue, labial mucosa, and soft palate.

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CME CE

CASE #1

Dermatologic Look-Alikes

Behçet’s disease

In 1924, a Turkish dermatologist named Huluis Behçet treated two individuals for loss of vision, oral aphthae, and genital aphthae.1 In 1931, a Greek physician named Bened ict Ad a m a nt iades reported a patient with iritis, oral and genital ulcers, phlebitis, and arthritis and ever since, the disorder has been known as Behçet’s disease.

Behçet’s disease is a rare disorder with approximately 0.12 cases occurring per 100,000 individuals in the United States and Europe. Internationally, the disease is most prominent along the ancient Silk Road, which encompasses the Middle East, Turkey, Saudi Arabia, Iran, China, and Japan. In these regions, the disease affects 1 out of every 1,000 individuals and is most prevalent among young men between the ages of 25 and 30 years.2,3 The precise pathogenesis of Behçet’s disease remains unknown. Evidence suggests that it is an autoimmune systemic vasculitis that may be triggered by immunologic or infectious agents. A strong association has been linked to the histocompatability antigen B-51.

Oral lesions occur most commonly in the oropharynx and soft palate and can last anywhere from one to three weeks.

The manifestations of Behçet’s disease are often intermittent. Patients complain of clinically evident exacerbations and remissions with an unpredictable frequency and duration. Approximately 99% of patients will develop oral aphthae, and this may be the presenting sign in 25% to 75% of cases. Oral lesions occur most commonly in the oropharynx and soft palate and can last anywhere from one to three weeks, with spontaneous resolution and no scarring.4 The aphthae usually occur in groups of five or more, vary in size (no larger than 6 mm in diameter), and are surrounded by diffuse erythema. Genital ulcerations are clinically similar to those in the oral cavity and are most commonly found on the perianal area, penis, vagina, vulva, and scrotum. Ocular involvement may take the

form of posterior uveitis, corneal ulceration, papilledema, and/or arteritis. Other signs of Behçet’s disease include erythema nodosum-like or pustular skin lesions, arthritis, renal disease, thrombophlebitis, central nervous system involvement, and GI symptoms.

Clinicians may perform a pathergy test by obliquely inserting a sterile 20-guage needle into the skin and reading the test one to two days later.1 A positive test is indicated by a pustule that will appear at the site within 24 hours. If the test is negative, repeat it at two to five points before accepting the results as negative. The subsequent skin hyper-reactivity, or pathergy, is a feature of Behçet’s disease that occurs in 40% to 88% of patients. However, this test may also be positive in such other diseases as pyoderma gangrenosum, acute febrile neutrophilic dermatosis, and bowel-associated dermatosis-arthritis syndrome.

Histologically, the oral ulcerations are characterized by a central diffuse neutrophilic infi ltrate with necrosis of the epithelium. The periphery of the lesion typically shows a lymphocyte-predominant infiltrate both in an extravascular and perivascular distribution with variable lymphocytic exocytosis. Genital aphthae have a similar appearance.

Cutaneous lesions show a range of cutaneous vasculopathy that includes a mononuclear cell vasculitis with variable mural and luminal fibrin deposition; a paucicellular thrombogenic vasculopathy; and a neutrophilic vascular reaction, which involves capillaries and veins of all calibers.

The diagnosis of Behçet’s disease may be difficult to make, as there are no pathognomonic diagnostic tests available. The diagnosis is based on the presence of oral aphthae that occur at least three times during a one-year period. The individual must also have at least two of the following criteria: retinal vasculitis, anterior uveitis, and/or posterior uveitis; recurrent genital aphthae; erythema nodosum-like or pustular skin lesions; and a positive pathergy test.5 Aphthous stomatitis, herpes simplex virus, pemphigus, erythema multiforme, Stevens-Johnson syndrome, pyoderma gangrenosum, and erythema nodosum are often considered in the differential diagnosis.

The ulcerations of Behçet’s disease usually heal spontaneously. When ulcers are present, advise the patient to avoid vigorous tooth-brushing and to use mild mouthwashes and toothpastes. Topical anesthetics may help to alleviate the associated pain. Colchicine (Colcrys), dapsone, and thalidomide (Thalomid) have all been used for the prevention of mucocutaneous lesions. Such other systemic treatments as methotrexate (Rheumatrex, Trexall), corticosteroids, azathioprine (Azasan, Imuran), chlorambucil (Leukeran),

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cyclosporine (Gengraf, Neoral, Sandimmune), interferon-␣, tumor necrosis factor antagonists, and cyclophosphamide (Cytoxan) should be reserved for severe refractory cases.

The prognosis depends upon the amount of systemic involvement, but patients should expect to have intermittent flares of the disease. Serious complications may include blindness, neurologic impairment, and vascular thrombosis.

The woman in this case was referred to ophthalmology and treated with thalidomide to prevent recurrence of the mucocutaneous disease. For pain control, she was given a mixture of equal parts lidocaine, aluminum and magnesium hydroxide (Maalox), and diphenhydramine. The mixture was held in the mouth for five minutes and then spit out, three times a day.

CASE #2

Recurrent aphthous stomatitis

Oral aphthae are also referred to as recurrent aphthous stomatitis (RAS), or more simply, canker sores. Aphthous is the ancient Greek word for ulcer.

Documentation of the history of RAS is essentially nonexistent, possibly because it is one of the most common oral mucosal pathologies and may have been considered a normal variant. RAS affects all races and has been documented to occur in 10% to 50% of the population. It is slightly more prevalent in females than in males, and for the most part, lesions appear during the adolescent years and recur throughout the individual’s life span.

The etiology remains evasive, but some studies have shown RAS to be a multifactorial disorder that is induced by a host of factors. A genetic predisposition has been demonstrated by the fact that children from parents with RAS have a 90% chance of also being affected. Triggering agents include trauma, hormonal fluctuations, psychological stress, tobacco products, food hypersensitivities, and HIV infection and other infectious agents. Nutritional deficiencies in iron, folate, and vitamin B12 can trigger an episode as well. Immune-system dysfunction is thought to result in mucosal destruction due to a T-cell-mediated immunologic reaction.6 The three categories of simple aphthous ulcers are minor, major, and herpetiform. Minor aphthae, also known as Mikulicz’s aphthae, are the most common type and comprise 80% of

cases. The ulcers are round to ovoid, shallow, and 3 mm to 10 mm in diameter. The lesions are covered by a creamy white pseudomembrane and surrounded by an erythematous halo.

Minor aphthae are most commonly found on nonkeratinized oral mucosa, including the buccal and labial mucosa, floor of the mouth, ventral tongue, oropharyngeal mucosa, and soft palate. If keratinized mucosa is affected, it is usually attributable to an extension of the adjacent nonkeratinized tissue.

Lesions tend to heal without scarring in one to two weeks.

Although most patients experience infrequent recurrences, others may suffer from nearly continuous lesions.

The major form of RAS is deeper and larger, ranging from 1 cm to 3 cm in diameter. Lesions usually occur in groups on the labial mucosa, soft palate, and tonsillar fauces.

Patients may experience fever, malaise, and extreme pain.

Due to the larger size of major aphthae, scarring may occur, and lesions usually take two to six weeks to heal.

As the name suggests, herpetiform aphthae look similar to a primary herpes infection. The lesions are small in size, ranging from 1 mm to 3 mm in diameter, and usually occur in groups of up to 100 or more. An episode can last from seven to 10 days. These painful ulcers are typically confined to the nonkeratinized tissue and are recurrent, which are features that may help to distinguish them from a primary herpes infection.

Histologic features of RAS are rather nonspecific. Early lesions may demonstrate a central ulcerated region covered by a fibrinopurulent membrane with a neutrophilic vesselbased submucosal infi ltrate.

History, physical examination, and long-term follow-up documenting the recurrence course in the absence of other symptoms are the best diagnostic tools. No laboratory test exists for a definitive diagnosis of RAS. Beçhet’s disease, cancers of the oral mucosa, cicatricial pemphigoid, pemphigus, contact stomatitis, erythema multiforme, StevensJohnson syndrome, HIV, infl ammatory bowel disease, hand-foot-and-mouth disease, herpes simplex, syphilis, candidiasis, lichen planus, and lupus erythematosus are all included in the differential diagnosis.

Treatment may depend on whether the lesions are simple or complex. Simple aphthosis is described as having fewer than three lesions, which tend to heal within one to two weeks and infrequently recur. Complex aphthosis is defined as having three or more lesions that are fairly constant due to the high recurrence rate and longer healing time. For simple and complex aphthosis, the primary goals of treatment should be pain management, prevention of recurrence, promotion of healing, and proper nutrition.7 At the fi rst

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signs of an outbreak, the patient should apply a thin fi lm of a superpotent topical corticosteroid gel several times daily to reduce the healing time and associated pain. There are also multiple topical analgesics that may help to temporarily alleviate the associated pain. Oral colchicine, dapsone, or thalidomide may be required for individuals with complex aphthosis. Correction of folate, iron, and vitamin B12 levels are warranted if found to be abnormal. Some studies have even documented improvement with cyanocobalamin when the vitamin B12 levels are normal.8 Most people are minimally inconvenienced by RAS because attacks are usually infrequent and heal spontaneously. When present, however, the lesions are painful, and speech and mastication may prove difficult. Luckily, the lesions tend to occur less frequently with age.

The man in this case was diagnosed with a major aphthous ulcer. Since it was healing at the time of presentation, no topical corticosteroid was given. For pain control, he was given a mixture of equal parts lidocaine, aluminum and magnesium hydroxide, and diphenhydramine. The mixture was held in the mouth for five minutes and then spit out, three times a day. ■

“Good afternoon, Ted, I’m your online presence.”

Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. Mr. Jutric is a second-year dental student at The University of Texas School of Dentistry, also in Houston.

References 1. Helm TN, Camisa C, Allen C, Lowder C. Clinical features of Behçet's disease. Report of four cases. Oral Surg Oral Med Oral Pathol. 1991;72:30-34.

Behçet's disease in the north of Israel. Clin Rheumatol. 2007;26:555-560.

3. Bardak Y. Epidemiologic and clinical features of Behçet’s disease. J Rheumatol.

2001;28:455-456. Available at www.jrheum.org/content/28/2/455.2.long.

4. Al-Otaibi LM, Porter SR, Poate TW. Behçet’s disease: a review. J Dent Res. 2005;84:209-222.

5. International Study Group for Behçet’s Disease: Criteria for diagnosis of Behçet’s disease, Lancet. 1990;335:1078-1080.

6. Rogers RS 3rd. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg. 1997;16:278-283.

7. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2005;49:31-47.

8. Gulcan E, Toker S, Hatipog˘lu H, et al. Cyanocobalamin may be beneficial in the treatment of recurrent aphthous ulcers even when vitamin B12 levels are normal. Am J Med Sci. 2008;336:379-382.

All electronic documents accessed December 15, 2012.

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2. Krause I, Yankevich A, Fraser A, et al. Prevalence and clinical aspects of

CE

POSTTEST Expiration date: January 2013

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 18

page 53

page 63

New paradigms in managing chronic kidney disease

Case #1: Diabetic dermopathy

Case #1: Behçet’s disease

1. What malignancy is associated with acanthosis nigricans? a. Hepatocellular carcinoma b. Adenocarcinoma of the stomach c. Pancreatic cancer d. Non-Hodgkin lymphoma

1. What is the presenting sign in 25% to 75% of cases of Behçet’s disease? a. Oral aphthae b. Perineal ulcerations c. Posterior uveitis d. Pustular skin lesions

2. What characteristic of necrobiosis lipoidica diabeticorum distinguishes it from diabetic dermopathy? a. Tends to affect middle-aged men b. Occurs uniquely in patients with diabetes mellitus c. Develops as well-demarcated, brown macules d. Lesions may ulcerate as they enlarge

2. What medication is used to prevent mucocutaneous lesions of Behçet’s disease? a. Chlorambucil (Leukeran) b. Cyclophosphamide (Cytoxan) c. Colchicine (Colcrys) d. Acyclovir (Zovirax)

1. What is a risk factor associated with chronic kidney disease (CKD)? a. Age older than 60 years b. Type 2 diabetes mellitus c. History of acute kidney injury d. All of the above 2. What method is used to determine kidney function in the outpatient setting? a. Albumin/creatinine ratio b. Estimated glomerular filtration rate c. Serum creatinine concentration d. Creatinine clearance 3. Current guidelines recommend what BP target to treat all types of kidney disease and to reduce cardiovascular risk? a. <140/90 mm Hg b. <135/85 mm Hg c. <130/80 mm Hg d. <125/75 mm Hg 4. What is first-line therapy if a CKD patient does not have diabetes or proteinuria? a. Thiazide diuretic b. ACE inhibitor c. Calcium channel blocker d. Angiotensin receptor blocker

TO TAKE THE POSTTEST please go to CliniAd.com/UJrKqf

Case #2: Porphyria cutanea tarda 3. Porphyria cutanea tarda (PCT) is most commonly caused by which nonsteroidal anti-inflammatory drug? a. Naproxen b. Celecoxib (Celebrex) c. Ibuprofen d. Sulindac (Clinoril) 4. What is the treatment of choice for PCT? a. Chelation therapy b. Dietary modification c. Therapeutic phlebotomy d. Low-dose antimalarial therapy

Case #2: Recurrent aphthous stomatitis 3. What is a triggering agent for recurrent aphthous stomatitis? a. Tobacco products b. Psychological stress c. Hormonal fluctuations d. All of the above 4. What are characteristics of the most common simple aphthous ulcer? a. Usually found in groups on the labial mucosa, soft palate, and tonsils b. Lesions are round to ovoid, covered by a creamy white pseudomembrane c. Usually occur in groups of >100 d. Lesions vary in size and are surrounded by diffuse erythema

TO TAKE THE POSTTEST please go to CliniAd.com/UJrKqf

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 67

CME

POSTTEST Expiration date: January 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of January 2013. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 18

page 53

page 63

New paradigms in managing chronic kidney disease

Case #1: Diabetic dermopathy

Case #1: Behçet’s disease

1. What malignancy is associated with acanthosis nigricans? a. Hepatocellular carcinoma b. Adenocarcinoma of the stomach c. Pancreatic cancer d. Non-Hodgkin lymphoma

1. What is the presenting sign in 25% to 75% of cases of Behçet’s disease? a. Oral aphthae b. Perineal ulcerations c. Posterior uveitis d. Pustular skin lesions

2. What characteristic of necrobiosis lipoidica diabeticorum distinguishes it from diabetic dermopathy? a. Tends to affect middle-aged men b. Occurs uniquely in patients with diabetes mellitus c. Develops as well-demarcated, brown macules d. Lesions may ulcerate as they enlarge

2. What medication is used to prevent mucocutaneous lesions of Behçet’s disease? a. Chlorambucil (Leukeran) b. Cyclophosphamide (Cytoxan) c. Colchicine (Colcrys) d. Acyclovir (Zovirax)

1. What is a risk factor associated with chronic kidney disease (CKD)? a. Age older than 60 years b. Type 2 diabetes mellitus c. History of acute kidney injury d. All of the above 2. What method is used to determine kidney function in the outpatient setting? a. Albumin/creatinine ratio b. Estimated glomerular filtration rate c. Serum creatinine concentration d. Creatinine clearance 3. Current guidelines recommend what BP target to treat all types of kidney disease and to reduce cardiovascular risk? a. <140/90 mm Hg b. <135/85 mm Hg c. <130/80 mm Hg d. <125/75 mm Hg 4. What is first-line therapy if a CKD patient does not have diabetes or proteinuria? a. Thiazide diuretic b. ACE inhibitor c. Calcium channel blocker d. Angiotensin receptor blocker

TO TAKE THE POSTTEST please go to CliniAd.com/UJrKqf

Case #2: Porphyria cutanea tarda 3. Porphyria cutanea tarda (PCT) is most commonly caused by which nonsteroidal anti-inflammatory drug? a. Naproxen b. Celecoxib (Celebrex) c. Ibuprofen d. Sulindac (Clinoril) 4. What is the treatment of choice for PCT? a. Chelation therapy b. Dietary modification c. Therapeutic phlebotomy d. Low-dose antimalarial therapy

Case #2: Recurrent aphthous stomatitis 3. What is a triggering agent for recurrent aphthous stomatitis? a. Tobacco products b. Psychological stress c. Hormonal fluctuations d. All of the above 4. What are characteristics of the most common simple aphthous ulcer? a. Usually found in groups on the labial mucosa, soft palate, and tonsils b. Lesions are round to ovoid, covered by a creamy white pseudomembrane c. Usually occur in groups of >100 d. Lesions vary in size and are surrounded by diffuse erythema

TO TAKE THE POSTTEST please go to CliniAd.com/ZY5cHo

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 67

CLASSIFIEDS

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

PA/NP WANTED

PA/NP WANTED

North Country Emergency Medical Consultant’s PC is recruiting a Physician Assistant or Nurse Practitioner to join our current group of 9 physicians, 5 physician assistants and 2 nurse practitioners.

NC-EMC, P.C. contracts with Samaritan Medical Center to staff the ED which has an annual volume of 53,000. The PAs work closely with the MDs and staff the ED in both the Urgent Care and Rapid Clinical Evaluation area.

SMC recently opened a new ED 11/10 which has in-ED radiology, CT scan, ED Ultrasound and point of care testing.

The compensation package includes $120,000.00 salary, plus benefits for approximately 144 hours/month. A RVU-based productivity bonus is awarded quarterly.

Upstate New York is an outdoor enthusiast’s paradise with 4-season recreation in the world famous Thousand Islands, Lake Ontario region and the Adirondack Mountains. Montreal, Toronto, Finger Lakes region and NYC are a short drive away. Syracuse International Airport is within a one hour drive.

If this opportunity interests you AND you have a minimum of 3 years Emergency Medicine/Urgent Care experience, please send your CV and cover letter to: Dr. Maja Lundborg-Gray President, North Country Emergency Medical Consultants, P.C. Emergency Department 830 Washington Street Watertown, New York 13601 Fax: 315-785-4314 Email: MLGRAY@shsny.com (preferred route)

PA WANTED

PA WANTED

NP WANTED

Our practice is seeking a highly motivated self-starter to join our practice.

This is a Monday - Friday position with weekend coverage every 5th weekend. The candidate will work very closely with our physicians and other mid-level providers. You will be required to do patient rounds at the hospital, office hours, stress testing, lipid clinic and CHF clinic. There is no call for this position. We offer a competitive salary and benefit package including health, dental, CME, Life, LTD and Profit Sharing/401K. Forward resume to: Pramsey@saracard.com or fax: 518-581-9759

Mountain Medical Services URGENT CARE is looking to hire Practitioners to work in a fast paced medical facility in upstate New York.

• Positions in primary care or urgent care settings • Four great locations - Lake Placid, Saranac Lake, Massena & Malone • Full-time, Part-time & Per Diem Positions • Salay dependent on experience • Prefer 1 - 2 years experience Please contact Lindsay LaPointe for more information.

To apply please email: llapointe@mountainmedical.net

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For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

PA WANTED

CLASSIFIEDS MEDICAL EDUCATION

Nocturnist Physician Assistant (PA) The Mount Sinai School of Medicine The Department of Medicine of the Mount Sinai School of Medicine in NYC is seeking qualified full-time, nocturnist Physician Assistant (PA) to provide care for hospitalized patients on the inpatient Medical Service. Responsibilities include taking histories, performing physical exams, ordering and interpreting laboratory tests and x-rays, and treating common inpatient conditions. PAs will collaborate closely with hospitalist physicians and may work with medical housestaff. Candidates must be graduates of an ARC-PA accredited program and certified by the National Commission on Certification of Physician Assistants with state licensure.

Interested applicants should submit their CV by email to: natasha.lawrence@mountsinai.org or call: (212) 241-1653 for more information.

Mount Sinai is an equal opportunity/affirmative action employer.

MEDICAL EDUCATION

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2013 69

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CLASSIFIEDS

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

MEDICAL EDUCATION

Introducing: My Peripheral Brain My Peripheral Brain is a medical information software program similar to Epocrates and other popular data retrieval programs with the following major advantages:

• Cost: Introductory price: $125. The Peripheral Brain has no annual renewal fee, nor an expiration date.

Purchase it once and it’s yours forever.

• Operates on more than 1 device: Data entry/retrieval software program can be downloaded on up to 3 computers (Windows, Mac, or any combination of the two). In addition, Android and Apple apps (included) allow data retrieval mode to be installed on up to 2 smartphones or their corresponding tablets.

• Data entry: Easily add your own information into the brain: allows an infinite number of edits, topics, and new brains. Excellent way to save your clinical pearls.

• Free updates: Over 670 topics and growing. New medical information added frequently.

• Cuts to the chase: Most relevant clinical information listed first: no more skimming through superfluous information.

• Customer able to create limitless medical and non-medical Brains: Create new brains of your own choosing on any topic inside and outside of medicine.

• For more information and to purchase, please visit our website at: http://myperipheralbrain.com

MEDICAL EDUCATION

70 THE CLINICAL ADVISOR • JANUARY 2013 • www.ClinicalAdvisor.com

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