February 2013 Clinical Advisor

THE CLINICAL ADVISOR •FEBRUARY 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

■ Updated CKD guideline ■ “Sit test” predicts mortality ■ Restrict kids’ milk intake ADVISOR FORUM

■ Scoliosis in a young girl ■ Diagnosing fatty liver ■ Vitamin D and psoriasis LEGAL ADVISOR

A man’s family disputes his “do not resuscitate” order

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■ Dermatology Clinic

ULCERATION ON AN INFANT’S SCALP PAGE 55

■ Dermatologic Look-Alikes VOLUME 16, NUMBER 2

PAINFUL AXILLARY EROSIONS PAGE 75 Take the Scavenger Hunt Challenge and Win an iPad! Turn to p. 23 for details

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SIMPLE AND COMPLICATED

UTIS IN WOMEN Uncomplicated UTIs are most often caused by Escherichia coli bacteria (pink).

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 • FEBRUARY 2013 3

CONTENTS FEBRUARY 2013

NEWS AND COMMENT

■ Hyperpigmented patches spread from

a girl’s wrist to her elbow.

10

82

Newsline ■ Revised diabetes guidance raises BP targets ■ Kidney guide features albuminuria testing ■ And more

34

Alternative Meds Update Reflexology stimulates impulses that trigger the release of endorphins.

75

CME/CE Dermatologic Look-Alikes Can you differentiate between these intertriginous erosions?

79

CME/CE Posttest

Commentary Diabetes update raises BP treatment goal 10

FEATURES 24

68

Managing urinary tract infections in women Treatment strategy is determined by whether the infection is classified as complicated or uncomplicated.

ADVISOR FORUM 44

CME/CE Evaluation and treatment of acute cerebral ischemia To ensure interventions begin in time, providers must recognize the clinical presentation of an acute ischemic stroke.

46

DEPARTMENTS Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com.

49

Legal Advisor A man’s living will conflicts with a “do not resuscitate” order.

55

CME/CE Dermatology Clinic ■ A small lesion on an infant’s scalp grows into a painful ulceration.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

Clinical Pearl ■ Gargle sore throat away

Uproar over “no heroic measures” request 49

48

Consultations ■ Underlying problems of scoliosis ■ Acetaminophen and fatty liver ■ Gluten-free diet or vitamin D supplementation for psoriasis?

Painful rash in the armpit and groin 75

Like us on Facebook facebook.com/TheClinicalAdvisor

46

Your Comments ■ Be explicit about your after-hours policy ■ Patients must learn what constitutes an emergency

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives ClinicalAdvisor.com/WebExclusives CDC: Novel norovirus replacing former dominant strain The new strain was responsible for the majority of contagious intestinal illness from September through December 2012.

Aspirin raises risk of age-related macular degeneration (AMD) Aspirin users had a 2.37 odds ratio for developing AMD after adjusting for age, sex, and history of smoking.

Fast food linked to allergies and eczema in children Eating fast food multiple times per week is associated with an increased risk of severe asthma, rhinoconjunctivitis, and eczema.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Sharon M. O’Brien, MPAS, PA-C Incorporating integrative health coaching in primary care What would health care be like if patients were involved in directing their own care?

Robyn Carlisle, MSN, CNM, WHNP Discriminating against smokers perfectly legal in health-care hiring Should more hospital systems institute smoke-free hiring policies?

Leigh Montejo, MSN, FNP-BC Incorporating friends and family in patient visits In general, the more people involved in treatment, the better the patient’s outcome. But is this feasible in primary care?

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

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© Roy Delgado

A woman with “mossy” legs A patient with a history of morbid obesity has thick, pebbly, warty skin changes on her lower legs. What is your diagnosis?

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Newsline

More cancer survivors in primary care page 16

Test predicts mortality in older adults page 12

F E B R U A R Y 2 0 13

Restrict kids’ milk intake to two cups a day page 16

© SCIENCE SOURCE / JIM VARNEY

Revised diabetes guidance raises BP targets

More intensive BP treatment has shown little additional benefit.

at bedtime, prior to exercise, prior to driving and other critical tasks, when low blood glucose is suspected, and after treating low blood glucose.

“Many patients will need to test six to eight times per day, but some will need to test more, depending on their activity level, how often they eat, and what other types of activities their day may include,” explained the ADA statement. “It is not reasonable or practical to set a specific number for all people with diabetes who are on intensive insulin regimens, as no two people’s lives are the same [and] no two days are exactly alike.”

Persons on less intensive insulin regimens or noninsulin therapies require ongoing education as to how frequently they need to participate in SMBG and how to adjust food intake, exercise, or medications to achieve specific blood glucose goals

Contraception among women aged 15–44 years Among women currently using contraception, the pill and female sterilization remain the most common methods.

30

1995

25

Percentage

THE AMERICAN Diabetes Association (ADA) has raised the recommended treatment goal for systolic high BP from <130 mm Hg to <140 (with a diastolic goal of <80) in its annual update to “Standards of Medical Ca re —Diabetes” (Diabetes Care. 2013;36:S11-S66; available at care.diabetesjournals.org /content/36/Supplement_1/S11. full, accessed January 15, 2013).

The change to the BP goals were made based on several new meta-analyses showing little additional benefit to achieving the lower targets. Although clinical trials have demonstrated health benefits to achieving a goal of <140, such as reducing cardiovascular events, stroke, or nephropathy, more intensive BP treatment has shown limited benefit with no significant reduction in mortality or nonfatal heart attacks. Tighter BP control does slightly reduce

stroke risk, but that benefit might be offset by the need for more medications to control BP and higher rates of side effects.

“Raising the recommended [BP] target, however, is not meant to downplay the importance of treating high [BP] in people with diabetes…nor should this be taken to mean that lower target rates are inappropriate,” cautioned the ADA in a statement.

Another guideline change involves the frequency of selfmonitoring of blood glucose (SMBG) for persons who take multiple daily doses of insulin or use an insulin pump. Whereas the ADA had previously recommended that such patients engage in SMBG “three or more” times throughout the day, the organization now urges them to test their blood glucose based on certain activities: prior to meals and snacks, occasionally after eating,

2006-2010

20 15 10

5 Source: Jones J, Mosher W, Daniels K. Current contraceptive use in the United States, 2006–2010. Natl Health Stat Rep 2012(60).

0

Female Male sterilization sterilization

10 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

Pill

Condom

Contraception method

Other hormonal methods

IUD

Newsline PROVIDERS ARE urged to test patients at high risk for chronic kidney disease (CKD) for protein in the urine in the revised, global version of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guideline.

Updated for the first time since it debuted in 2002, Chronic Kidney Disease: Evaluation, Classification, Stratification retains the definition of CKD but augments the classification system to include albuminuria and cause of disease as well as glomerular filtration rate (GFR) stage. GFR stage 3 is now subdivided into categories 3a and 3b.

The albuminuria level helps clinicians better stratify risk and evaluate likely outcomes, knowledge that influences management and treatment, noted the NKF in

a statement accompanying the release of the document.

“The new staging predicts meaningful outcomes for patients more accurately based on both blood and urine tests instead of one or the other test alone,” affirmed Joseph Vassalotti, MD, Chief Medical Officer of the NKF. He added that primary-care practitioners could more routinely use inexpensive, readily available albuminuria testing for people at risk for kidney disease. “Our goal is to encourage primarycare [clinicians] to screen those with diabetes, high [BP], and a family history of kidney disease,” Vassalotti commented.

Estimated GFR should be determined using creatinine, but cystatin C can also be used. In addition, risk for overall mortality,

© SCIENCE SOURCE / CC STUDIO

Kidney guide features albuminuria testing

Albuminuria testing is inexpensive and readily available.

cardiovascular disease, end-stage kidney failure, acute kidney injury, and CKD progression should be defined through the relationship between eGFR and albuminuria.

Patients with very low GFR (<15 mL/min/1.73 m2) or very high albuminuria (>300 mg) should be referred to a nephrologist.

THE ABILITY to sit down on the floor and then rise back to a standing position was a significant predictor of all-cause mortality in older adults, a recent study revealed.

Although cardiorespiratory fitness is strongly related to survival, data on musculoskeletal fitness indicators are limited, explained Leonardo Barbosa Barreto de Brito and colleagues in European Journal of Preventive Cardiology. To evaluate the association between the ability to sit on and rise from the floor and all-cause mortality, the investigators had 2,002

Participants were told to get up off the floor in a stable way, unaided.

persons aged 51 to 80 years per form a sitting-rising test (SRT).

Participants were told to sit on the floor and then get up in a stable way, unaided. Speed was not a concern, but the men and women were told to use the minimum support necessary to complete the task. Each of the two movements was given a score of zero to five points, with one point subtracted for each hand or knee support used.

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

A total of 159 study participants (7.9%) died over a median follow-up of 6.3 years. Lower SRT scores were associated with higher mortality, and each unit increase in SRT score conferred a 21% improvement in survival.

Only two of the deaths occurred in participants with a composite SRT score of 10, but having a composite score below 8 (that is, requiring more than one hand or knee support to sit down and then rise again from the floor in a stable way) was associated with twofold-higher death rates over the study period.

© THINKSTOCK

“Sit test” predicts mortality in older adults

Newsline AS MORE patients with cancer transition back to primary care, greater coordination of care and more attention to health promotion and disease prevention in survivors is needed, according to the American Society of Clinical Oncology (ASCO).

An article published online ahead of print in the Journal of Clinical Oncology (available at jco.ascopubs. org/content/early/2013/01/07/ JCO.2012.46.6854.long, accessed January 15, 2013) points out that the number of cancer survivors has increased dramatically as a result of improved early detection and effective therapies. There are currently more than 13 million cancer survivors in the United States—a group that is expected to grow to 18 million by 2022.

ASCO is working toward greater collaboration between primarycare providers and oncologists, and toward designing guidance applicable to all medical settings and disseminated broadly for implementation on a large scale not

The number of cancer survivors may grow to 18 million by 2022.

only to oncologists but to nurse practitioners, physician assistants, primary-care physicians, and the patients themselves.

Recent studies have emphasized relationships between cancer and a condition very familiar to primary-care providers: diabetes.

Dr. Lorraine Lipscombe and colleagues reported in Diabetologia that postmenopausal survivors of breast cancer have an increased risk of developing diabetes, particularly in the first two years of receiving adjuvant therapy.

Sanjeev Kumar, MBBS, and team found an association between the use of the widely used diabetes drug metformin and improved survival among women with ovarian cancer (Cancer; online ahead of print).

In Population Health Management, a group led by Lauren Irizarry described how persons with diabetes often let disease management lag when it coexists with cancer, despite the dangers of uncontrolled blood glucose.

Kids should have two cups of milk per day Because too much cow’s milk can deplete a child’s iron levels, intake should be restricted to two cups per day.

As detailed in the journal Pediatrics, a team led by pediatrician Jonathon L. Maguire, MD, MSc, found that greater consumption of cow’s milk was associated with decreasing serum ferritin and increasing 25-hydroxyvitamin D levels.

Two cups of cow’s milk per day maintained 25-hydroxyvitamin D above 75 nmol/L

(above 30.05 ng/mL) with minimal negative effect on serum ferritin for most children.

Children with darker skin pigmentation required three to four cups of cow’s milk per day during the winter months to maintain that vitamin D level. However, providing these children with vitamin D supplementation rather than the extra milk during the winter might be a more appropriate way of increasing their vitamin D stores while preserving their iron stores.

16 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

BENZODIAZEPINES were associated with an increased risk of, and mortality from, community-acquired pneumonia (CAP) in a large case-control study.

Previous research has linked this class of drugs with an increased incidence of infections, and mortality from sepsis, in the critically ill. In the current study, data from 29,697 controls and 4,694 CAP cases showed that people using benzodiazepines were 54% more likely than nonusers to contract pneumonia. Individually, diazepam (Valium), lorazepam (Ativan), and temazepam (Restoril), but not chlordiazepoxide, were associated with an increased incidence of CAP. People taking benzodiazepenes also were 22% more likely to die within 30 days of being diagnosed with CAP and 32% more likely to die within three years of diagnosis than were nonusers.

Cases were more likely than controls to have had previous pneumonia; heart attack, depression, psychotic illness, or other serious illness; or underlying illnesses, and were more likely to be current smokers. Eneanya Obiora and fellow investigators cautioned in their report for the journal Thorax that their findings do not definitively prove cause and effect. However, the results suggest a need for further research into the immune safety profile of benzodiazepines. ■

© THINKSTOCK

Expect more cancer survivors Benzos may raise risk of pneumonia

Take the Scavenger Hunt Challenge February 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/WZ8r9G. QUESTIONS 1. What new treatment goal for high systolic BP does the American Diabetes Association recommend? (p. 10) 2. Approximately how many cancer survivors are there currently in the United States? (p. 16) 3. What is the annual health-care cost of urinary tract infections? (p. 24) 4. Approximately what percentage of community-acquired infections is caused by Escherichia coli? (p. 26) 5. According to the National Stroke Association, how many strokes occur in the United States each year? (p. 34) 6. What score on the NIH Stroke Scale is predictive of a good recovery? (p. 37) 7. What is another term for a living will? (p. 50) 8. Infantile hemangiomas affect what percentage of white infants at age 1 year? (p. 56) 9. What American physician significantly advanced the modern practice of reflexology? (p. 68) 10. In which sex is Langerhans cell histiocytosis more commonly seen? (p. 77)

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FEATURE: JOAN E. ZACCARDI, DRNP, APRN-BC

Managing urinary tract infections in women Urinalysis and physical exam determine if the infection is complicated or uncomplicated, primary or recurrent, and guide treatment strategy.

I

nfection of the lower urinary tract is a common health issue encountered by primarycare providers, gynecologists, urologists, and other health-care professionals. Urinary tract infections (UTIs) are more prevalent in women than in men, with greater than 50% of women having at least one infection in their lifetime.

Approximately 25% of these women will have another UTI in six months, while 50% will have another within one year.1 UTIs result in close to 7 million office visits per year and run up a health-care tab of nearly $1.6 billion dollars.1 Although the diagnosis and treatment of an acute uncomplicated infection is basic and straightforward, treatment of recurrent and/ or complicated UTIs can be difficult and quite frustrating for patients and providers. Clinicians must be aware of the signs, symptoms, and pathophysiology of the disease; know how to clinically evaluate and test for diagnosis; and stay up to speed on the latest treatment strategies for both simple and complicated infections.

© SCIENCE SOURCE / STEVE GSCHMEISSNER

Classification and pathophysiology

Escherichia coli bacteria (pink) are responsible for most uncomplicated UTIs in women.

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

Classification of UTI as uncomplicated or complicated is based on the type of infecting organisms, the functioning of the urinary system, and the general health of the patient. Uncomplicated UTIs generally occur in a healthy person with a normal urinary tract and are easily treated with limited testing and without adverse consequences. Complicated infections, on the other hand, occur in a person with a compromised immune system or with a functionally or structurally

MANAGING UTIS

abnormal urinary tract. These infections can be caused by pathogens with increased virulence and antibiotic resistance, making them more difficult to treat and cure.2 Escherichia coli is the pathogen most often responsible for UTI.2 E. coli is normally found in the digestive tract and has the potential to ascend into the bladder following colonization at the vaginal introitus. Although the female urethra is short and located close to the vagina and anus, it contains antimicrobial defenses that help prevent bacteria from entering and adhering to the urethra and bladder. Interference with any of the host’s defense mechanisms, such as vaginal atrophy, high pH, trauma, or genitourinary surgery, can open the door to ascending infection. Uropathogenic E. coli is a virulent gram-negative bacterium with an affinity for the genitourinary tract. This pathogen has fingerlike projections called fimbriae that allow it to adhere to the urethra and bladder wall rather than be flushed from the urinary system through voiding. Sometimes, E. coli can “seed” the bladder by creating podlike structures that house the bacteria and lead to resistant or recurrent infections.2 Approximately 85% of community-acquired infections and 50% of nosocomial infections are caused by E. coli.2 Other pathogens commonly responsible for UTIs in premenopausal women include Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis. Pathogens most often encountered in postmenopausal women include E. coli, P. mirabilis, and K. pneumoniae. Women with diabetes are most often infected with Klebsiella, while Pseudomonas bacteria are predominant in those with indwelling catheters.3 Evaluation

The evaluation of the genitourinary tract begins with a focused history of presenting symptoms. The diagnosis of UTI often can be made on history alone, as the symptoms of dysuria, frequency and urgency, pressure, and hematuria raise the probability of a UTI to greater than 50%.4 History consistent with past UTIs; abnormalities of the urinary system; previous surgery involving the urinary tract; frequent sexual activity; and such medical conditions as diabetes, neurologic disorders, sickle cell disease, and pelvic organ prolapse increases Table 1. Risk factors for UTI

What percentage of your female patients have you treated for a urinary tract infection?

POLL POSITION

n=622

35% 17%

41%

29%

Fewer than 10% 10% - 25% 25% - 50% More than 50%

For more polls, visit CliniAd.com/10TDwDb

the likelihood of an infection. Other risk factors for UTI are listed in Table 1. Any pain in the suprapubic area, flank, or lower back should be noted, along with associated symptoms of nausea, vomiting, malaise, fever, or chills.

Physical exam follows the patient history and includes checking vital signs to assess for fever, tachycardia, and tachypnea.

Suprapubic and costovertebral angle tenderness is checked with palpation and percussion of the abdomen and back. Observe skin turgor and urine output to assess for dehydration.

When UTI is suspected, an in-office urine dipstick is appropriate. If the dipstick reads positive (leukocytes and/ or nitrites), the likelihood of infection is 25%, and treatment with antibiotics can be initiated.2 A negative dipstick does not rule out an infection. In a case of suspected UTI, a culture is definitely indicated, and treatment decisions should be made on an individual basis. Such other testing as clean-catch urine specimen for urinalysis (UA) and culture and sensitivity (C&S) is indicated in women with recurrent infections. A catheterized urine specimen may be indicated in women who have repeated contaminated urine specimens, in women with microscopic hematuria, and in women who are elderly and functionally impaired or obese.3 Continues on page 29

Table 2. Differential diagnosis of UTI • Vaginitis/urethritis

• Overactive bladder/ urge incontinence

• AIDS

• Trauma/previous bladder surgery

• Pelvic organ prolapse

• Indwelling catheters

• Urologic abnormalities

• Interstitial cystitis

• Bladder cancer

• Incomplete bladder emptying

• Decreased functional ability

• Irritant urethritis

• Bacterial vaginosis

• Pregnancy

• Diabetes

• Older age

• Multiple sclerosis

• Spinal-cord injury

26 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

MANAGING UTIS

Table 3. Medication regimens for UTI Medication

Dose

Efficacy

Cautions

Side effects

Nitrofurantoin (Furadantin, Macrobid)

• 100 mg b.i.d. for seven days

• Escherichia coli, grampositive pathogens, most gram-negative pathogens

• Take with food • Renal clearance

• GI upset, headache, dizziness, pulmonary disorders

Trimethoprim/ sulfamethoxazole (TMP/ SMX) (Bactrim, Septra)

• One doublestrength tablet or two regularstrength tablets every 12 hours for three to five days

• E. coli (resistance up to 39% in some areas)

• Take with plenty of fluids • Hepatic/renal dysfunction

• GI upset, blood dyscrasia, fever, rash, ataxia

Quinolones

• 250 mg every 12 hours for three to five days

• Gram-negative coverage (expanded to include specific gram-positive organisms)

• Tendonitis or tendon rupture, hyperglycemia

• GI upset, central nervous system effects, arrhythmias

Tetracyclines

• 250 mg–500 mg four times a day for seven to 10 days

• Test for sensitive infections

• Take with fluids one hour before meals or two hours after meals

• GI upset, esophagitis, headache, rash

Cephalosporins

• 250 mg–500 mg b.i.d. for seven to 10 days

• Test for sensitive infections

• Renal impairment

• GI upset, abdominal pain, liver dysfunction, headache

Macrolides

• 500 mg b.i.d.

• Test for sensitive infections

• Hepatic dysfunction

• GI upset, abdominal pain, superinfection

Fosfomycin (Monurol)

• One 3-g sachet of granules

• Uncomplicated UTIs in women

• Decreased serum levels with GI medications

• GI upset, back pain, dizziness

Adapted from Monthly Prescribing Reference. Oral therapy for UTIs in adults. Available at media.empr.com/documents/2/uro-ot_a_1159.pdf, accessed January 15, 2013.

A pelvic exam is performed based on symptoms and sexual history, and in cases of recurrent or complicated infection. Check for vaginal pH and the integrity of the urethra and vaginal mucosa. Presence of vaginal discharge and any urethral and/or cervical tenderness should be noted.

Because symptoms of dysuria, frequency, and urgency are also present in individuals with urethritis and vaginitis, a vaginal exam, cultures, wet mount, and laboratory testing for sexually transmitted infection (STI) is appropriate.3 Additional and invasive testing may be considered in women who have persistent or complicated infections and in those who present with physiologic or functional abnormalities. Because women with pelvic organ prolapse frequently have incomplete bladder emptying, a catheterized specimen can be sent for UA and C&S as well as to provide documentation of post-void residual urine. Renal and pelvic ultrasound is used to evaluate the urinary system and to identify stones and obstructions.

CT scan with and without contrast can further evaluate for stones, masses, and hematuria.

Cystoscopy is a valuable tool in the differential diagnosis of complicated and recurrent infections, especially in

women with suspected fi stulas or hematuria and in those with previous bladder or pelvic surgery (Table 2). 3 Treatment strategies

Uncomplicated or first-time UTIs may be treated empirically with antibiotics based on symptoms with or without a positive urine dipstick in the office. Management strategies include rest and fluids. Such bladder-irritating substances as coffee, tea, carbonated beverages, dietary sweeteners, and tomato-based foods can exacerbate symptoms and should be avoided.2 When prescribing antibiotics to treat UTI, consider the following general guidelines: (1) the likelihood that the medication will be effective according to geographic resistance patterns; (2) the ability of the medication to concentrate in the urine; (3) limited toxicity for the patient; (4) reasonable cost; and (5) a low alteration of vaginal or bladder flora.2,3 Short-term antibiotic treatment (i.e., three days) is adequate to treat uncomplicated infections and has been shown to be as effective as seven days of medication.5 Nitrofurantoin (Furadantin, Macrobid) and trimethoprim/sulfamethoxazole (TMP/SMX) (Bactrim, Septra)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 29

MANAGING UTIS

are well-tolerated, inexpensive, and good first-line choices for the treatment of uncomplicated UTI. Nitrofurantoin is effective against most genitourinary pathogens and has developed little resistance in most areas. However, nitrofurantoin is not effective against Pseudomonas infection and can result in pulmonary toxicity, especially in the elderly.

The sulfa-based medication TMP/SMX is very effective.

Resistance is typically low but has increased in certain areas. Side effects and allergies are the major disadvantages of this medication.6 Fosfomycin (Monurol) is a broad-spectrum antibiotic that can be effective in the treatment of uncomplicated UTI. Fosfomycin has an affinity for the bladder with good tissue penetration (it is excreted unchanged in the urine).

Bacterial resistance remains low, and this medication has 90% efficacy against genitourinary bacteria, including methicillin-resistant Staphylococcus aureus, E. coli, Enterococcus faecalis, and Klebsiella. Fosfomycin is a single-dose medication with a long half-life and low allergic profi le. The downside to this medication is its cost and the fact that it is not readily available and might need to be ordered, thereby delaying treatment.6 Quinolones are strong broad-spectrum antibiotics and should be reserved for complicated infections, infections with Pseudomonas, or the treatment of resistant bacteria.

Cephalosporins and macrolides also should be reserved for complicated or resistant infections. These three classes of medications are most effective for sensitive bacteria following positive urine cultures in women with complicated or recurrent infections.6,7 A number of prophylactic treatment options are recommended for recurrent and/or complicated UTIs: (1) daily low-dose antibiotic therapy, such as nitrofurantoin (50 mg or 100 mg) or TMP-SMX (half-strength tablet) for three to six months; (2) a self-treatment option with a pre-prescribed three-day course of antibiotics to be taken when symptoms start; (3) postcoital antibiotics (nitrofurantoin 100 mg) to be taken one hour before or after sexual relations. If symptoms worsen or are not controlled, the patient should be reevaluated.5 For a list of medications commonly prescribed for treatment of UTI, see Table 3.

PEER PERSPECTIVES

CLINICAL SLIDESHOW For more information on a woman with bladder discomfort and urinary frequency, view the slideshow at CliniAd.com/WWhFoK

Prevention

Prevention strategies can be initiated for women with recurrent infections and for those with medical comorbidities after complete evaluation of the genitourinary system. Always treat acute infections prior to initiating prevention measures.

Cranberry juice or capsules are the most well-known preventive agent for UTIs. Cranberry is believed to deter infections by preventing the adherence of fimbriae, thereby assisting in the flushing out of bacteria through voiding. A review of the literature determined that cranberry products significantly reduced the incidence of UTIs over a 12-month period compared with placebo/control.8 Methenamine hippurate has been studied for its preventive benefits, especially if taken with vitamin C. This combination ensures the acidity of the urine and is believed to form formaldehyde in the urine that can initiate the breakdown of the bacterium protein. Methenamine with vitamin C is a good option for women with uncomplicated recurring infections and also has been used in women with recurrent UTIs related to incomplete bladder emptying. This use has not been supported in the literature, however.9 In postmenopausal women with recurrent UTIs, treatment with vaginal estrogen is thought to change the vaginal pH, creating a less conducive environment for colonization and ascending infection.4 Vaginal and oral probiotics are thought to have the same benefit through change in the vaginal pH, but the evidence and efficacy are still under investigation.

A number of herbal formulations are available, but their efficacy and safety have not been studied. Caution patients that herbal products are known to interact with other medications or foods and can have serious side effects.

Continues on page 32

“I have been seeing an increase in UTIs with resistant bacteria in my preoperative orthopedics patients.

Enterococcus faecalis is showing up more frequently, and IM/IV ertapenem [Invanz] has been my choice from the sensitivities list. However, this medication is not cheap for the patients.”

Carrie Cole, PA, Gadsden, Ala. (via ClinicalAdvisor.com)

30 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

MANAGING UTIS

Summary

UTIs in women are prevalent and often prompt an office visit. Uncomplicated UTIs are easily managed, and treatment is tailored to alleviating symptoms. Urine testing and C&S, although not necessary with first infections, can eventually be important for documentation and treatment strategies if symptoms become recurrent or persistent.

Antibiotic treatment with nitrofurantoin or TMP/SMX will most likely resolve uncomplicated or first-time UTIs. A urine C&S is imperative in cases of recurrent UTI, with treatment of the active infection first followed by the additional initiation of prevention techniques. The three acceptable prophylactic treatment options for recurrent UTIs are low-dose antibiotics daily for three to six months, self-start antibiotics, and postcoital antibiotics.

Follow-up and documentation of recurrent infections combined with ongoing communication and individualized testing and treatment strategies is the best approach to this common medical problem. ■

2. Hanno MP. Lower urinary tract infections in women and pyelonephritis.

In: Hanno PM, Malkowicz SB, Wein AJ, Penn Clinical Manual of Urology.

Philadelphia, Pa.: Saunders Elsevier; 2007:155-176.

3. Grimes CL, Lukacz ES. Urinary tract infections. Female Pelvic Med Reconstr Surg. 2011;17:272-278.

4. Litza JA, Brill JR. Urinary tract infections. Prim Care. 2010;37:491-507.

5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 91: Treatment of urinary tract infections in nonpregnant women. Obstet Gynecol. 2008;111:785-794. Available at www.guidelines .gov/content.aspx?id=12628 6. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52:e103-e120. Available at cid.oxfordjournals. org/content/52/5/e103.long.

7. Sivick KE, Mobley HL. Waging war against uropathogenic Escherichia coli: winning back the urinary tract. Infect Immun. 2010;78:568-585. Available at iai.asm.org/content/78/2/568.long.

8. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections.

Dr. Zaccardi is a nurse practitioner and the administrative practice manager of Urogynecology Arts of New Jersey, in New Brunswick.

Cochrane Database Syst Rev. 2008;1:CD001321.

9. Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev.

References

2012;10:CD003265.

1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, All electronic documents accessed January 15, 2013.

“See? There’s no monster in the corner— it’s just a pile of old skulls.”

32 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

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

and economic costs. Am J Med. 2002;113 (Suppl 1A):5S-13S.

CME CE

PROGRAM OUTLINE FEBRUARY 2013

0.5 CREDITS

Page 34 FEATURE Evaluation and treatment of acute cerebral ischemia Michel Statler, MLA, PA-C Michel Statler, MLA, PA-C, has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Describe the classic ophthalmologic symptom of transient ischemic attack.

• Explain the clinical presentation of a stroke that involves Broca’s area.

• List the recommended dose of recombinant tissue plasminogen activator (rtPA).

• Recall the symptoms that require immediate discontinuation rtPA infusion.

0.5 CREDITS

Page 55 DERMATOLOGY CLINIC Red scalp plaque with painful ulceration Adam Rees, MD Adam Rees, MD, has no relationships to disclose relating to the content of this article.

Discolored patches from wrist to elbow Esther Stern, NP Esther Stern, NP, 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 75 DERMATOLOGIC LOOK-ALIKES Intertriginous erosions Kerri Robbins, MD Kerri Robbins, MD, has no relationships to disclose relating to the content of this article.

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

Page 79 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 February 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 • FEBRUARY 2013 33

■ LEARNING OBJECTIVES :

CME CE FEATURE

• Describe the classic ophthalmologic symptom of transient ischemic attack.

• Explain the clinical presentation of a stroke that involves Broca’s area.

• List the recommended dose of recombinant tissue plasminogen activator (rtPA).

• Recall the symptoms that require immediate discontinuation rtPA infusion.

■ COMPLETE THE POSTTEST: Page 79 ■ ADDITIONAL CME/CE: Pages 55, 75 Turn to page 33 for additional information on this month’s CME/CE courses.

MICHEL STATLER, MLA, PA-C

Evaluation and treatment of acute cerebral ischemia To ensure that therapeutic interventions begin in time, providers must be able to recognize the clinical presentation of an acute ischemic stroke.

© SCIENCE SOURCE / ZEPHYR

S

In this intracerebral hemorrhage, blood (red) is leaking into the ventricles of the brain, causing a hematoma.

troke remains a leading cause of morbidity and mortality in the United States. The National Stroke Association estimates that approximately one person suffers a stroke every 40 seconds, amounting to at least 795,000 strokes annually. Strokes are the third leading cause of death behind heart disease and cancer. However, strokes remain the leading cause of disability and result in an estimated $73 billion in health-care related costs every year.1 Strokes are classified as ischemic or hemorrhagic. Ischemic strokes occur more commonly and account for approximately 87% of all cerebrovascular accidents.2 Etiologies for ischemic stroke include thrombotic or embolic events resulting from large-vessel disease (most common); smallor penetrating-artery disease; or such cardiac causes as atrial fibrillation, valvular disease, or left ventricular akinesia.

Hemorrhagic strokes can present as either intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH). ICH can be attributed to poorly

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

controlled hypertension, anticoagulation therapy, and arteriovenous malformations; SAH is associated with intracranial saccular aneurysms and trauma.3 Risk factors

The risks for stroke can be attributed both to nonmodifiable and modifiable factors. Stroke risks are cumulative, with higher risk associated with the presence of a greater number of risk factors. Nonmodifiable risk factors include increasing age, race (increased risk for black patients), gender (higher risk for men), and a positive family history of cerebrovascular disease. Modifiable risk factors include hypertension, smoking, diabetes, atrial fibrillation, hyperlipidemia, and a history of transient ischemic attacks (TIAs).1,4,5 Transient ischemic attacks

TIAs are defi ned as a temporary episode of neurologic dysfunction secondary to focal brain or retinal ischemia without evidence of acute infarction. This definition has been revised over the years to better reflect the underlying pathophysiology associated with the event. The one-hour time window in a previous definition has been removed since it does not clearly distinguish between events with or without infarction. The bottom line, however, is to recognize that a TIA represents an increased risk for stroke due to brain ischemia. An estimated 10% to 15% of patients presenting with a TIA will have a stroke within three months; approximately half of those patients will suffer a stroke within 48 hours.5 A classic symptom of a TIA is amaurosis fugax, which patients describe as someone pulling a shade down over their vision in one eye. Amarousis fugax represents emboli to the ophthalmic artery from atherosclerotic disease affecting the ipsilateral carotid artery. Symptoms of a TIA vary, however, depending on the vascular territory that is affected.6,7 Pathophysiology

Thrombi and emboli within the cardiovascular system can cause an acute occlusion of a cerebral blood vessel, leading to ischemia of the neurons in that affected distribution. If blood flow is not restored, irreversible cell death occurs. Dying neurons then release glutamate, which causes neighboring neurons to increase absorption of calcium. The increased absorption of calcium leads to the death of adjacent neurons, spreading a toxic cascade outward from the original zone of ischemia. This ischemic penumbra, or peripheral zone of injury, represents compromised cellular function that may be reversible with rapid reperfusion.7,8

Clinical presentation

The ability to localize the signs and symptoms to a particular vascular territory is the key to diagnosing stroke in a timely fashion. Treatment is determined by the type of stroke suffered (i.e., ischemic or hemorrhagic) rather than the anatomic location.

Symptoms referable to the anterior circulation—specifically, anterior and middle cerebral artery vascular territories— include contralateral motor and sensory losses. Strokes specifically involving the anterior cerebral artery distribution are associated with a hemiparesis or hemiplegia affecting the lower extremity and can be associated with urinary incontinence and changes in personality; facial movement will be spared. In contrast, strokes in the middle cerebral artery (MCA) territory present with contralateral weakness and sensory losses affecting the face and upper extremities.

The particular type of facial weakness is known as a central VII palsy since only the lower portion of the face is affected.

The patient is still able to raise his or her eyebrows bilaterally due to bilateral innervation of the forehead.8 Language can be affected with MCA strokes if the damage occurs in the patient’s dominant hemisphere. Involvement of Broca’s area will result in expressive aphasia, which may present as anything from word-finding difficulty to total mutism. As long as Wernicke’s area remains intact, the patient will be able to understand language and follow commands.

On the other hand, if the stroke only affects Wernicke’s area, the patient will not be able to understand language or follow comments; speech will be fluent but nonsensical. If both Broca’s and Wernicke’s areas are affected, the patient will exhibit global aphasia with the total loss of language function.

If the non-dominant hemisphere is affected, the patient will exhibit apraxia and hemineglect.8 Posterior circulation strokes include involvement of either the posterior cerebral artery (PCA) distribution or the vertebrobasilar system. Deficits associated with a PCA stroke include a contralateral hemisensory loss, contralateral visual field deficit (homonymous hemianopia), cortical blindness, and visual agnosia. Signs referable to the vertebrobasilar distribution include alterations in mental status, cranial nerve palsies (e.g., diplopia, vertigo, dysarthria), motor weakness, sensory loss, and ataxia.8 Such nonfocal or nonlocalizing fi ndings as headache, nausea, vomiting, altered mental status, and papilledema are consistent with increased intracranial pressure and may be seen with large hemispheric strokes, as well as with intracerebral or subarachnoid hemorrhages.9 Continues on page 36

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 35

CME CE

ACUTE CEREBRAL ISCHEMIA

TABLE 1. National Institutes of Health Stroke Scale Tested Item

Title

Responses and scores

1A

Level of consciousness

0 – alert 1 – drowsy 2 – obtunded 3 – coma/unresponsive

1B

Orientation questions (2)

0 – answers both correctly 1 – answers one correctly 2 – answers neither correctly

1C

Response to commands (2)

0 – performs both tasks correctly 1 – performs one task correctly 2 – performs neither task correctly

2

Gaze

0 – normal horizontal eye movements 1 – partial gaze palsy 2 – complete gaze palsy

3

Visual fields

0 – no visual field deficit 1 – partial hemianopia 2 – complete hemianopia 3 – bilateral hemianopia

4

Facial movement

0 – normal 1 – minor facial weakness 2 – partial facial weakness 3 – complete unilateral palsy

5

Motor function (arm) a. Left b. Right

0 – no drift 1 – drift before five seconds 2 – falls before five seconds 3 – no effort against gravity 4 – no movement

6

Motor function (leg) c. Left d. Right

0 – no drift 1 – drift before five seconds 2 – falls before five seconds 3 – no effort against gravity 4 – no movement

7

Limb ataxia

0 – no ataxia 1 – ataxia in one limb 2 – ataxia in two limbs

8

Sensory

0 – no sensory loss 1 – mild sensory loss 2 – severe sensory loss

9

Language

0 – normal 1 – mild aphasia 2 – severe aphasia 3 – mute or global aphasia

10

Articulation

0 – normal 1 – mild dysarthria 2 – severe dysarthria

11

Extinction or inattention

0 – absent 1 – mild (loss of one sensory modality) 2 – severe (loss of two sensory modalities)

Adapted from Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:16551711. Available at stroke.ahajournals.org/content/38/5/1655.long. Accessed January 15, 2013.

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

Imaging studies

A

As previously noted, neuroimaging is the first step in the diagnostic evaluation of an individual presenting with the signs and symptoms of an acute stroke. Radiographic findings consistent with an ischemic injury include hypodensity changes and effacement in the affected areas (Figure 1).

Given the size of the stroke depicted in Figure 1 (greater than one third of the hemisphere), thrombolytic therapy would be contraindicated for this patient.

Indications of a hemorrhagic stroke include focal areas of hemorrhage consistent with ICH or diffuse bleeding in the basilar cisterns or the inter-hemispheric fissures, or over the convexity of the brain with subarachnoid bleeds (Figures 2 and 3).12 Recent imaging guidelines from the American Heart Association indicate that diffusion-weighted MRI is the most sensitive and specific imaging study to demonstrate an acute infarction. However, MRI should be used only if it does not delay the timely administration of IV thrombolytics.13

B

Management C

D

FIGURE 1. Non-contrast axial CT images show hypodensity and effaced sulci (arrows) in the distribution of the right middle cerebral artery consistent with an acute ischemic stroke.

The NIH Stroke Scale10 (NIHSS) (Table 1) is a standardized and objective means of assessing neurologic function at varying intervals, including baseline and two hours post-treatment, as well as 24 hours, seven to 10 days, and three months from the onset of symptoms.3 NIHSS scoring correlates with the patient’s prognosis. A score on the NIHSS of 6 or less is predictive of a good recovery; a score of 16 or more is consistent with severe disability or the high probability of fatal outcome.11 Diagnostic evaluation

Time is of the essence in establishing the diagnosis of stroke and determining whether the patient is a candidate for thrombolytic therapy, ideally initiated within the “golden hour” after arrival at the hospital. Neuroimaging with either a non-contrast head CT or brain MRI is critical to rule out a hemorrhagic stroke, since evidence of intracranial bleeding is an absolute contraindication to the use of thrombolytics.

Additional diagnostic studies are separated into those tests that are indicated for all patients vs. those that are indicated for selected patients on a case-by-case basis (Table 2).3,10

The management of a patient presenting with an acute stroke begins with the ABCs (Airway, Breathing, and Circulation). Patients should be placed on cardiac monitoring due to increased risk for cardiac dysrhythmias, atrial fibrillation being the most common. Patients also should receive supplemental oxygen to prevent hypoxia; individuals with altered mental status and evidence of brain-stem compromise should be intubated and placed on ventilator support. Fever is associated with increased metabolic demands and can lead to increased morbidity and mortality; accordingly, acetaminophen and cooling blankets can be used to lower the patient’s body temperature.3,10 Elevated BP is commonly seen in the setting of acute cerebral ischemia and is attributable to pre-existing hypertension, the stress of the event, or a response to hypoxia or increasing intracranial pressure. Poorly controlled BP is associated with the development of cerebral edema and the risk of converting an ischemic infarct into a hemorrhagic stroke, which is why BP parameters are especially important in patients who are candidates for thrombolytic therapy.

For patients to be eligible for treatment with IV recombinant tissue plasminogen activator (rtPA), systolic BP needs to be <185 mm Hg and diastolic BP <110 mm Hg. Treat elevations of BP (i.e., systolic pressure >180 mmHg or diastolic pressure >105 mmHg) with IV labetalol (Normodyne, Trandate) to minimize the risk of hemorrhage or the development of cerebral edema. Bear in mind, however, that BP should be

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

CME CE

ACUTE CEREBRAL ISCHEMIA

A FIGURE 2. Non-contrast axial CT image shows a large hemorrhagic cerebellar infarction (arrow).

B

FIGURE 3. Image A. Non-contrast axial CT shows an extensive subarachnoid hemorrhage in the suprasellar cistern (arrow). Image B from the subsequent angiogram shows an aneurysm arising from the distal internal carotid artery (arrow).

lowered no more than 15% over the first 24 hours to maintain cerebral perfusion pressure.3,10 Guidelines for thrombolytic therapy

The FDA approved thrombolytic therapy with rtPA in 1996 based largely upon the findings from the National Institute of Neurologic Disorders Stroke Study. In this trial, patients who received rtPA showed evidence of improvement within the first 24 hours after onset of symptoms as well as improved neurologic outcomes at three months. Strict guidelines for the indications and contraindications were also established for the safe administration of rtPA.14 The indications for thrombolytic therapy include the diagnosis of an acute ischemic stroke with a clearly defined

onset of symptoms in less than three hours, as well as no evidence of a hemorrhagic stroke on a non-contrast head CT scan (Table 3). Similarly, the size of an infarct cannot be greater than one third of the middle cerebral artery territory.10 The time window has been expanded to 4.5 hours for selected patients. However, precautions for the expanded time window include age older than 80 years, anticoagulation therapy, a prior history of stroke and diabetes, and an NIHSS score of >25. The risk of intracranial hemorrhage is 6.4% for patients who have received rtPA within three hours; the risk of hemorrhage rises to 7.9% when the window is increased to 4.5 hours.15,16 The dose of rtPA is 0.9 mg/kg, not to exceed a total dose of 90 mg. Ten percent of the total dose is administered via bolus;

TABLE 2. Diagnostic studies to determine candidacy for thrombolytic therapy All patients

Selected patients

• Non-contrast head CT or brain MRI • Blood glucose • Electrolytes, renal-function tests • Electrocardiogram • Markers of cardiac ischemia • Complete blood count, including platelet count • Prothrombin time/international normalized ratio • Activated partial thromboplastic time • Oxygen saturation

• Hepatic function tests • Toxicology screen • Blood alcohol level • Pregnancy test • Arterial blood gases (if hypoxia suspected) • Chest x-ray (if lung disease suspected) • Lumbar puncture (if subarachnoid hemorrhage suspected and CT scan negative for blood) • Electroencephalogram (if seizures suspected)

Adapted from Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:16551711. Available at stroke.ahajournals.org/content/38/5/1655.long. Accessed January 15, 2013.

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

TABLE 3. Conditions for treatment with recombinant tissue plasminogen activator • Diagnosis of ischemic stroke causing measurable neurologic deficit • Neurologic signs should not be clearing spontaneously.

• Neurologic signs should not be minor and isolated.

• Exercise caution when treating a patient with major deficits.

• Symptoms of stroke should not be suggestive of subarachnoid hemorrhage.

• Onset of symptoms fewer than three hours before beginning treatment • No head trauma or prior stroke in the previous three months • No MI in the previous three months • No GI or urinary tract hemorrhage in previous 21 days • No history of previous intracranial hemorrhage • BP not elevated (systolic <185 mm Hg and diastolic <110 mm Hg) • No evidence of active bleeding or acute trauma (fracture) on examination • Not taking an oral anticoagulant or, if anticoagulant being taken, INR ≤1.7 • If receiving heparin in previous 48 hours, aPTT must be in normal range.

• Platelet count ≥100,000/mm3 • Blood glucose concentration ≥50 mg/dL • No seizure with postictal residual neurological impairments • CT does not show a multilobar infarction (hypodensity > 1/3 cerebral hemisphere).

• The patient or family members understand the potential risks and benefits of treatment.

INR = international normalized ratio; aPTT = activated partial thromboplastin time Adapted from Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711. Available at stroke.ahajournals.org/content/38/5/1655. long. Accessed January 15, 2013.

the remaining 90% is administered through an IV infusion over one hour. The patient’s vital signs and neurologic function need to be assessed frequently during and following the infusion: Vital sign and neurologic checks are done every 15 minutes for the first two hours, every 30 minutes for the next six hours, and then hourly until 24 hours post-treatment.

The infusion of rtPA should be discontinued immediately if the patient develops a severe headache, acutely elevated hypertension, nausea, or vomiting; obtain an emergency non-contrast head CT to rule out hemorrhage.

Alternate treatment options

Although thrombolytics can produce dramatic responses for those patients who are eligible to receive treatment, the actual number of people who qualify for this therapy is extremely limited. This limitation is attributable to the number of contraindications to therapy as well as to the tight time window allowed for safe administration of the medication. Extensive research into alternative means to reestablish blood flow and preserve neurologic function has led to the development of other therapies.

Intra-arterial thrombolysis. Intra-arterial administration of rtPA can be used for a select group of patients who are found to have an acute ischemic stroke secondary to an occlusion of the middle cerebral artery. Since the thrombolytic medication can be administered directly to the clot, smaller doses are required, and the time window can be expanded up to six hours. Intra-arterial thrombolysis also can be used for patients who have contraindications for IV administration (e.g., recent surgery). The rate-limiting step for intra-arterial thrombolytic therapy is the availability of experienced interventional radiologists to perform the procedure.16 Mechanical extraction. Endovascular interventions, including mechanical extraction of the clot, have also been used to reestablish blood flow. Mechanical clot extraction can be accomplished with or without the use of IV or intra-arterial thrombolytics. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) is one of several available thrombectomy devices that have been used successfully to remove thrombi and recanalize cerebral blood vessels. Mechanical thrombectomy is most effective when acute cerebral ischemia is caused by an occlusion of a large intracranial blood vessel (i.e., the middle cerebral artery).17,18 Summary

Research evaluating various pharmacologic and mechanical means of restoring blood flow and improving clinical outcomes for patients with acute ischemic stroke is ongoing. To date, however, the best treatment for stroke is prevention. The mainstays of prevention are identification and modification of risk factors through such means as control of hypertension and cessation of smoking. Similarly, educating patients to recognize the symptoms of stroke and reinforcing the need to call 911 if a stroke occurs is key to timely diagnosis and treatment to improve patient outcomes. ■ Ms. Statler is Senior Director, Academic Affairs, Physician Assistant Education Association, Adjunct Faculty, Physician Assistant Program, George Washington University in Washington, DC. She is also Director, Professional Affairs and Education for the Physician Assistant Education Association in Alexandria, Va. References 1. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke.

2011;42:517-584. Available at stroke.ahajournals.org/content/42/2/517.long.

2. Summers D, Leonard A, Wentworth D, et al. Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient:

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a scientific statement from the American Heart Association. Stroke.

Academy of Neurology affirms the value of this guideline as an educational

2009;40:2911-2944. Available at stroke.ahajournals.org/content/40/8

tool for neurologists. Stroke. 2007;38:1655-1711. Available at stroke

/2911.full.

.ahajournals.org/content/38/5/1655.long.

3. Uchino K, Pary JK, Grotta JC. Acute Stroke Care, 2nd ed. Cambridge, UK:

11. Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score

Cambridge Press; 2011:101-113

strongly predicts outcome after stroke: A report of the Trial of Org 10172

4. Kirshner HS. Differentiating ischemic stroke subtypes: risk factors and

in Acute Stroke Treatment (TOAST). Neurology. 1999;53:126-131.

secondary prevention. J Neurol Sci. 2009;279:1-8.

12. Renfrew D. Symptom Based Radiology. Sturgeon Bay, Wis.: Symptom

5. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of

Based Radiology Publishing; 2010.

transient ischemic attack: a scientific statement for healthcare profession-

13. Latchaw RE, Alberts MJ, Lev MH, et al. Recommendations for imaging

als from the American Heart Association/American Stroke Association

of acute ischemic stroke: a scientific statement from the American Heart

Stroke Council; Council on Cardiovascular Surgery and Anesthesia;

Association. Stroke. 2009;40:3646-3678. Available at stroke.ahajournals.

Council on Cardiovascular Radiology and Intervention; Council on

org/content/40/11/3646.long.

Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral

14. Tissue plasminogen activator for acute ischemic stroke. The National

Vascular Disease. Stroke. 2009;40:2276-2293.

Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.

6. Current management of amaurosis fugax. The Amaurosis Fugax

N Engl J Med. 1995;333:1581-1587. Available at www.nejm.org/doi/

Study Group. Stroke. 1990;21:201-208. Available at stroke.ahajournals

full/10.1056/NEJM199512143332401.

.org/content/21/2/201.long.

15. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window

7. Jovin TG, Demchuk AM, Gupta R. Pathophysiology of acute ischemic

for treatment of acute ischemic stroke with intravenous tissue plasmino-

stroke. Continuum (Minneap Minn). 2008;14:28-45.

gen activator: a science advisory from the American Heart Association/

8. Maas MB, Safdieh J. Ischemic stroke: pathophysiology and principles

American Stroke Association. Stroke. 2009;40:2945-2948. Available at

of stroke localization. In: Atri A, Milligan T, eds. Hospital Physician

stroke.ahajournals.org/content/40/8/2945.long.

Neurology Board Review Manual. Vol 13, Part 1. Wayne, Pa.: Turner White

16. Molina CA. Reperfusion therapies for acute ischemic stroke: current

Communications; 2009:1-16.

pharmacological and mechanical approaches. Stroke. 2011;42:S16-S19.

9. Rangel-Castilla L, Gopinath S, Robertson CS. Management of

Available at stroke.ahajournals.org/content/42/1_suppl_1/S16.long.

intracranial hypertension. Neurol Clin. 2008;26:521-541. Available at

17. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute

www.ncbi.nlm.nih.gov/pmc/articles/PMC2452989/.

ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39:1205-

10. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early

1212. Available at stroke.ahajournals.org/content/39/4/1205.long.

management of adults with ischemic stroke: a guideline from the American

18. Devlin TG, Baxter BW, Feintuch TA, Desbiens NA. The Merci

Heart Association/American Stroke Association Stroke Council, Clinical

Retrieval System for acute stroke: the Southeast Regional Stroke Center

Cardiology Council, Cardiovascular Radiology and Intervention Council,

experience. Neurocrit Care. 2007;6:11-21.

and the Atherosclerotic Peripheral Vascular Disease and Quality of Care

“Was I supposed to answer?

I thought it was a rhetorical text.”

All electronic documents accessed January 15, 2013.

“I cased the joint, and it turns out they’ll just give you money if you work thirty-five hours a week as a teller.”

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

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

Outcomes in Research Interdisciplinary Working Groups: the American

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 FEBRUARY 2013

Consultations Underlying problems of scoliosis. . . . .44 Acetaminophen and fatty liver . . . . . .45 Gluten-free diet or vitamin D supplementation for psoriasis?. . . . . .45

Clinical Pearl Gargle sore throat away . . . . . . . . . . .46

Your Comments Be explicit about your after-hours policy . . . . . . . . . . . . . .46 Patients must learn what constitutes an emergency . . . . . . . . .46

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.

CONSULTATIONS UNDERLYING PROBLEMS OF SCOLIOSIS Two years ago, I discovered previously undocumented scoliosis in a girl, aged 7 years. Her primary-care physician agreed with my recommendation to send her to an orthopedist. The girl’s parent has told me that the orthopedist seemed unconcerned and merely told her to come back if there is a problem. Recently, the girl returned to my clinic complaining of ankle pain. On examination, it appeared that the scoliosis had worsened (4° to 6° increase on x-ray).

I am sending her back to the orthopedist but am worried about the possibility of such other underlying problems as neurofibromatosis. What should I be looking for if she is only advised to wear a brace? It is my understanding that there are usually other problems when scoliosis occurs at such an early age.—KATHLEEN AMBROSE, MSN, CFNP, Allentown, Mich.

It is hard to determine the degree of curvature in this girl’s spine given the information provided. Therefore, I also cannot determine whether it needs any treatment. It would be ideal if you could communicate your concerns directly to the orthopedist and ask for an explanation of his or her opinion. Communication between consulting physicians and patients is not always optimal, and misunderstandings do occur.

Neurofibromatosis-1 (NF-1) occurs in approximately 10% of patients with early-onset scoliosis. Precocious puberty can also be associated

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 Texas Medical Center, Houston.

44 THE CLINICAL ADVISOR • FEBRUARY 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.

with NF-1, so it is important to assess this variable as well, especially since it will be necessary to follow the patient’s curve progression closely during the pubertal growth spurt. Early-onset scoliosis is not the only sign required for diagnosis of NF-1, and such cutaneous manifestations as café au lait spots or axillary freckling are usually present as well. Other rare genetic syndromes (e.g., Angelman) can also be associated with early scoliosis. If any suspicion of a syndrome exists, a genetic referral might be helpful. However, it is also possible that your patient has a slight congenital scoliosis that may or may not continue to progress and, depending on skeletal maturation, needs treatment only once it reaches a certain point. Discuss this with the referring orthopedist. If you get an unsatisfactory answer, send your patient for a second opinion.—Julee B. Waldrop, DNP (172-1)

ACETAMINOPHEN AND FATTY LIVER I recently treated an obese white man, aged 29 years, who reported waking to a bloody nose and blood-soaked pillow two times in the past year. He was taking acetaminophen for headache and ibuprofen for chronic neck and back pain.

His prothrombin time [PT], partial thromboplastin time [PTT], complete blood count, and international normalized ratio were all normal. His alanine aminotransferase [ALT] was 105 units/L; other liver function tests were unremarkable. A hepatitis C antibody test is pending. The man, who has had tattoos since the 1980s, has no history of trauma or nose-picking and uses a high-humidity furnace at home. I suspect fatty liver. Is this a reasonable diagnosis?—TODD W. CHRISTIE, PA-C, Miamisburg, Ohio Fatty liver manifests as hepatomegaly and mildly increased aminotransferase levels. Acetaminophen is a common culprit. Although ALT is more specific to the liver than is aspartate aminotransferase, one would expect elevation of both enzymes in liver disease. Elevation of a single

liver enzyme is often sporadic and will not be found on repeat testing.

Coagulopathy caused by liver disease invariably results in prolonged PT and PTT. A common but easily missed etiology of spontaneous bleed with normal PT, PTT, and platelets is von Willebrand disease.

The bleeding time will be prolonged. Aspirin and aspirinlike products will increase risk of spontaneous yet mild bleeds. This effect may be enhanced with certain dietary products, such as grapefruit.—Claire Babcock O’Connell, MPH, PA-C (172-2)

GLUTEN-FREE DIET OR VITAMIN D SUPPLEMENTATION FOR PSORIASIS? There is a known association between psoriasis and low levels of vitamin D. Gluten is thought to reduce vitamin D absorption, and a gluten-free diet (GFD) is often recommended for those with psoriasis. Would it be beneficial to give suprapharmacologic doses of vitamin D3 in cases of severe psoriasis? Would vitamin D3 combined with acitretin (Soriatane) result in a synergistic action?—BRIJESH BABIO, MD, Delhi, India Psoriasis has a similar inflammatory cytokine profile as celiac disease (CD); a GFD in CD patients improves the absorption of essential nutrients and prevents alimentary deficiencies of iron and certain vitamins. An increased incidence of immunoglobulin (Ig)G/IgA antigliadin antibodies has been observed in individuals with psoriasis; in these patients, disease severity improved after three months of a GFD (Indian J Dermatol Venereol Leprol. 2010;76:103-115). In a pilot study, psoriatic plaques resolved or moderately improved in two of eight psoriasis patients after two to six months of treatment with an oral vitamin D3 derivative (Mayo Clin Proc. 1993;68:835-841).

Subsequently, a prospective randomized study of oral calcitriol (Rocaltrol) with acitretin compared with acitretin alone in psoriasis patients showed a greater reduction in the Psoriasis Area and Severity Index in 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 • FEBRUARY 2013 45

Advisor Forum individuals receiving combination therapy (Acta Derm Venereol. 2007; 87:449-450).—Philip R. Cohen, MD (172-3)

CLINICAL PEARL GARGLE SORE THROAT AWAY For my patients with pharyngitis/laryngitis, I advise gargling two to three times a day with a mixture of 8 oz warm water, one crushed aspirin, one tablespoon hydrogen peroxide, and a quarter teaspoon of salt.—VICTORIA VAMOS, NP, White Plains, N.Y. (172-4)

YOUR COMMENTS

“I should have bought toys with better posture.”

Editor’s note: The following comments were written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at CliniAd.com/VwgfCl.

PATIENTS MUST LEARN WHAT CONSTITUTES AN EMERGENCY The answer lies in patient education. The vast majority of my patients in the emergency department (ED) have either private insurance or Medicaid. Many Medicaid patients overuse the ED because it is convenient and costs them nothing. A number of my patients have no concept of preventive health care or primary care. They go to the health department for immunizations and come to the ED for everything else. These patients waste health-care dollars by the millions. Until we educate people and create a disincentive for unnecessary ED visits, the problem will never go away.—MICKI BURGER, CPNP-PC/AC, Tulsa, Okla. (172-6) ■

“If only I’d thought to take my damn phone with me, I could be getting some work done.”

“I used to call people, then I got into e-mailing, then texting, and now I just ignore everyone.”

46 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

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

BE EXPLICIT ABOUT YOUR AFTER-HOURS POLICY The unnecessary calls Ms. Carlisle mentions can truly burn you out (“New strategies needed for after-hours call triage,” January 14, 2013). Consider a brochure on the limitations of your after-hours call services that can be included in the office visit. In particular, your office needs very firm limits on medication-refi ll procedures. Questions regarding test results, clarifications, etc., need to be addressed during office hours. HIPAA-compliant secure messaging may allow patients to input questions and requests during off-hours, and the office staff can respond during the business day.— SHERRY KAHN, CPNP, Dayton, Ohio (172-5)

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit CliniAd.com/10KIbCF. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

A woman with “mossy” legs A 63-year-old woman with a history of morbid obesity was evaluated for thick, pebbly, warty skin changes on her lower legs. In her 40s, she had lower-extremity venous stasis. Compression stockings were prescribed but never worn. She had been admitted to the hospital on multiple occasions for lower-extremity cellulitis.

WHAT IS YOUR DIAGNOSIS?

• • • •

Lipedema Noonan syndrome Stewart-Treves syndrome Elephantiasis nostras verrucosa

● See the full case at CliniAd.com/SCwoHs

Exaggerated skin markings on the posterior neck At his annual skin check, a 76-year-old man with a history of basal- and squamous-cell carcinoma presented with wrinkles across the back of his neck.

The wrinkles formed a distinct crisscross pattern.

WHAT IS YOUR DIAGNOSIS?

• • • •

Poikiloderma of Civatte Cutis rhomboidalis nuchae Solar purpura Favre-Racouchot syndrome

● See the full case at CliniAd.com/WblqWk

Have you missed any recent Derm Dx cases? Go to CliniAd.com/10KIbCF for a complete archive of past quizzes as well as additional images of last month’s other cases.

An itchy rash on the trunk

48 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

Bumps on a patient’s back

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LEGAL ADVISOR CASE

“Do not resuscitate” stops CPR

BY ANN W. LATNER, JD

What happens when an elderly man tells his clinician that he wants no “heroic measures” taken to prolong his life, but his family has other ideas?

In this month’s case, a physician, a nurse, and the hospital that employs them all end up in court because of mixed messages. Whose instructions do you follow?

Ms. C was a nurse working in a mid-sized hospital in a suburban area. She’d been at the facility for more than two decades and was well respected at her job, particularly by the physicians with whom she worked.

One morning, Dr. L, a pulmonologist and trusted colleague, had been summoned to the emergency department (ED).

“Ms. C,” the physician said, pulling her over in the hallway.“I’d appreciate it if you would come with me to speak to this particular patient. The prognosis is poor and I want to make sure he understands his choices.”

Dr. L went on to explain patient’s medical history. Mr. B, aged 78 years, was a resident of a nursing home and had been brought to the ED due to shortness of breath. Mr. B had a long list

© ISTOCKOHOTO

An elderly man opted for “no heroics” if things went wrong in surgery, but his family felt differently.

At trial, Mr.Y’s family talked about the shock of witnessing their father’s death, and how they had begged the nurses to continue CPR.

of serious medical conditions, including a recent intracranial hemorrhage.

“We ran a CT “that showed massive and extensive blood clotting in Mr. B’s lungs, subsequently affecting the flow of blood to his left leg,” recounted Dr. L. “The scan also shows congestive heart failure. We can’t use blood thinners because of his history of intracranial bleeding, so the only option is surgical.The problem is that Mr. B’s is not a great candidate because of his poor general health. So, I’ve got to explain the options to him and his family.”

The two clinicians went to the patient’s room where Mr. B was breathing with some difficulty, but Ms. C noted that he was alert, able to talk, was oriented to place and time, and understood what was happening.

Dr. L gently explained the situation to the patient and his adult children, pointing out that blood 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.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 49

LEGAL ADVISOR thinners were not an option for Mr. B.The only option, said Dr. L, would be to surgically insert a filter in Mr. B’s groin.

“That’s really all we can do,” Dr. L told Mr. B and his family.

“These blood clots are very large and can stop your heart. But there is also a good chance you won’t survive the operation.

Have you thought about whether you would want ‘heroic measures’ taken—CPR, a breathing machine, or electric shocks to try to start your heart—if you went into cardiac arrest?”

The patient sat up straight, shook his head, and said, “No, I don’t want that. I’ll have the operation, but if something happens, just let me go.”

Ms. C looked at the stunned family.

“Do you know what’s happening?” she asked the family.

“Yes,” one of the children answered.The others nodded.

Dr. L wrote the following in the patient’s chart, and had Ms. C sign that she had witnessed this as well: “Do Not Resuscitate. I discussed with the patient whether he would want CPR, heart defibrillation, or mechanical ventilation. He was quite clear that he did not wish this. I then addressed with the family members in attendance why I did this and whether they understood, and all expressed their agreement.”

The procedure itself went well, and Mr. B was instructed to stay in bed for four hours as part of the recovery.At the end of that time, he wanted to use the restroom. A nurse’s aide was helping him walk there when he suddenly stopped breathing and collapsed.The aide began CPR and called code while the horrified family looked on.

Ms. C was in the hallway when she heard the code. She rushed to Mr. B’s room to find the aide performing CPR. She instructed the aide to stop. “He has a DNR order.”

The aide stopped performing CPR, and Ms. C tried to get the family out of the room. Mr. B’s daughters were crying hysterically, and his son was shouting.

“Do the CPR!” yelled the son, frantically.“Give him CPR! I’m his health-care proxy! I’m telling you to do it!”

Ms. C had to call several nurses to pull the son out of the room. In the hallway, she saw Dr. L speaking to the son. The patient died, and Ms. C went home from her shift with an uneasy feeling that they had not seen the last of Mr. B’s son.

The family of Mr. B hired an attorney and ultimately sued Dr. L, Ms. C, and the hospital for the wrongful death of Mr. B. The case eventually proceeded to trial.

At trial, Mr. B’s children testified about the shock of witnessing their father’s death, and how they had begged the nurses to continue CPR. The son testified that he was the health-care proxy for his father, that his father had a living will created two years prior that stated Mr. B did want CPR in the event he needed it.

Dr. L and Ms. C testified about their conversation with Mr. B, and how he’d clearly, and in front of his children, told them that he did not want to be resuscitated. The defense introduced medical experts who testified that Mr. B’s prognosis was grim, and that it was very unlikely that he would have left the hospital alive, even in the best of circumstances.

The jury deliberated only briefly before finding Dr. L, Ms. C, and the hospital not liable for the death of Mr. B. Legal background

A living will, also called an advance health-care directive, is a set of written instructions in which a person specifies which actions should or should not be taken if he or she can no longer make his or her own health-care decisions. Some of these documents set out specifically what treatments the patient wants or doesn’t want, and what measures health-care practitioners should take if there is an emergency. Some of these documents appoint a third person as the health-care proxy, and that person is authorized to make decisions on behalf of the patient in the event that the patient becomes incapacitated.

Protecting yourself

Mr. B’s living will allowed for CPR and other measures when necessary.The document also appointed his son as his health-care proxy in the event he could no longer make decisions. However, this document was created two years prior to this event, and when presented with new information about the severity of his condition, Mr. B opted to decline heroic measures.

While Dr. L and Ms. C could not protect themselves from this lawsuit, they did protect themselves from being found liable by carefully documenting the conversation with both the patient and his family, and by both signing off on it. In addition, it was clear to both practitioners (and they noted this in the file) that Mr. B was competent, and that his decision,to have a DNR order superseded the living will from two years earlier.

While Mr. B may have wanted heroic measures several years earlier, by the time he arrived at the hospital, he was already recovering from a stroke, suffering from congestive heart failure, and experiencing blood clots. It is understandable that with this new information, his wishes might have changed.

As so many cases do, this one hinged on proper documentation. Without it, although the outcome might have been the same for Mr. B, it would certainly have been different for Dr. L, Ms. C, and the hospital. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

CME CE

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

■ COMPLETE THE POSTTEST: Page 79

■ ADDITIONAL CME/CE: Pages 34, 75

Turn to page 33 for additional information on this month’s CME/CE courses.

CASE #1

Red scalp plaque with painful ulceration ADAM REES, MD

The parents of a white infant, aged 3 months, were concerned about a lesion on the child’s scalp. A very small bruise-like lesion was present at birth; the pediatrician thought it was caused by trauma from delivery. At age 3 weeks, however, the “bruise” became a pink patch that grew into a firm, rubbery, red, and slightly blanchable nodule over the next several months. The lesion recently developed a painful ulceration that began crusting over. On physical examination, the baby appeared healthy. Complete physical and neurologic exam was significant only for the red, ulcerated nodule.

What is your diagnosis? Turn to page 56

CASE #2

Discolored patches from wrist to elbow ESTHER STERN, NP

A girl, aged 11 years, presented to the dermatology clinic with complaints of a slowly spreading discoloration on her right arm.

The discoloration started six months earlier as a small dark patch on her dorsal wrist and spread upward toward the elbow. She was previously treated for a presumed fungal infection with a topical antifungal and a medium-potency topical steroid. Physical examination revealed smooth, shiny, and firm hyperpigmented patches on the dorsal wrist, forearm, and elbow. Mobility of the local joints was normal. The girl had no significant medical history and was taking no medication.

What is your diagnosis? Turn to page 57 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 55

CME CE

CASE #1

Dermatology Clinic

Infantile hemangioma

Infantile hemangiomas are the most common benign tumor in children, affecting 10% to 12% of white infants at age 1 year. Female sex, prematurity, advanced maternal age, Caucasian race, placenta previa, pre-eclampsia, and multiple-gestation pregnancies are risk factors for the development of infantile hemangiomas. Hereditary factors may play a role since approximately 10% of patients have a positive family history.1,2 Infantile hemangiomas can be described as deep, superficial, or mixed. A deep hemangioma is a subcutaneous compressible tumor, often with an overlying blue tint and superficial telangectasias. A superficial infantile hemangioma appears as a bright-red rubbery nodule, papule, or plaque. A mixed infantile hemangioma combines features of both. Infantile hemangiomas are not present at birth but become evident at age 2 to 3 weeks. However, as many as 30% to 50% of infantile hemangiomas develop from a precursor lesion that is present at birth. Precursor lesions have variable appearances and may appear as telangectasias, an area of pale skin, bruise-like, scratch-like, or ulceration.

A fully formed infantile hemangioma present at birth is not an infantile hemangioma and is considered a congenital hemangioma instead.1,2 After becoming evident, the infantile hemangioma enters a proliferative growth phase. Approximately 80% of superficial infantile hemangiomas complete their growth by age 5 months. Deep hemangiomas typically proliferate for one month longer. However, large hemangiomas, particularly those with a deep component, may continue to proliferate for up to one to two years.

When the growth phase is completed, the infantile hemangioma enters the involution phase. During the involution phase, the infantile hemangioma flattens, shrinks in size, becomes less red, and ultimately disappears. Infantile hemangiomas involute at a much slower rate than they proliferate.

The rate of complete involution is estimated to be 10% per year. For example, 40% of infantile hemangiomas will be completely involuted by age 4 years, and 80% completely involute by age 8 years. Involution can result in completely normal skin, but some individuals may be left with atrophy, scar, fibrofatty masses, or telangectasias.1,2

Ulceration is the most common complication of infantile hemangiomas and occurs in 16% of patients. This complication may result in pain, bleeding, scarring, and/ or infection.1,2 Hemangiomas involving large segmental portions of the face may be associated with the “PHACES” syndrome, which involves Posterior fossa malformations, Hemagioma, Arterial anomalies, Cardiac anomalies and aortic coarctation, Eye abnormalities, and Sternal clefting and supraumbilical abdominal raphe. When the beard area of the face is involved, there is risk of hemangiomas involving the upper airway, which can lead to airway obstruction. PHACES syndrome may be the most common neurocutaneous syndrome.1,2 Other particularly problematic infantile hemangiomas are those involving the nasal tip, as this can lead to permanent disfigurement, and those that involve the periorbital skin and eyelids, which can obstruct the visual axis. There is a risk of associated spinal dysraphism when infantile hemangiomas are located perianally and extend towards the gluteal cleft or are located over the lumbosacral spine.1,2 Visceral involvement is another complication of infantile hemangiomas, with the liver being the most commonly involved organ. It is currently recommended that infants with five or more cutaneous hemangiomas undergo a liver ultrasound. Hepatic hemangiomas are usually asymptomatic but occasionally lead to high-output heart failure, hepatomegaly, or thrombocytopenia.1,2 The diagnosis of infantile hemangioma is made by classic physical-examination fi ndings and patient history. Biopsy is rarely indicated. Histologically, infantile hemangiomas stain for GLUT-1 (erythrocyte-type glucose transporter); all other forms of hemangioma are negative for GLUT-1.1, 2 The differential diagnosis includes other vascular tumors.

Congenital hemangiomas are fully formed at birth and may or may not involute. Other vascular tumors in the differential include kaposiform hemangioendothelioma, tufted angioma, and pyogenic granuloma. Each of these tumors has distinctive clinical and histopathologic characteristics that distinguish it from an infantile hemangioma.1,2 Most infantile hemangiomas do not require active treatment, as the lesions will involute spontaneously at a rate of approximately 10% per year. Parental education and guidance is critical during this period. No therapy is typically recommended until the individual is school-aged. By the time the patient enters school, the bulk of the infantile hemangioma will have regressed spontaneously, at which

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

helP INTeRcePT ThRomBoTIc RISk

with the versatility of multiple indications

11

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).

For the reduction in the risk of recurrence of DVT and of PE following initial 6 months treatment for DVT and/or PE.

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

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

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

point vascular laser therapy can be offered to improve the appearance of any residual red color. Occasionally, patients are referred to a plastic surgeon for excision of residual fibrofatty tissue.1,2 Wound-care measures, antibiotics, and as-needed analgesics are used to manage ulcerated infantile hemangiomas.

Pulse-dye laser may also be useful.1,2 When infantile hemangiomas involve the nasal tip, interfere with visual axis, involve the airway, obstruct the ear canal, or have the potential to cause any morbidity or mortality, options include intralesional or oral corticosteroids, oral propranolol (Inderal, InnoPran, Pronol), vincristine (Oncovin, Vincasar), or surgical excision.1,2 Oral propranolol has proven to be a very safe and effective medication for the management of problematic hemangiomas. This observation is supported by recent studies demonstrating that oral propranolol is more effective, requires fewer surgical referrals after treatment, is better tolerated, is more cost-effective, and has fewer adverse effects that systemic corticosteroids, which have historically been considered the gold standard for medical management of infantile hemangiomas. Oral propranolol can be considered a first-line agent.3 The ulcerated hemangioma in this case was managed conservatively with topical white petrolatum. The ulceration was completely healed within one month. By age 3.5 years, the hemangioma had completely regressed with only a small scar at the site of prior ulceration. The patientâ&#x20AC;&#x2122;s hair covered the scar completely, and no further management was required.

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

References 1. Hurwitz S. Vascular disorders of infancy and childhood. In: Paller AS, Mancini AJ. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 4th edition. Philadelphia, Pa.: Elsevier Saunders; 2011:268-275.

2. Maguiness SM, Frieden IJ. Vascular birthmarks. In: Schachner LA, Hansen RC. Pediatric Dermatology. Philadelphia, Pa.: Elsevier Saunders; 2011:1135-1141.

3. Price CJ, Lattouf C, Baum B, et al. Propranolol vs corticosteroids for infantile hemangiomas: a multicenter retrospective analysis. Arch Dermatol. 2011;147:1371-1376. Available at archderm.jamanetwork.com /article.aspx?articleid=1105192.

All electronic documents accessed January 15, 2013.

CASE #2

Morphea

A 4-mm punch biopsy was ordered and was consistent with morphea, a form of localized cutaneous scleroderma.

Scleroderma, an autoimmune connective-tissue disorder, presents in localized and systemic forms. When the disease is localized to the skin and underlying connective tissue only, it is referred to as morphea or localized scleroderma.

Morphea appears with atrophic ivory or dyspigmented patches and plaques, most commonly on the trunk. The affected area appears firm or sclerotic, and local skin elasticity is greatly diminished.

Plaque-type morphea, the most common presentation in adults and the second most common presentation in children, begins with erythematous or ivory patches that evolve into a hyperpigmented or ivory induration over the course of weeks to months. A conspicuous violaceous peripheral border is often present. The size of the plaques ranges from a few centimeters to several inches. Guttate morphea, a subtype of plaque morphea, presents with multiple scattered 1-mm to 3-mm superficial papules on the trunk and/or extremities.

Linear morphea is the most common presentation in children and presents with linear bands of induration and either hyperpigmentation or hypopigmentation. Linear morphea that involves the frontal scalp is termed en coup de sabre and may cause neurologic complications. Parry-Romberg syndrome represents a more severe form of linear facial morphea, with progressive atrophy of half the face. Linear scleroderma that involves an extremity in a pediatric patient may cause stunted growth of the limb and possibly joint contractures. When linear scleroderma involves the chest and breast area in prepubertal females, it can cause underdevelopment of the breasts.

Generalized morphea presents with widespread tight indurated plaques that may be pink, ivory, or hyperpigmented.

Muscle atrophy may be present. Both pansclerotic morphea and morphea profunda have deeper involvement, including the dermis, panniculus, fascia, muscle, or even bone.

Localized scleroderma has been reported to have an incidence of 0.4 to 1.0 per 100,000. The localized form is 10 times more common than the systemic form in children. Whites and females are affected at a significantly higher rate.

The pathogenesis of scleroderma is multifactorial. Both vascular damage and autoimmune dysfunction are thought

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ FEBRUARY 2013 57

Dermatology Clinic

to be involved. Environmental triggers and trauma may play a role in genetically susceptible patients. An association between morphea and Borrelia burgdorferi infection has been investigated,1 but no clear conclusion has been presented.

Although the diagnosis of morphea is often made clinically, lesional skin biopsy is necessary in questionable cases.

Histologic examination of morphea shows an inflammatory cell infi ltrate and thickened collagen bundles within the dermis at earlier stages, and sclerosis, atrophy, and closely packed collagen later in the course of the disease.

Treatment for cutaneous scleroderma is challenging.

Some individuals, particularly children, may experience spontaneous improvement within three to five years when the disease is localized.2 However, the pigment change— and occasionally the atrophy—may persist. Treatment with topical calcipotriene (Dovonex) early in the course of the disease may halt progress. Potent topical steroids may hasten resolution of the lesions, but the risk of localized atrophy must be considered.

More severe disease requires systemic treatment. Low-dose methotrexate (Rheumatrex, Trexall) in combination with pulsed high-dose systemic steroids offers very promising results and is often considered first-line therapy for severe disease.3 Other options include oral mycophenolate mofetil (CellCept), oral calcitriol (Rocaltrol), and psoralen plus UVA light therapy (PUVA).

Tightening of the skin may lead to impaired function of the affected area. Cosmetic appearance is often a concern.

The patient in this case was treated with clobetasol ointment applied in the mornings and calcipotriene foam (Sorilux) applied in the evenings. Six months later, the disease was stable, and the patient had noticed no worsening of the discoloration or skin texture. ■

“Just for kicks, Leon, let’s shut down the F.B.I. again.”

Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Prinz JC, Kutasi Z, Weisenseel P, et al. “Borrelia-associated early-onset morphea”: a particular type of scleroderma in childhood and adolescence with high titer antinuclear antibodies? Results of a cohort analysis and presentation of three cases. J Am Acad Dermatol. 2009;60:248-255.

2. Paller AS, Mancini AJ. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 4th edition. Philadelphia, Pa.: Elsevier Saunders; 2011:522.

3. Kreuter A, Gambichler T, Breuckmann F, et al. Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma. Arch Dermatol. 2005;141:847-852.

“That’s the gist of what I want to say.

Now get me some statistics to base it on.”

58 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

© The New Yorker Collection 2010 from cartoonbank.com. All Rights Reserved.

CME CE

XARELTO® (rivaroxaban) tablets

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

“What flower says you’re sorry without admitting wrongdoing?”

“Can I overwhelm you with a menu?” © 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].

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.

Reflexology

© THINKSTOCK / PHILIP AND KAREN SMITH

Human beings have always sought methods of easing discomfort. Whether emotional or physical, any feeling that is less than optimal drives us to find something to ease the pain. Ancient literature is filled with formulas, descriptions of remedies, and examples of maneuvers and procedures aimed at easing pain. While many of these have been forever lost to history, such practices as reflexology have not only survived, but are enjoying a resurgence in popularity. Research focusing on this technique’s potential utility in pain management is increasing.

Background It is commonly believed that reflexology began in China roughly 5,000 years ago. The ancient Chinese, particularly the Taoists, were known to heal the whole body by tapping pressure points on the feet.

However, reflexology actually might have originated in Egypt around 2500 B.C. Archaeological evidence unearthed at the tomb of Ankmahor, at Saqqara, details an elaborate foot treatment ritual.1 Surviving pictographs found in this tomb depict two seated men receiving massages on their hands and feet at some time during the Sixth Dynasty (circa 2450 B.C.).1 A series of hieroglyphic inscriptions beneath the images suggests a doctor/patient exchange.

Although it is difficult to pinpoint precisely where the practice originated and how it evolved, one fact is clear. William Fitzgerald, MD, an American ear, nose, and throat specialist, significantly advanced the modern practice of reflexology.2 In 1913, Dr. Fitzgerald started studying what he called zone

analgesia. He exerted pressure on specific body parts, or zones, in patients to determine whether this provided substantive— and lasting—pain relief. In addition he believed that applying pressure to regions of the foot corresponded to relief in other, more centrally located areas of the body. Fitzgerald’s research led him to divide the human body into 10 equal longitudinal zones running from head to toe.

Reflexology’s use of controlled pressure for analgesia may be as effective for promoting good health and for preventing illness as it may be for relieving symptoms of stress, injury, and illness.1 Reflexologists today work from maps of predefined pressure points located on the hands and feet.1 In theory, these pressure points can affect the bodily organs and glands.

Science Reflexology uses subtle pressure on specific muscle areas of the feet or hands to stimulate blood flow and nerve impulses that then trigger the release of endorphins and retained toxins.3 The

68 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE majority of clinical trials examining the efficacy of reflexology have targeted conditions involving pain management and anxiety.

In a recent analysis of several randomized, placebocontrolled trials evaluating the efficacy of reflexology, the practice was found to be weakly positive.4 While objective data may not support the use of reflexology, subjective data were more positive.

To evaluate the potential effect of reflexology on conditions affecting 21 elderly nursing-home residents with dementia, researchers conducted an eight-week crossover controlled study.3 Participants were given either foot-reflexology therapy or no therapy, with groups reversed at four weeks.They were evaluated based on end points of physiologic distress (measured by salivary alpha-amylase), observed pain (by the Checklist of Nonverbal Pain Indicators), and observed affect (by the Apparent Affect Rating Scale).3 Persons in the treatment phase showed significant reduction in both observed pain and salivary alpha-amylase measurements.3 In a small pilot study exploring the effects of reflexology on persons with advanced cancer, 17 patients completed the six-week protocol.5 Although no placebo control was used in this study, patients were all scored using the Hospital Anxiety and Depression Scale both before and after the six-week trial. The overall outcome of the study showed no statistically significant effects, but there was a positive notation of increased appetite and mobility in participants.5

Cost, safety

Patients with severe osteoarthritis may benefit from reflexology.

The majority of clinical trials examining the efficacy of reflexology have targeted conditions involving pain management and anxiety.

Reflexology therapy costs vary widely, but the average fee per session is $40 to $50. Many practices combine this therapy with other similar alternative practices, such as chiropractic treatment or acupuncture, so the cost is often a combination of more than one type of treatment. No clinical trials noted found any adverse effects of the therapy. On the contrary, most anecdotal comments were positive. Subtle benefits such as the ability to perform reflexology without having to move a bedfast individual or remove clothing to access the foot are attractive reasons for geriatric and immobile patients to try the therapy.

Summary When choosing any sort of alternative therapy, the first question is always safety. Having found no adverse safety issues with this practice, one could surmise that the worst outcome of reflexology would be no effect at all. Health-care professionals that support the holistic treatment of patients should have no misgivings about trying reflexology, specifically those who desire natural treatments. ■ References 1. History of reflexology page. International Institute of Reflexology website. Available at www.reflexology-usa .net/history.htm.

2. Norman L, Cowan T, Coran T. The Reflexology Handbook:

Regulation

A Complete Guide. Little, Brown Book Group; London, United Kingdom: 2006:17-24.

3. Hodgson NA, Andersen, S. The clinical efficacy of reflexology in nursing home residents with dementia. J Altern Complement Med. 2008;14:269-275.

4. Ernst E, Posadzki P, Lee MS. Reflexology: An update of a systematic review of randomized clinical trials. Maturitas.

2011;62:116-120.

5. Ross CS, Hamilton J, Macrae G, et al. A pilot study to evaluate the effect of reflexology on mood and symptom rating of advanced cancer patients. Palliat Med. 2002; 16:544-545.

6. Home page. American Reflexology Certification Board website. Available at www.arcb.net/cms.

All electronic documents accessed on January 15, 2013.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2312 71

© SCIENCE SOURCE / PHILIPPE GARO

Not unlike many other alternative therapies, no certification is required to practice reflexology in the United States.6 However, several accrediting agencies do exist, and completion of such a program is often considered a standard for being viewed as a qualified therapist by potential clients.

In 1991, the American Reflexology Certification Board was established, and training standards were set for a certification examination.6 Requirements for certification include a minimum age of 18 years, a high-school diploma, 110 hours of training including 10 hours of supervised practice, and performance of at least 90 postgraduate therapy sessions.6

myCME.com

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Available now on myCME! Developed by NPACE, one of the nation’s leading providers of nurse practitioner continuing nursing education, these courses will help you meet your state and national certification pharmacology credit requirements in one convenient web-based location.

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CME CE

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

■ COMPLETE THE POSTTEST: Page 79

■ ADDITIONAL CME/CE: Pages 34, 55

Turn to page 33 for additional information on this month’s CME/CE courses.

Intertriginous erosions KERRI ROBBINS, MD

CASE #1

CASE #2

A man, aged 25 years, presented with a painful, pruritic, and malodorous rash in bilateral axillae. The rash appeared three months earlier, and a family practitioner originally diagnosed it as allergic contact dermatitis, most likely caused by antiperspirant. The patient had since discontinued the use of antiperspirants and was using a mild-potency topical corticosteroid with only moderate improvement. Erythematous macerated plaques were noted in bilateral axillae. Family history was notable for a father with similar lesions in the axillae and groin.

An otherwise healthy man, aged 23 years, complained of a painful, pruritic rash in bilateral axillae and inguinal folds for two months. He had discontinued the use of antiperspirants and had not been using any treatment.

Review of systems was negative for polydipsia, polyuria, bone pain, and shortness of breath. No family members had a history of similar lesions. Physical exam revealed moist erythematous plaques with yellow discharge.

Superimposed impetiginization was noted in bilateral axillae and inguinal folds.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 75

CME CE

CASE #1

Dermatologic Look-Alikes

Hailey-Hailey disease

Hailey-Hailey disease, also known as familial benign chronic pemphigus, was first described in 1939 by Howard and Hugh Hailey, who were brothers studying dermatology at Emory University in Atlanta.

Controversy surrounded the brothers and their new discovery because in 1933, a pair of French dermatologists named Gougerot and Allee described a disease they termed pemphigus congenital familial hereditaire.

However, there was no histopathology to correlate with the cases, and after investigation, the clinical picture was thought to be more consistent with epidermolysis bullosa simplex.1 There was also a debate as to whether Hailey-Hailey was a unique disease or a variant of Darier disease. This debate was solved after the molecular genetics of each disease was better understood. Although there are no exact data on the epidemiology, incidence estimates range from one to two per 100,000 people. Men and women are equally affected.

Hailey-Hailey is an uncommon autosomal dominant disorder in which mutations in the ATP2C1 gene on the 3q2124 chromosome cause dysfunction of a Golgi-associated calcium ATPase pump, thus interfering with intracellular calcium signaling.2,3 ATP2C1 produces a protein product, hSPCA1, that transports calcium and magnesium and sequesters calcium to the Golgi lumen. Mutations in this gene lead to impaired calcium sequestration, which eventually leads to acantholysis. Normal Golgi calcium levels are needed to process proteins through the Golgi apparatus.

When the calcium levels are reduced, the processing of junctional proteins, which are required for normal cell-tocell adhesion, becomes impaired. Calcium deprivation also leads to actin reorganization within keratinocytes. This can alter the formation of the adherens junctions, which are also required for normal cell-to-cell adhesion.

The initial lesions usually appear in the second or third decades but presentation may be delayed until the fourth or fi fth decade. Sites of predilection include the axillary folds, groin, lateral aspects of the neck, and perianal region. The scalp, antecubital and popliteal fossae, trunk, and inframammary regions are less commonly involved.

The initial lesion appears as a flaccid vesicle on normal or erythematous skin. These lesions tend to rupture easily and progress into macerated or crusted erosions, which spread in

a peripheral fashion. Crusts and small vesicles may be seen within circinate borders upon close examination. Lesions tend to be painful and may interfere with daily activities.

Malodor and pruritus can add to the social suffering.

The histologic picture of Hailey-Hailey disease is one of widespread acantholysis throughout the epidermis, giving the appearance of a dilapidated brick wall. A superficial perivascular lymphocytic infi ltrate may also be appreciated. In contrast to Darier disease, necrotic keratinocytes are uncommon. In more advanced lesions, acanthosis, parakeratosis, and focal crusts may be seen. Direct immunofluorescence is negative, helping to differentiate HaileyHailey disease from pemphigus vulgaris.

Given the intertriginous distribution of Hailey-Hailey disease, inverse psoriasis, intertrigo, irritant dermatitis, and candidiasis are often considered in the differential diagnosis.

The presence of flaccid vesicles and erosions, along with the histologic examination, are often the key to the diagnosis. Although usually clinically distinguishable, Darier disease may have significant overlap with Hailey-Hailey disease. Palmoplantar papules, nail changes, and mucosal involvement are distinguishing features of Darier disease.

Histologically, there is often more dyskeratosis and less acantholysis than Hailey-Hailey disease. Grover’s disease may also have a similar histopathologic picture; however, the acantholysis in Grover’s disease tends be more focal and the clinical picture is unique, with lesions occurring in older men on the trunk. Langerhans cell histiocytosis, although clinically similar, may be confi rmed by positive immunostaining for CD1a, S100, and Langerin. As mentioned previously, direct immunofluorescence is negative in Hailey-Hailey disease, thus helping to distinguish it from pemphigus vulgaris.

Patients should be instructed to wear lightweight clothing to prevent excessive friction and sweating, as these are common triggers. Topical corticosteroids, along with topical antimicrobials and cleansers, are an effective treatment regimen for many patients. If corticosteroid application commences early enough, healing of developing lesions can occur. Refractory cases may be treated with intralesional corticosteroids at the lowest effective potency. Botulinum toxin A or surgical wide excision with grafting has also been reported to be successful in refractory cases. Such superficial ablative surgical techniques as dermabrasion, carbon dioxide, or erbium:YAG laser allow the epidermis to heal from uninvolved adnexal structures and may be equally effective.4 There is no strong evidence to support the use of systemic therapy in Hailey-Hailey disease.

76 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

Healing usually occurs without scarring; however, postinflammatory hyperpigmentation is not uncommon. The disease course is unpredictable, and patients should be instructed to avoid excessive friction or heat. Complete remission as well as flares are common. Life expectancy is normal.

A biopsy performed on this patient confirmed a diagnosis of Hailey-Hailey disease. Direct immunofluorescence was negative. The patient was advised to wear lightweight clothing and avoid excessive heat. Improvement was noted after treatment with triamcinolone 0.1% ointment twice daily as needed and topical clindamycin 1% solution.

CASE #2

Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal proliferative disease of Langerhans cells that primarily affects young children between age 1 and 3 years. The reported incidence of LCH varies widely, ranging from at least five per million in children to approximately one to two per million in adults. LCH is seen more commonly in boys, with a maleto-female ratio of 2:1. LCH is rarely seen in adults, but when present, there may be a slight female predominance.

The most commonly affl icted sites in adults include the skin, lung, and bone.

In 1868, Paul Langerhans was the first to discover the epidermic dendritic cell, which is now known as a Langerhans cell. The four well-described variants of LCH include congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease), Hand-Schüller-Christian disease, Letterer-Siwe disease, and eosinophilic granuloma. The latter three were first described in the early twentieth century, and in 1953, Lichtenstein grouped the trio into a single disease entity termed histiocytosis X.5 In 1978, Hashimoto and Pritzker described congenital self-healing reticulohistiocytosis. After immunologic and ultrastructural studies, congenital selfhealing reticulohistiocytosis and histiocytosis X were reclassified into a single disease spectrum known as LCH. The pathogenesis of LCH remains unknown. Viral and immunologic etiologies have been considered, but there has been no evidence to implicate either as the cause.6

Such cytokines as IL-1, IL-2, IL-4 and IL-10, TNF-alpha, interferon-gamma, and GM-CSF have been found in elevated numbers within the lesions of patients with LCH. While these cytokines are not thought to be responsible for the development of the disease, they may promote disease-related symptoms and morbidity. A few cases of LCH appear to be hereditary; hence, a genetic basis now appears likely.7 There is significant clinical overlap between the four variants of LCH. Because of its clinical similarity to HaileyHailey disease, this discussion focuses mainly on the acute diffuse form of LCH, Letterer-Siwe disease. The disease usually develops prior to age 2 years, and most patients present prior to age 1 year. The eruptions consist of 1-to2-mm erythematous to skin-colored papules, pustules, or vesicles that are most commonly seen in the flexural regions of the axilla, groin, and neck, as well as the scalp and trunk.

The lesions tend to coalesce and may develop petechiae, purpura, crust, and secondary impetiginization. During the course of the disease, clonal LCH cells may infi ltrate the lung, liver, lymph node, and bone.

The triad of bone lesions, exophthalmos, and diabetes insipidus characterizes Hand-Schüller-Christian disease.

Most patients present between ages 2 and 6 years, and these individuals tend to have a chronic progressive course.

Cutaneous lesions are present in approximately 30% of patients, and early lesions are similar to those seen in Letterer-Siwe disease. As the disease progresses, the lesions may become xanthomatous.

Eosinophilic granuloma is a localized variant of LCH that usually affects older children and has a predilection for the cranium. The classic manifestation of the disease is a single asymptomatic granulomatous lesion of the bone.

Congenital self-healing reticulohistiocytosis (HashimotoPritzker disease) is a rapidly self-healing variant of LCH. These patients present with erythematous to brown papulonodules at birth or within the first few days of life. Several weeks after onset, the papules crust and involute.

Just as there is significant overlap between the clinical manifestations of the various subtypes of LCH, there is also histologic overlap. In a typical lesion, Langerhans cells, which are large cells with a reniform (kidney-shaped) nucleus, occupy the papillary dermis. There are usually interface changes with some epidermal infi ltration of Langerhans cells. Admixed with the LCH cells within the dermis are eosinophils, neutrophils, lymphocytes, mast cells, and plasma cells. Older lesions may become granulomatous, xanthomatous, or fibrous. LCH cells show

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 77

Dermatologic Look-Alikes

positive immunostaining for CD1a, S100, and Langerin (CD207). They do not stain positive for factor XIIIa (a marker for dermal dentrocytes) or CD68, Mac387, and HAM56 (macrophage/monocyte markers).

The clinical differential diagnosis for LCH is vast and includes Hailey-Hailey disease, Darier disease, candidiasis, seborrheic dermatitis, intertrigo, scabies, and eczema. One should begin to suspect LCH if the disease is not getting better on routine treatment for more common conditions. The distinctive histologic features of LCH, along with positive immunostaining for CD1a, S100, and Langerin, help clinch the diagnosis. Electron microscopy may also demonstrate Birbeck granules, which are racquet-shaped cytoplasmic structures that are pathognomonic for Langerhans cells.

Any individual with suspected LCH should undergo hematologic, pulmonary, hepatic, renal, and skeletal system evaluation to determine the extent of the disease. The organ involved and the extent of involvement dictate treatment.

If skin treatment is desired, topical corticosteroids, topical antibacterial agents, photochemotherapy (psoralen UVA), and topical nitrogen mustard have been reported to be effective. Thalidomide (Thalomid) has been used in cases with extensive skin disease, including LCH.8 Multidrug chemotherapy is reserved for those with multisystem disease.

Patients with multisystem disease, especially those who are under age 2 years, have a high mortality rate, ranging from 38% to 54%.9 Patients who do not fall into this category tend to fare better.

Two biopsies taken on different occasions each revealed the diagnosis of LCH in this patient. A swab culture was positive for Staphylococcus aureus, which cleared with systemic antimicrobials. The man was referred to hematologyoncology, where the workup was completed. No other organ system was found to be involved. The skin disease is being treated with triamcinolone 0.1% ointment b.i.d. as needed with improvement. The patient continues to be monitored for progression to systemic disease. ■

2003;121:688-694. Available at www.nature.com/jid/journal/v121/n4/ full/5601953a.html.

4. LeBlanc KG Jr, Wharton JB, Sheehan DJ. Refractory Hailey-Hailey disease successfully treated with sandpaper dermabrasion. Skinmed.

2011;9:263-264.

5. Lichtenstein L. Histiocytosis X: integration of eosinophilic granuloma of bone, Letterer-Siwe disease and Hand-Schüller-Christian disease as related manifestations of a single nosologic entity. AMA Arch Pathol. 1953;56:84-102.

6. McClain K, Jin H, Gresik V, Favara B. Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol. 1994;47:16-20.

7. Aricò M, Nichols K, Whitlock JA, et al. Familial clustering of Langerhans cell histiocytosis. Br J Haematol. 1999;107:883-888.

8. Chen M, Doherty SD, Hsu S. Innovative uses of thalidomide. Dermatol Clin. 2010;28:577-586.

9. Gadner H, Grois N, Aricò M, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138:728-734.

All electronic documents accessed January 15, 2013.

“I think you’re using lawnmower repair to avoid intimacy.”

Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

References 1. Steffen C, Thomas D. Was Henri Gougerot the first to describe “Hailey-Hailey Disease”? Am J Dermatopathol. 2003;25:256-259.

2. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65.

3. Behne MJ, Tu CL, Aronchik I, et al. Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. J Invest Dermatol.

“Will I still be able to not exercise?”

78 THE CLINICAL ADVISOR • FEBRUARY 2013 • www.ClinicalAdvisor.com

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

CME CE

CE

POSTTEST Expiration date: February 2014

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 34

page 55

page 75

Evaluation and treatment of acute cerebral ischemia

Case #1: Infantile hemangioma

Case #1: Hailey-Hailey disease

1. What risk factor is associated with infantile hemangioma? a. Advanced maternal age b. Caucasian race c. Female sex d. All of the above

1. Hailey-Hailey disease has a predilection to appear at what anatomic site? a. Axillary folds b. Inframammary region c. Trunk d. Popliteal fossae

2. What is used in the management of problematic hemangiomas? a. Quinapril (Accupril) b. Propranolol (Inderal, InnoPran, Pronol) c. Diltiazem d. Clonidine (Catapres)

2. In contrast to Darier disease, what is a distinguishing characteristic of HaileyHailey disease? a. Mucosal involvement b. Palmoplantar papules c. Flaccid vesicles and erosions d. Truncal lesions in older men

Case #2: Morphea

Case #2: Langerhans cell histiocytosis (LCH)

1. What describes the classic ophthalmologic symptom of transient ischemic attack? a. Shade pulled down over vision in one eye b. Sudden central vision loss with absence of pain c. Acute onset of severe pain with photophobia d. Blurring of vision with reflex blepharospasm 2. What is the clinical presentation when a stroke involves Broca’s area? a. Hemiparesis affecting lower extremity b. Expressive aphasia with word-finding difficulty c. Fluent but nonsensical speech d. Contralateral hemisensory loss 3. What is the recommended dose of recombinant tissue plasminogen activator (rtPA)? a. 0.3 mg/kg b. 0.6 mg/kg c. 0.9 mg/kg d. 0.12 mg/kg 4. What symptoms require immediate discontinuation of rtPA infusion? a. Severe headache b. Acutely elevated hypertension c. Nausea or vomiting d. All of the above TO TAKE THE POSTTEST please go to CliniAd.com/1122FqL

3. What is the clinical appearance of morphea? a. Erythematous or ivory patch with violaceous border b. Thick plaque with mild scaling c. Discrete, waxy, umbilicated papule d. Raised papule with distinct margin 4. What medication is used with highdose systemic steroids as first-line treatment for severe disease? a. Sulfasalazine (Azulfidine) b. Hydroxychloroquine (Plaquenil) c. Methotrexate (Rheumatrex, Trexall) d. Cyclosporine (Gengraf, Neoral, Sandimmune)

3. What characterizes Hand-SchüllerChristian disease? a. Bone lesions b. Diabetes insipidus c. Exophthalmia d. All of the above 4. Which medication has been used in cases of extensive LCH? a. Doxorubicin (Adriamycin, Rubex) b. Thalidomide (Thalomid) c. Vincristine (Oncovin, Vincasar) d. Dexamethasone (Decadron, Dexamethasone Intensol, Dexpak Taperpak)

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 79

CME

POSTTEST Expiration date: February 2014

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 February 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 34

page 55

page 75

Evaluation and treatment of acute cerebral ischemia

Case #1: Infantile hemangioma

Case #1: Hailey-Hailey disease

1. What risk factor is associated with infantile hemangioma? a. Advanced maternal age b. Caucasian race c. Female sex d. All of the above

1. Hailey-Hailey disease has a predilection to appear at what anatomic site? a. Axillary folds b. Inframammary region c. Trunk d. Popliteal fossae

2. What is used in the management of problematic hemangiomas? a. Quinapril (Accupril) b. Propranolol (Inderal, InnoPran, Pronol) c. Diltiazem d. Clonidine (Catapres)

2 In contrast to Darier disease, what is a distinguishing characteristic of HaileyHailey disease? a. Mucosal involvement b. Palmoplantar papules c. Flaccid vesicles and erosions d. Truncal lesions in older men

Case #2: Morphea

Case #2: Langerhans cell histiocytosis (LCH)

1. What describes the classic ophthalmologic symptom of transient ischemic attack? a. Shade pulled down over vision in one eye b. Sudden central vision loss with absence of pain c. Acute onset of severe pain with photophobia d. Blurring of vision with reflex blepharospasm 2. What is the clinical presentation when a stroke involves Broca’s area? a. Hemiparesis affecting lower extremity b. Expressive aphasia with word-finding difficulty c. Fluent but nonsensical speech d. Contralateral hemisensory loss 3. What is the recommended dose of recombinant tissue plasminogen activator (rtPA)? a. 0.3 mg/kg b. 0.6 mg/kg c. 0.9 mg/kg d. 0.12 mg/kg 4. What symptoms require immediate discontinuation of rtPA infusion? a. Severe headache b. Acutely elevated hypertension c. Nausea or vomiting d. All of the above TO TAKE THE POSTTEST please go to CliniAd.com/1122FqL

3. What is the clinical appearance of morphea? a. Erythematous or ivory patch with violaceous border b. Thick plaque with mild scaling c. Discrete, waxy, umbilicated papule d. Raised papule with distinct margin 4. What medication is used with highdose systemic steroids as first-line treatment for severe disease? a. Sulfasalazine (Azulfidine) b. Hydroxychloroquine (Plaquenil) c. Methotrexate (Rheumatrex, Trexall) d. Cyclosporine (Gengraf, Neoral, Sandimmune)

3. What characterizes Hand-SchüllerChristian disease? a. Bone lesions b. Diabetes insipidus c. Exophthalmia d. All of the above 4. Which medication has been used in cases of extensive LCH? a. Doxorubicin (Adriamycin, Rubex) b. Thalidomide (Thalomid) c. Vincristine (Oncovin, Vincasar) d. Dexamethasone (Decadron, Dexamethasone Intensol, Dexpak Taperpak)

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 79

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NP/PA WANTED

PA WANTED

Established Family Practice Clinic in Santa Teresa, NM seeking NP/PA for full-time position.

40 hrs/wk, no call, no weekends.

Salary negotiable upon experience.

Call Minerva De Veau at: (575) 589-1144.

NP/PA WANTED

NP/PA WANTED

PHYSICAN ASSISTANT NURSE PRACTITIONERS / MINNESOTA PA or NP - General Surgery/Bemidji, Minnesota PA or NP - Orthopedic Surgery/Bemidji, Minnesota PA or NP - Emergency Room Department/Bagley, Minnesota Live and work in a community that offers exceptional schools, a state university with NCAA Division I hockey and community symphony and orchestra. With over 500 miles of trails and 400 surrounding lakes, this active community was ranked #27 by Outdoor Life Magazine. Enjoy a fulfilling lifestyle and rewarding career.

Contact Celia Beck Sanford Physician and Advanced Practice Recruitment (218) 333-5056 • fax (218) 333-5360, Celia.Beck@sanfordhealth.org • www.sanfordhealth.org

Sanford is an AA/EOE. Drug-free/Smoke-free workplace.

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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

NP WANTED

Desert Horizons Psych NP position Phoenix, Arizona We are looking for a Psychiatric Nurse Practitioner to join our team at the District Medical Group Desert Horizons Clinic. The clinic provides outpatient behavioral health services in the East Valley and is seeking a full-time nurse practitioner to join our staff of adult and child and adolescent psychiatrists and master’s level social workers. The position would include employment with District Medical Group Inc. (DMG), a multispecialty group with over 300 clinical providers. The position involves providing evaluation and primarily medication management services to a population of adolescents and adults, most of whom have private insurance coverage.

Qualified candidates must have an Arizona NP license with specialization in Psychiatry. Strong interpersonal skills and previous clinical experience are preferred.

DMG offers an outstanding work environment and competitive compensation and benefits package, including 4 weeks of PTO (personal time off), one week of continuing education time, CME allowance, pension plan and employer paid malpractice insurance.

NP WANTED

MEDICAL EDUCATION

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

PA WANTED An Eastern NC practice is seeking a PA. We provide EMR, competitive salary, negotiable benefits, and a great work environment in our spacious well-equipped facility.

Candidates must have a Current NC License, federal and commercial insurance credentialing is a plus.

You may submit your resume via email or fax.

Email: billing@downeastfamilymedicine.com Fax: 910-353-0967

For consideration, forward your CV to: practice@dmgaz.org

EOE

CLASSIFIEDS

Email for ad info: ca@russelljohns.com

RN First Assisting School for the NP or CNS Professional Assistants PRN since 1986

Provides the education the Advanced Nurse Practitioner needs to assume the role of first assist and to comply with scope of practice in the role in which they are practicing or anticipate entering.

2013 CLASS DATES: Mar 28-31: Jun 20-23: Sept 19-22 For additional information/application: www.RNFA@swfc.edu/rnfa or www.professionalassistantsprn.com Professional Assistants PRN C/O SWFC 3910 Riga Blvd Tampa, FL 33619 Meets AORN Education Standards for RN First Assistant programs and accepted by CCI. Intensive didactic program with suture labs followed by an independent clinical internship in your facility.

In conjunction with Southwest Florida College

Call 877.761.2462

MEDICAL EDUCATION

PA WANTED

Well established primary care/ urgent care clinic in Southeastern, SC is in need of a physician assistant.

Excellent compensation package.

401k, profit sharing and defined benefit plans are available.

Health insurance coverage, short and long term disability plans, relocation expenses, and malpractice insurance plans are also available.

Starting Salary of $70,000.

For inquiries contact Dr. Nicole, PA Recruiters at: 803-467-4346 or fax CV to: 803-774-7004 or 803-403-8483 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2013 81

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COMMENTARY Debra Clements Coats, RN, BSN, CRNP-FNP student, who recently completed a pediatric rotation, works in an internal-medicine practice and an infectious-diseases practice.

Infant safety: part of the primary-care job Each year, hundreds of children in the United States younger than age 1 year die of injuries, most of which could have been easily prevented. In 2009, the CDC recorded 1,181 deaths caused by events falling under the heading of “unintentional injury” among children younger than age 1 year; the majority (907) were caused by suffocation, followed by motor-vehicle traffic accidents (91) (MMWR. 2012;61:1-7, available at www.cdc.gov/mmwr/preview/mmwrhtml /mm61e0416a1.htm; accessed January 15, 2013). In the same year, a total of 1,466 youths aged 1 to 4 years succumbed to drowning (450 children), motor-vehicle traffic accidents (362), and burns

The high incidence of infant suffocation reflects the importance of a safe sleeping area.

(169), among other injuries. Primary-care clinicians need to educate parents of young children on dangers such as suffocation, car safety, falls, burns, and choking. Specific prevention strategies exist for children in each age group. For instance, parents who have a child younger than age 6 months should receive instruction on the proper installation of car seats and stairway gates, and be reminded to never carry a baby and hot foods or hot drinks at the same time.

The CDC notes in its report that the high incidence of infant suffocation underscores the importance of a safe sleeping environment as recommended by the American Academy of Pediatrics (AAP), including supine positioning, a firm sleep surface, room-sharing without bed-sharing, and avoidance of loose bedding.

In addition, the agency has developed the Sudden Unexpected Infant Death (SUID) Case Registry, aimed at better understanding and ultimately preventing SUID deaths, which include suffocation in bed.

Car seats for babies should be installed according to the product’s instructions and the recommendations found in the automobile owner’s manual. Be sure the parent also knows whether the car seat should be rear-facing or frontfacing. A 2007 report in the BMJ journal Injury Prevention concluded that rear-facing childsafety seats are more protective than front-

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facing seats for children up to age 23 months (2007;13:398-402). A 2011 policy statement from the AAP advises parents to keep children in rear-facing car seats until age 2 years or until the child reaches the maximum height and weight for the seat (available at pediatrics. aappublications.org/content/early/2011/03/21 /peds.2011-0213; accessed January 15, 2013).

The Mayo Clinic provides some excellent suggestions for fall prevention in the home, such as never leaving a baby alone on a bed, a changing table, or a piece of furniture; discouraging play near windows and patio doors, which could lead to a fall through glass; and using night-lights in the child’s bedroom, in the bathroom, and in hallways to prevent falls at night (available at www.mayoclinic.com/health/child-safety /FL00003; accessed January 15, 2013).

One easy way to educate new parents is by cell phone. Text4baby (www.text4baby.org) is a program that sends educational text messages at no charge, starting from the mother’s pregnancy and continuing throughout the baby’s first year of life. The cell-phone messages are timed to the mother’s due date or the baby’s date of birth so that the tips and information the mother receives are coordinated with the baby’s prenatal and postnatal growth and development. Some topics covered are birth-defect prevention, developmental milestones, and immunizations. ■