December 2013 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • DECEMBER 2013

A F O RU M F O R N U R S E P R AC T I T I O N E R S

NEWSLINE

■■CVD prevention guidance ■■Too few treated for hep C ■■Malaria cases on the rise

ADVISOR FORUM

■■Testing for multiple STDs ■■The life span of mono ■■Relief of oral mucositis

| D E C E M B E R 2 013 | www.ClinicalAdvisor.com

CE: RADIATION RISK IN

CT SCANNING A large subdural hematoma (red) is visible on head CT.

LEGAL ADVISOR

Fatal dosage error caused by an illegible prescription

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n Dermatology Clinic

SCATTERED, OPEN COMEDONES PAGE 113

VOLUME 16, NUMBER 12

n Dermatologic Look-Alikes

LOCALIZED VESICLES ON THE TRUNK PAGE 119

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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers with the latest information about conditions seen in everyday practice. Running no more than 3,000 words, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and Web sites. In addition, include your curriculum vitae, which should list all current titles and affiliations. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affiliations, and curriculum vitae. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a brief description of the patient and/or his presentation, without giving away the diagnosis. This is followed by a 750- to 1,000-word summary that includes a fuller description of the ailment, how the correct diagnosis was achieved, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 700 words in length. To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@ClinicalAdvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2013 5

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz 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 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 16, Number 12, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send address change to DMD Data Inc. 10255 W. Higgins Rd, Suite 280, Rosemont, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2013.

THE PEER NETWORK Join The Peer Network! What is it? The Peer Network is a social rewards system in which you earn points and badges for doing the things you love on our site, all while sharing your clinical knowledge with other users. How do I join? If you already have an account with ClinicalAdvisor.com, just log in. Otherwise, click on “Join now” to register for free and become a part of The Peer Network. How does it work? You start earning points right away. For example, you’ll receive 25 points just for reading an article.You can get even more points by leaving a comment. Each time you earn points, a notification will appear at the bottom of your screen. With each action, you’ll work your way toward unlocking a new level and earn badges to keep track of your accomplishments.You might start out as just a Scholar, but one day you could be the Dean!

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6 THE CLINICAL ADVISOR • DECEMBER 2013 • www.ClinicalAdvisor.com

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LEVEL

CONTENTS DECEMBER 2013

NEWS AND COMMENT 28 Newsline ■■Before-and-after CVD prevention guide ■■Vitamin D won’t add to calcium absorption ■■Too few patients get hepatitis C treatment ■■Nosebleed fixes vary, results don’t ■■Measles shot by 15 months reduces risks ■■Malaria cases on the rise in the U.S. ■■ACP says no to routine kidney screening ■■And more

92 What you should know about medical marijuana Federal criminalization of this drug— most commonly used in the treatment of HIV, pain, and glaucoma—has limited research into its effectiveness.

Guidelines cover CVD prevention 28

DEPARTMENTS 104 Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com.

42 Drug Update ■■Inhalant for agitation in schizophrenia ■■SNRI for adults with MDD ■■Antiretroviral inhibits HIV-1 integrase

105 Legal Advisor An illegible prescription leads clinicians to engage in guesswork to decipher the intended dosage.

128 Commentary Risks and benefits of CT scanning 56

FEATURES 56 CME/CE Minimizing radiation risk from diagnostic imaging In addition to increasing radiation exposure, CT scanning often uncovers incidental findings that may lead to emotional stress for the patient. 66 Understanding the changes in the DSM-5 The latest revision of the diagnostic manual does away with the complex multiaxial organization in favor of a simpler chapter listing of disorders.

MAKING CONTACT

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97 Treating hypertension in older patients In those older than age 65 years, high BP heightens risk for various forms of heart disease as well as for chronic kidney disease and diabetes mellitus.

107 Clinical Challenge A teenager complains of wrist pain, yet shows no swelling and exhibits symmetric bilateral range of motion.

Continues on page 23

Potassium overdose in a kidney patient 105

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INVOKANATM is the # branded therapy prescribed by endocrinologists when adding or switching non-insulin type 2 diabetes medications*

ENVISION NEW POSSIBILITIES *Data on file. Based on NBRx data sourced from IMS NPA Market Dynamics Database, weekly data through 9/20/13.

INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >>History of a serious hypersensitivity reaction to INVOKANA™. >>Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease, or patients on dialysis.

Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

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THIS ADVERTISEMENT PREPARED BY NeON Client: J&J Product: Invokana Job#: 5CNT_CAUS_I0062 Job Name: 10062_A3_Sita_Ad Colors: 4C Sizes: Bleed: 8.75” w x 11.5” h Lg. Trim: 8.5” w x 11” h Sm Trim: 7.75” w x 10.5” h Live: 6.75” w x 9.5” h

Publications:

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Date

Time

Time Spent

Spell Check

COVERED FOR >75% OF COMMERCIALLY INSURED PATIENTS WITHOUT PRIOR AUTHORIZATION3

INVOKANATM 300 mg demonstrated greater reductions in A1C vs Januvia® 100 mg at 52 weeks…

Adjusted Mean Change in A1C From Baseline (%): INVOKANA™ 300 mg vs Januvia® 100 mg, Each in Combination With Metformin + a Sulfonylurea1

DIFFERENCE FROM JANUVIA®

– 0.37*

(95% CI: –0.50, –0.25); P<0.05

Januvia® 100 mg + metformin and a sulfonylurea (n=378; mean baseline A1C: 8.13%) INVOKANA™ 300 mg + metformin and a sulfonylurea (n=377; mean baseline A1C: 8.12%)

–0.66

Incidence of Hypoglycemia

Convenient Once-Daily Oral Dosing1

With metformin + a sulfonylurea over 52 weeks: INVOKANATM (canagliflozin) 300 mg: 43.2%; Januvia® 100 mg: 40.7%1

>>Recommended starting dose: INVOKANA™ 100 mg >>Dose can be increased to 300 mg in patients tolerating 100 mg who have an eGFR ≥60 mL/min/1.73 m2 and require additional glycemic control * INVOKANA™ + metformin is considered noninferior to Januvia® + metformin because the upper limit of the 95% confidence interval is less than the prespecified noninferiority margin of 0.3%.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensin-convertingenzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. >>Impairment in Renal Function: INVOKANA™ increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. >>Hyperkalemia: INVOKANA™ can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the reninangiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

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Change in Body Weight†

INVOKANATM provides SGLT2 inhibition, reducing renal glucose reabsorption and increasing urinary glucose excretion.1

Signiﬁcant reductions in body weight at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)1 >>Difference from Januvia®‡: 300 mg: –2.8%

Adverse Reactions In 4 pooled placebo-controlled trials, the most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.1§

Change in SBP† Signiﬁcant lowering of SBP at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)2 >>Difference from Januvia®‡: 300 mg: –5.9 mm Hg INVOKANATM is not indicated for weight loss or as antihypertensive treatment.

–1.03

>>Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue1

...as well as greater reductions in body weight† and systolic blood pressure (SBP)†

References: 1. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 2. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508-2515. 3. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. Data as of 9/17/13. SGLT2 = sodium glucose co-transporter-2. Included 1 monotherapy and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.

†Prespeciﬁed secondary endpoint.

Indicated trademarks are registered trademarks of their respective owners.

‡Adjusted mean.

Learn more at INVOKANAhcp.com/journal

>>Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >>Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >>Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™. If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >>Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA™. Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >>Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug. Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

ENVISION NEW POSSIBILITIES 10/30/13 12:13 PM

COVERED FOR >75% OF COMMERCIALLY INSURED PATIENTS WITHOUT PRIOR AUTHORIZATION3

INVOKANATM 300 mg demonstrated greater reductions in A1C vs Januvia® 100 mg at 52 weeks…

Adjusted Mean Change in A1C From Baseline (%): INVOKANA™ 300 mg vs Januvia® 100 mg, Each in Combination With Metformin + a Sulfonylurea1

DIFFERENCE FROM JANUVIA®

– 0.37*

(95% CI: –0.50, –0.25); P<0.05

Januvia® 100 mg + metformin and a sulfonylurea (n=378; mean baseline A1C: 8.13%) INVOKANA™ 300 mg + metformin and a sulfonylurea (n=377; mean baseline A1C: 8.12%)

–0.66

Incidence of Hypoglycemia

Convenient Once-Daily Oral Dosing1

With metformin + a sulfonylurea over 52 weeks: INVOKANATM (canagliflozin) 300 mg: 43.2%; Januvia® 100 mg: 40.7%1

004991-131021_10160246_A_Sita_Ad_FR2.indd 2-3

Change in Body Weight†

INVOKANATM provides SGLT2 inhibition, reducing renal glucose reabsorption and increasing urinary glucose excretion.1

Signiﬁcant reductions in body weight at 52 weeks, each in combination with metformin + a sulfonylurea (P<0.001)1 >>Difference from Januvia®‡: 300 mg: –2.8%

Adverse Reactions In 4 pooled placebo-controlled trials, the most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.1§

–1.03

>>Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue1

...as well as greater reductions in body weight† and systolic blood pressure (SBP)†

†Prespeciﬁed secondary endpoint.

Indicated trademarks are registered trademarks of their respective owners.

‡Adjusted mean.

Learn more at INVOKANAhcp.com/journal

ENVISION NEW POSSIBILITIES 10/30/13 12:13 PM

INVOKANA™

IMPORTANT SAFETY INFORMATION (cont’d)

>> Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in

utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo). >> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium. The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

Janssen Pharmaceuticals, Inc.

Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended. OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. ADVERSE REACTIONS >> The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritus, thirst, nausea, and constipation. Please see brief summary of full Prescribing Information on the following pages.

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DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control.

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information. IndIcatIons and Usage INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. contraIndIcatIons • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WarnIngs and PrecaUtIons Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. adverse reactIons The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] clinical studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to

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INVOKANA™

IMPORTANT SAFETY INFORMATION (cont’d)

Janssen Pharmaceuticals, Inc.

Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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November 2013

004991-131021

K02CAN13149

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INVOKANA™ (canagliflozin) tablets

INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled studies reported in ≥ 2% of InvoKana-treated Patients* InvoKana InvoKana Placebo 100 mg 300 mg Adverse Reaction n=646 n=833 n=834 3.2% 10.4% 11.4% Female genital mycotic infections† Urinary tract infections‡ 4.0% 5.9% 4.3% 0.8% 5.3% 4.6% Increased urination§ 0.6% 4.2% 3.7% Male genital mycotic infections¶ Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst# 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2). The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA

100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dosedependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. table 2: Proportion of Patients With at Least one volume depletion-related adverse reactions (Pooled results from 8 clinical trials) comparator InvoKana InvoKana group* 100 mg 300 mg Baseline characteristic % % % Overall population 1.5% 2.3% 3.4% 2.6% 4.9% 8.7% 75 years of age and older† eGFR less than 2.5% 4.7% 8.1% 60 mL/min/1.73 m2† Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dosedependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. table 3: changes in serum creatinine and egFr associated with InvoKana in the Pool of Four Placebo-controlled trials and Moderate renal Impairment trial

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA was associated with an increased incidence of renalrelated adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. table 4: Incidence of Hypoglycemia* in controlled clinical studies

table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

004991-131021_10160246_A_Sita_Ad_FR2.indd 6-7

Placebo n=646 Creatinine (mg/dL)

0.84

0.82

eGFR (mL/min/1.73 m2)

87.0

88.3

88.8

Week 6 Change

Creatinine (mg/dL)

0.01

0.03

0.05

eGFR (mL/min/1.73 m2)

-1.6

-3.8

-5.0

End of Treatment Change*

Creatinine (mg/dL)

0.01

0.02

0.03

eGFR (mL/min/1.73 m2)

-1.6

-2.3

-3.4

Baseline Pool of Four PlaceboControlled Trials

InvoKana InvoKana 100 mg 300 mg n=833 n=834

InvoKana InvoKana Placebo 100 mg 300 mg n=90 n=90 n=89 Baseline Moderate Week 3 Renal Impairment Change Trial End of Treatment Change*

Creatinine (mg/dL)

1.61

1.62

1.63

40.1

39.7

38.5

Creatinine (mg/dL)

0.03

0.18

0.28

eGFR (mL/min/1.73 m2)

-0.7

-4.6

-6.2

Creatinine (mg/dL)

0.07

0.16

0.18

eGFR (mL/min/1.73 m2)

-1.5

-3.6

-4.0

eGFR (mL/min/1.73

m 2)

* Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

Monotherapy (26 weeks) Overall [N (%)] In combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with sulfonylurea (18 weeks) Overall [N (%)] In combination with Metformin + sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0

In combination with Metformin + sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7)

InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3)

Placebo (n=565) 208 (36.8) 14 (2.5)

InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensinconverting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions]. Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-HighDensity Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebocontrolled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions]. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. drUg InteractIons Ugt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

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INVOKANA™ (canagliflozin) tablets

table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

004991-131021_10160246_A_Sita_Ad_FR2.indd 6-7

Placebo n=646 Creatinine (mg/dL)

0.84

0.82

eGFR (mL/min/1.73 m2)

87.0

88.3

88.8

Week 6 Change

Creatinine (mg/dL)

0.01

0.03

0.05

eGFR (mL/min/1.73 m2)

-1.6

-3.8

-5.0

End of Treatment Change*

Creatinine (mg/dL)

0.01

0.02

0.03

eGFR (mL/min/1.73 m2)

-1.6

-2.3

-3.4

Baseline Pool of Four PlaceboControlled Trials

InvoKana InvoKana 100 mg 300 mg n=833 n=834

InvoKana InvoKana Placebo 100 mg 300 mg n=90 n=90 n=89 Baseline Moderate Week 3 Renal Impairment Change Trial End of Treatment Change*

Creatinine (mg/dL)

1.61

1.62

1.63

40.1

39.7

38.5

Creatinine (mg/dL)

0.03

0.18

0.28

eGFR (mL/min/1.73 m2)

-0.7

-4.6

-6.2

Creatinine (mg/dL)

0.07

0.16

0.18

eGFR (mL/min/1.73 m2)

-1.5

-3.6

-4.0

eGFR (mL/min/1.73

m 2)

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0

sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7)

InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3)

Placebo (n=565) 208 (36.8) 14 (2.5)

InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

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INVOKANA™ (canagliflozin) tablets

UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. Use In sPecIFIc PoPULatIons Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information]. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information]. Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information].

overdosage There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. PatIent coUnseLIng InForMatIon See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur. Active ingredient made in Belgium Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 Janssen Pharmaceuticals, Inc. 10282400 K02CAN13080B

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CONTENTS 113 CME/CE Dermatology Clinic n A young man with a family history of severe acne presented with open comedones and inflammatory pustules.

n Intermittent pneumatic compression

n Linear hyperpigmented streaks

appeared on the trunk and extremities of a man being treated with chemotherapy for Hodgkin lymphoma. 117 Alternative Meds Update A fruit that is rich in hydroxycitric acid, Garcinia cambogia enhances satiety and is being studied for its weight-loss potential.

Hyperpigmented macules and scars 113

ADVISOR FORUM

119 CME/CE Dermatologic Look-Alikes Two women—one aged 18 years and the other aged 62 years—present with localized vesicles on the trunk. 123 CME/CE Posttest 124 Evidence-Based Medicine n Antibiotic prophylaxis might reduce symptomatic UTI after removal of urinary catheters in some postsurgical patients, but evidence is insufficient to support routine use

appears to reduce risk of DVT after acute stroke n In patients with high-risk smoldering myeloma, early treatment may delay disease progression and increase survival n Colchicine hastens resolution and reduces recurrence after first attack of acute pericarditis n In twin pregnancy with cephalic presentation of first twin, planned vaginal delivery does not increase neonatal risks compared with planned cesarean delivery

Hemorrhagic vesicles on the abdomen 119

100 Consultations ■■Testing for multiple STDs ■■The life span of mononucleosis ■■Is estrogen plus progesterone necessary in vaginal atrophy? ■■And more 103 Clinical Pearls ■■Is it a wart or a callus? ■■Quick relief of oral mucositis ■■What aortic stenosis sounds like ■■And more

HOW TO CONTACT US

TO CONTACT AN EDITOR: • Editor@ClinicalAdvisor.com • Call 646.638.6077

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NEWSLINE

■ CVD prevention guidance ■ Too few treated for hep C ■ Malaria cases on the rise ADVISOR FORUM

■ Testing for multiple STDs ■ The life span of mono ■ Relief of oral mucositis

CE: RADIATION RISK IN

CT SCANNING A large subdural hematoma (red) is visible on head CT.

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Fatal dosage error caused by an illegible prescription

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Achieving quality value-based health care Different hospitals produce different results on different procedures, making choosing a clinician a high-stakes guessing game. Stefan Larsson looks at when outcomes are measured and shared to see which techniques are the most effective.

Basic NP/PA diabetes care similar to that delivered by physicians However, those with more complex conditions tended to experience worse outcomes in several areas when treated by NP/PA teams vs. physicians only.

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Gerald Erickson, MMSc, PA-C The problem with performance-based compensation models Checking the appropriate boxes in an electronic health record may garner more reimbursement, but may not necessarily translate into better-quality patient care.

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Jim Anderson, MPAS, PA-C, ATC Applying for the AAPA’s Board of Directors Does having a complex leadership application process exclude valuable perspectives?

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Robyn Carlisle, MSN, CNM, WHNP Discuss labor fears with expecting mothers Fear often predicts the level of difficulty pregnant women experience during labor and delivery.

Skin-colored papules on the lower eyelids An Asian man, aged 55 years, presents for an evaluation of skin-colored papules on his bilateral lower eyelids.

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Newsline

Not enough hep C patients get treatment page 30

D E C E M B E R 2 0 13

CDC reports a rise in number of malaria cases page 32

Prostate cancer and melanoma may be linked page 35

Before-and-after CVD prevention guide

PRIMARY-care providers seeking the most up-to-date information on cardiovascular health for their patients should have all bases covered by a series of new guidelines focusing on the primary and secondary prevention of cardiovascular events. The A mer ican Hear t Association (AHA) started the ball rolling in October with a scientific statement in the AHA journal Circulation, “Secondary Prevention of Atherosclerotic Cardiovascular Disease in Older Adults.” The document updates the initial scientific statement issued in 2002. “Over the decade since the original scientific statement was published, there has been an explosion of randomized controlled trials addressing secondary prevention of [atherosclerotic CVD] especially with regard to the treatment of hypertension,

Colored x-ray shows stenosis of the coronary artery (orange).

hyperlipidemia, diabetes mellitus, and antithrombotic therapy,” wrote Jerome L. Fleg, MD, and guideline coauthors. In November 2013, the AHA and the Amer ican College of Cardiology (ACC) jointly released three other clinical practice guidelines in Circulation and in Journal of the American College of Cardiology. The “2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk,” last updated in 2004, now adds in stroke risk in with coronary heart disease risk in the assessment of cardiovascular risk. “We were leaving a lot of risk on the table by focusing on coronary heart disease alone,” acknowledged Donald M. Lloyd-Jones, MD, ScM, co-chair of the work group that developed this set of guidelines, in an accompanying statement from the ACC.

Another guideline, “2013 ACC/ AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults,” written by Neil J. Stone, MD, and colleagues, identifies four major groups of patients for whom statins have the greatest chance of preventing stroke and MI: persons with CVD; persons with an LDL level >190 mg/dL; persons aged 40 to 75 years with type 2 diabetes; and persons aged 40 to 75 years whose estimated 10-year risk of CVD is >7.5%. In addition, the AHA and ACC teamed up with The Obesit y Societ y (TOS) on “2013 ACC/AHA Guideline on Lifestyle Management to Reduce Cardiovascular Risk,” and “2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults.”

Prevalence of hypertension among U.S. adults, by race The age-adjusted prevalence of hypertension was highest among non-Hispanic black adults.

Non-Hispanic white 28.0%

Non-Hispanic black 42.1%

Non-Hispanic Asian 24.7% Source: CDC/NCHS, National Health and Nutrition Examination Survey, 2011–2012

Hispanic 26.0%

28 THE CLINICAL ADVISOR • DECEMBER 2013 • www.ClinicalAdvisor.com

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Newsline THERE IS no need to recommend vitamin D for increasing calcium absorption in normal subjects, said researchers after finding that vitamin D doses up to 2,400 IU daily did not enhance calcium absorption in women with vitamin D insufficiency. To test the common notion that vitamin D should be used to increase calcium absorption, Christopher J. Gallagher, MD, and fellow investigators randomized 198 white and black women, aged 25 to 45 years, with vitamin D insuff iciency (serum 25-hydroxyvitamin D [25OHD] <20 ng/mL) to vitamin D3 400 IU, 800 IU, 1,600 IU, or 2,400 IU, or to placebo. The women were given a calcium supplement to increase mean calcium intake

at baseline from 706 mg/day to 1,031 mg/day. Ga l lagher and col leag ues measured calcium absorption at baseline and after 12 months. Mean baseline serum 25OHD was 13.4 ng/mL, increasing to 40 ng/mL at the highest vitamin D dose (2,400 IU). But as the group described in Journal of Bone and Mineral Research, 12-month calcium absorption did not increase compared with baseline on any dose of vitamin D in either the white or the black participants. No significant relationship was found between 12-month calcium absorption and f inal serum 25OHD. There also was no evidence of a threshold decrease in calcium absorption or in serum 1,25(OH)2D among the groups

Vitamin D won’t add to calcium absorption

Absorption did not increase on any dose of vitamin D.

with the lowest baseline levels of serum 25OHD. The findings suggest that active transport of calcium is saturated at very low serum 25 OHD levels (<5 ng/mL).

ONLY one-fourth of apporoximately 30,000 patients with hepatitis C (HCV) seen in the Veterans Affairs (VA) health system underwent treatment for the liver disease, and less than 5% of the total group achieved an undetectable viral load. Jeffrey McCombs, PhD, and colleagues reviewed data from 28,769 of the 360,587 individuals in the VA health system clinical registry of HCV patients. Only 24.3% received treatment, and 16.4% of that subset (4% of the total group) achieved an undetectable viral load. Achieving viral suppression

Antiviral therapy can lead to viral eradication and reduced event risk.

reduced risk of a composite of liver-related clinical events by 27% and mortality by 45%. “While antiviral therapy can lead to viral eradication and reduced event risk, its effectiveness under real-world clinical conditions is limited by adverse effects and other factors,” wrote McCombs’ group in JAMA Internal Medicine. “In this study, only 1 in 4 patients with HCV and a detectable viral load were willing to initiate treatment. Once treated, only a fraction of patients achieved the minimum treatment response of a single undetectable viral load test.”

The authors noted that it remains to be determined whether newer treatment regimens can offer higher response rates with fewer adverse effects in real-world settings. Separately, Stuart C. Gordon, MD, and colleagues at Henry Ford Hospital in Detroit reported at the 2013 meeting of the American Association for the Study of Liver Diseases that 56% of approximately 4,000 patients with HCV were not receiving treatment either because of absolute contraindications to current therapy or because the patient or the clinician were waiting for newer therapies.

Too few patients get hepatitis C treatment

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

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Newsline Nosebleed Get measles vax by 15 months fixes vary, results don’t

The CDC advises a two-dose series of measles vaccines.

had received a measles-containing vaccine from 2001 through 2011. Following immunization, fever and seizures were more common during postimmunization days 7-10 than at any other time during the 42-day postimmunization observation period. In keeping with previous studies, the incidence of fever and seizures during the 7-10 days following MMRV (measles, mumps, rubella, varicella) immunization was significantly greater than that following immunization with MMR+V. The researchers also discovered that the incidence of fever steadily declined from age 12-13 months to age 19-23 months, but that seizure incidence was highest in children aged 16-18 months. Compared with children age 12-15 months, those aged 16-18 months had a significantly greater relative risk of fever and seizures, as well as a significantly greater risk of seizures attributable to the vaccine, during the 7-to-10-day risk interval.

Malaria cases on the rise in the United States THE CDC has recorded its largest number of malaria cases in 40 years, according to a recent Morbidity and Mortality Weekly Report issued by the agency (2013;62[5]:1-17). A total of 1,925 persons experienced the onset of malaria symptoms in 2011. This marked the most cases reported to the CDC since 1971, when the agency noted 3,180 such cases. The authors affirmed that the majority of malaria infections in the United States occur among persons

who have traveled to regions with ongoing malaria transmission. However, persons who have not traveled out of the country occasionally develop the disease through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitio-borne transmission. Most of the 2011 cases were imported. Among the rest, one was lab-acquired, one was transfusion-related, two were congenital cases, and one was a cryptic case.

TREATMENT for epistaxis is highly variable, with no difference seen in outcomes, indicates an analysis of several interventions. Jennifer A. Villwock, MD, and Kristin Jones, MD, reviewed hospital data from the 2008-2010 Nationwide Inpatient Sample for patients admitted with a primary diagnosis of epistaxis. Of the 57,039 cases of primary epistaxis identified, 21,872 patients (38.3%) were treated conservatively; 30,389 (53.3%) were treated with nasal packing or cauterization; 2,706 (4.7%) were treated with arterial ligation; and 1,956 (3.4%) were treated with embolization. The researchers constructed multivariate models to compare treatment modalities, using the outcomes of mortality, stroke, blindness, length of stay, and total cost.As reported in JAMA Otolarynology— Head & Neck Surgery, persons who underwent embolization subsequently had higher odds of experiencing a stroke than did the nasal-packing patients, possibly due to disease severity, with no significant difference seen compared with surgical ligation. No significant differences emerged in the odds of mortality or blindness between any of the study groups. The highest total hospital costs were incurred by people undergoing embolization:These costs were nearly double the costs of ligation, with no corresponding increase in length of hospital stay.

CHILDREN who receive their first dose of measles-containing vaccine at age 12 months to 15 months are at lower increased risk of subsequent seizures than are children who receive these immunizations at age 16 months to 23 months, researchers have found. The first dose of live attenuated measles-containing vaccine is associated with an increased risk of febrile seizures 7-10 days following immunization among children aged 12 to 23 months, explained Ali Rowhani-Rahbar, MD, and fellow investigators in their report for JAMA Pediatrics. The CDC recommends a two-dose series of measles-containing vaccines, with the first dose administered at age 12 months to 15 months and the second dose at age 4 years to 6 years. Most children are aged 12 months to 23 months when they receive the first dose. Dr. Rowhani-Rahbar’s group conducted a retrospective cohort study of 840,348 children aged 12 months to 23 months who

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

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Newsline NEW guidelines from the American College of Physicians (ACP) recommend against routine screening for chronic kidney disease (CKD) in asymptomatic adults with no risk factors. Amir Qaseem, MD, PhD, MHA, and coauthors found no randomized, controlled trials evaluating the benefits and harms of screening for stage 1 to 3 CKD (published by Annals of Internal Medicine). No studies had tested the sensitivity and specificity of one-time screening in the general population using estimated glomerular filtration rate or albuminuria for the diagnosis of CKD. The American Society of Nephrology (ASN), however, confirmed in a subsequent statement that the ASN “strongly recommends” regular screening for

kidney disease, regardless of an individual’s risk factors. The ASN asserts that because CKD is largely asymptomatic in its early stages, early detection and intervention can slow progression of the disease. The ASN also disagrees with the ACP’s recommendation advising against testing for proteinuria in adults with or without diabetes who are taking an ACE inhibitor or an angiotensin II receptor blocker (ARB). Citing high BP and diabetes as the two leading risk factors for the development of CKD, the ASN “emphasizes the importance” of proteinuria testing in adults being treated with antihypertensives. In a joint announcement, the National Kidney Foundation (NKF) and the Renal Physicians Association (RPA) agreed with

ACP says no to routine kidney screening

Urinalysis is often used to detect kidney damage.

the ACP’s recommendation against routine CKD testing in the absence of risk conditions. However, like the ASN, the two organizations oppose the ACP’s stand against testing for proteinuria in patients taking an ACE inhibitor, an ARB, or certain other antihypertensive agents.

MEN WITH a history of prostate cancer exhibited an increased risk for melanoma in an evaluation of data from the Health Professionals’ Follow-Up Study (HPFS). Jiali Han, PhD, and colleagues identified 539 melanomas among 42,372 participants in the HPFS. Men who had had prostate cancer were found to be at heightened risk of developing melanoma (hazard ratio [HR]: 1.83). Their risk for nonmelanoma skin cancer was also slightly higher (HR: 1.08). Han’s group confirmed the link between prostate cancer and risk of incident melanoma using data

Melanoma may be associated with changes in androgen levels.

from 18,603 participants of the Physicians’ Health Study. The investigators pointed out in Journal of Clinical Oncology that melanoma risk was not associated with personal history of any other cancers among the men studied. Steroid hormones, particularly androgens, play a major role in the development of prostate cancer, and previous research has suggested that melanoma may be associated with changes in androgen levels. In other research also reported in Journal of Clinical Oncology, Oriana Yu, MD, and associates

found that men who used statins after receiving a diagnosis of prostate cancer had a decreased risk of disease-related mortality, particularly if they had been on statin therapy prior to diagnosis. According to Yu’s team, postdiagnostic use of statins was associated with lower risks of prostate-cancer mortality (HR: 0.76) and all-cause mortality (HR: 0.86) compared with no use of statins. Men who had been taking statins before diagnosis as well as after were even less likely to die from prostate cancer (HR: 0.55) or any cause (HR: 0.66).

Prostate cancer may raise melanoma risk

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

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Indication BELVIQ is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: • 30 kg/m2 or greater (obese), or • 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes). Limitations of Use • The safety and efficacy of coadministration of BELVIQ with other products intended for weight loss, including prescription drugs (eg, phentermine), over-the-counter drugs, and herbal preparations, have not been established. • The effect of BELVIQ on cardiovascular morbidity and mortality has not been established.

Important Safety Information Contraindication

• BELVIQ should not be taken during pregnancy or by women who are planning to become pregnant.

Warnings and Precautions

• BELVIQ is a serotonergic drug. The development of potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported during use of serotonergic drugs, including, but not limited to, selective serotoninnorepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, dietary supplements such as St. John’s Wort and tryptophan, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors), dextromethorphan, lithium, tramadol, antipsychotics or other dopamine

APPROVED for chronic weight management

Make weight loss matter BELVIQ®—the first and only selective 5-HT2C receptor agonist for chronic weight management1,2 • Prescription therapy for use in conjunction with a reduced-calorie diet and increased physical activity1 • Novel mechanism of action believed to promote satiety. The exact mechanism of action is not known1,2

Visit BELVIQhcp.com for information and offers. antagonists, particularly when used in combination. Patients should be monitored for the emergence of serotonin syndrome symptoms or NMS-like reactions, including agitation, hallucinations, coma, tachycardia, labile blood pressure, hyperthermia, hyperreflexia, incoordination, nausea, vomiting, diarrhea, and muscle rigidity. Treatment with BELVIQ and any concomitant serotonergic or antidopaminergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated. • Patients should not take BELVIQ in combination with drugs that have been associated with valvular heart disease (eg, cabergoline). In clinical trials, 2.4% of patients taking BELVIQ and 2.0% of patients taking placebo developed valvular regurgitation: none of these patients were symptomatic. BELVIQ should be used with caution in patients with congestive heart failure (CHF). Patients who develop signs and symptoms of valvular heart disease, including dyspnea, dependent edema, CHF, or a new cardiac murmur, should be evaluated and discontinuation of BELVIQ should be considered. • Impairment in attention, memory, somnolence, confusion, and fatigue, have been reported in patients taking BELVIQ. Patients should not drive a car or operate heavy machinery until they know how BELVIQ affects them. • The recommended dose of 10 mg twice daily should not be exceeded, as higher doses may cause euphoria, hallucination, and dissociation. Monitor patients for the development or worsening of depression, suicidal thoughts or behaviors, and/ or any changes in mood. Discontinue BELVIQ in patients who develop suicidal thoughts or behaviors. • Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are being treated with antidiabetic medications, so measurement of blood sugar levels before and during treatment with BELVIQ is recommended. Decreases in doses of antidiabetic BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH. BELV1134

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medications or changes in medication regimen should be considered. • Men who experience priapism should immediately discontinue BELVIQ and seek emergency medical attention. BELVIQ should be used with caution with erectile dysfunction medications. BELVIQ should be used with caution in men who have conditions that might predispose them to priapism (eg, sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis, or Peyronie’s disease). • Because BELVIQ may cause a slow heartbeat, it should be used with caution in patients with a history of bradycardia or heart block greater than first degree. • Consider monitoring for CBC changes, prolactin excess, and pulmonary hypertension.

Most Common Adverse Reactions

• In patients without diabetes: headache (17%), dizziness (9%), fatigue (7%), nausea (8%), dry mouth (5%), and constipation (6%). • In patients with diabetes: hypoglycemia (29%), headache (15%), back pain (12%), cough (8%), and fatigue (7%).

Nursing Mothers

• BELVIQ should not be taken by women who are nursing. BELVIQ is a federally controlled substance (CIV) because it may be abused or lead to dependence. Please see Brief Summary of Prescribing Information and references on adjacent pages.

BRIEF SUMMARY: For prescribing information, see package insert. INDICATIONS AND USAGE BELVIQ is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of: • 3 0 kg/m2 or greater (obese), or • 2 7 kg/m2 or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes) Limitations of Use: • The safety and efficacy of coadministration of BELVIQ with other products intended for weight loss including prescription drugs (e.g., phentermine), over-the-counter drugs, and herbal preparations have not been established • The effect of BELVIQ on cardiovascular morbidity and mortality has not been established DOSAGE AND ADMINISTRATION The recommended dose of BELVIQ is 10 mg administered orally twice daily. Do not exceed recommended dose. BELVIQ can be taken with or without food. Response to therapy should be evaluated by week 12. If a patient has not lost at least 5% of baseline body weight, discontinue BELVIQ, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. CONTRAINDICATION • Pregnancy WARNINGS AND PRECAUTIONS Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions. BELVIQ is a serotonergic drug. The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported during use of serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements such as St. John’s Wort and tryptophan, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), dextromethorphan, lithium, tramadol, antipsychotics or other dopamine antagonists, particularly when used in combination. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The safety of BELVIQ when coadministered with other serotonergic or antidopaminergic agents, including antipsychotics, or drugs that impair metabolism of serotonin, including MAOIs, has not been systematically evaluated and has not been established. If concomitant administration of BELVIQ with an agent that affects the serotonergic neurotransmitter system is clinically warranted, extreme caution and careful observation of the patient is advised, particularly during treatment initiation and dose increases. Treatment with BELVIQ and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Valvular Heart Disease. Regurgitant cardiac valvular disease, primarily affecting the mitral and/ or aortic valves, has been reported in patients who took serotonergic drugs with 5-HT2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT2B receptors on cardiac interstitial cells. At therapeutic concentrations, BELVIQ is selective for 5-HT2C receptors as compared to 5-HT2B receptors. In clinical trials of 1-year duration, 2.4% of patients receiving BELVIQ and 2.0% of patients receiving placebo developed echocardiographic criteria for valvular regurgitation at one year (mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation): none of these patients was symptomatic. BELVIQ has not been studied in patients with congestive heart failure or hemodynamicallysignificant valvular heart disease. Preliminary data suggest that 5HT2B receptors may be overexpressed in congestive heart failure. Therefore, BELVIQ should be used with caution in patients with congestive heart failure. BELVIQ should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists and are known to increase the risk for cardiac valvulopathy (e.g., cabergoline). Patients who develop signs or symptoms of valvular heart disease, including dyspnea, dependent edema, congestive heart failure, or a new cardiac murmur while being treated with BELVIQ should be evaluated and discontinuation of BELVIQ should be considered. Cognitive Impairment. In clinical trials of at least one year in duration, impairments in attention and memory were reported adverse reactions associated with 1.9% of patients treated with BELVIQ and 0.5% of patients treated with placebo, and led to discontinuation in 0.3% and 0.1% of these patients, respectively. Other reported adverse reactions associated with BELVIQ in clinical trials included confusion, somnolence, and fatigue. Since BELVIQ has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BELVIQ therapy does not affect them adversely. Psychiatric Disorders. Events of euphoria, hallucination, and dissociation were seen with BELVIQ at supratherapeutic doses in short-term studies. In clinical trials of at least 1-year in duration, 6 patients (0.2%) treated with BELVIQ developed euphoria, as compared with 1 patient (<0.1%) treated with placebo. Doses of BELVIQ should not exceed 10 mg twice a day. Some drugs that target the central nervous system have been associated with depression or suicidal ideation. Patients treated with BELVIQ should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue BELVIQ in patients who experience suicidal thoughts or behaviors. Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti-diabetic Therapy. Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas); hypoglycemia was observed in clinical trials with BELVIQ. BELVIQ has not been studied in combination with insulin. Measurement of blood glucose levels prior to starting BELVIQ and during BELVIQ treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for anti-diabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting BELVIQ, appropriate changes should be made to the anti-diabetic drug regimen. Priapism. Priapism (painful erections greater than 6 hours in duration) is a potential effect of 5-HT2C receptor agonism. If not treated promptly, priapism can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention. BELVIQ should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease). There is limited experience with the combination of BELVIQ and medication indicated for erectile dysfunction (e.g., phosphodiesterase type 5 inhibitors). Therefore, the combination of BELVIQ

and these medications should be used with caution. Heart Rate Decreases. In clinical trials of at least 1-year in duration, the mean change in heart rate (HR) was -1.2 beats per minute (bpm) in BELVIQ and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in BELVIQ and -0.4 bpm in placebo-treated patients with type 2 diabetes. The incidence of HR less than 50 bpm was 5.3% in BELVIQ and 3.2% in placebo-treated patients without diabetes and 3.6% in BELVIQ and 2.0% in placebotreated patients with type 2 diabetes. In the combined population, adverse reactions of bradycardia occurred in 0.3% of BELVIQ and 0.1% of placebo-treated patients. Use with caution in patients with bradycardia or a history of heart block greater than first degree. Hematological Changes. In clinical trials of at least one year in duration, adverse reactions of decreases in white blood cell count (including leukopenia, lymphopenia, neutropenia, and decreased white cell count) were reported in 0.4% of patients treated with BELVIQ as compared to 0.2% of patients treated with placebo. Adverse reactions of decreases in red blood cell count (including anemia and decreases in hemoglobin and hematocrit) were reported by 1.3% of patients treated with BELVIQ as compared to 1.2% treated with placebo. Consider periodic monitoring of complete blood count during treatment with BELVIQ. Prolactin Elevation. Lorcaserin moderately elevates prolactin levels. In a subset of placebocontrolled clinical trials of at least one year in duration, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, measured both before and 2 hours after dosing, occurred in 6.7%, 1.7%, and 0.1% of BELVIQ-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively. Prolactin should be measured when symptoms and signs of prolactin excess are suspected (e.g., galactorrhea, gynecomastia). There was one patient treated with BELVIQ who developed a prolactinoma during the trial. The relationship of BELVIQ to the prolactinoma in this patient is unknown. Pulmonary Hypertension. Certain centrally-acting weight loss agents that act on the serotonin system have been associated with pulmonary hypertension, a rare but lethal disease. Because of the low incidence of this disease, the clinical trial experience with BELVIQ is inadequate to determine if BELVIQ increases the risk for pulmonary hypertension. ADVERSE REACTIONS Clinical Trials Experience. In the BELVIQ placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 BELVIQ vs. 3437 placebo; age range 18-66 years, 79.3% women, 66.6% Caucasians, 19.2% Blacks, 11.8% Hispanics, 2.4% other, 7.4% type 2 diabetics), a total of 1969 patients were exposed to BELVIQ 10 mg twice daily for 1 year and 426 patients were exposed for 2 years. In clinical trials of at least one year in duration, 8.6% of patients treated with BELVIQ prematurely discontinued treatment due to adverse reactions, compared with 6.7% of placebo-treated patients. The most common adverse reactions leading to discontinuation more often among BELVIQ treated patients than placebo were headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%). Most Common Adverse Reactions Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions for non-diabetic patients (greater than 5% and more commonly than placebo) treated with BELVIQ compared to placebo were headache, dizziness, fatigue, nausea, dry mouth, and constipation. The most common adverse reactions for diabetic patients were hypoglycemia, headache, back pain, cough, and fatigue. Adverse reactions that were reported by greater than or equal to 2% of patients and were more frequently reported by patients taking BELVIQ compared to placebo are summarized in Table 1 (non-diabetic subjects) and Table 2 (subjects with type 2 diabetes mellitus). Table 1. Adverse Reactions Reported by Greater Than or Equal to 2% of BELVIQ Patients and More Commonly than with Placebo in Patients without Diabetes Mellitus

Adverse Reaction Gastrointestinal Disorders Nausea Diarrhea Constipation Dry mouth Vomiting General Disorders And Administration Site Conditions Fatigue Infections And Infestations Upper respiratory tract infection Nasopharyngitis Urinary tract infection Musculoskeletal And Connective Tissue Disorders Back pain Musculoskeletal pain Nervous System Disorders Headache Dizziness Respiratory, Thoracic And Mediastinal Disorders Cough Oropharyngeal pain Sinus congestion Skin And Subcutaneous Tissue Disorders Rash

Number of Patients (%) BELVIQ Placebo 10 mg BID N=3185 N=3195 264 (8.3) 207 (6.5) 186 (5.8) 169 (5.3) 122 (3.8)

170 (5.3) 179 (5.6) 125 (3.9) 74 (2.3) 83 (2.6)

229 (7.2)

114 (3.6)

439 (13.7) 414 (13.0) 207 (6.5)

391 (12.3) 381 (12.0) 171 (5.4)

201 (6.3) 65 (2.0)

178 (5.6) 43 (1.4)

537 (16.8) 270 (8.5)

321 (10.1) 122 (3.8)

136 (4.3) 111 (3.5) 93 (2.9)

109 (3.4) 80 (2.5) 78 (2.4)

67 (2.1)

58 (1.8)

Table 2. A dverse Reactions Reported by Greater Than or Equal to 2% of BELVIQ Patients and More Commonly than with Placebo in Patients with Type 2 Diabetes Mellitus

Adverse Reaction Gastrointestinal Disorders Nausea Toothache

Number of Patients (%) BELVIQ Placebo 10 mg BID N=252 N=256 24 (9.4) 7 (2.7)

20 (7.9) 0 (Table continues)

Table 2. (cont’d.)

Adverse Reaction General Disorders And Administration Site Conditions Fatigue Peripheral edema Immune System Disorders Seasonal allergy Infections And Infestations Nasopharyngitis Urinary tract infection Gastroenteritis Metabolism And Nutrition Disorders Hypoglycemia Worsening of diabetes mellitus Decreased appetite Musculoskeletal And Connective Tissue Disorders Back pain Muscle spasms Nervous System Disorders Headache Dizziness Psychiatric Disorders Anxiety Insomnia Stress Depression Respiratory, Thoracic And Mediastinal Disorders Cough Vascular Disorders Hypertension

Number of Patients (%) BELVIQ Placebo 10 mg BID N=252 N=256 19 (7.4) 12 (4.7)

10 (4.0) 6 (2.4)

8 (3.1)

2 (0.8)

29 (11.3) 23 (9.0) 8 (3.1)

25 (9.9) 15 (6.0) 5 (2.0)

75 (29.3) 7 (2.7) 6 (2.3)

53 (21.0) 2 (0.8) 1 (0.4)

30 (11.7) 12 (4.7)

20 (7.9) 9 (3.6)

37 (14.5) 18 (7.0)

18 (7.1) 16 (6.3)

9 (3.5) 9 (3.5) 7 (2.7) 6 (2.3)

8 (3.2) 6 (2.4) 3 (1.2) 5 (2.0)

21 (8.2)

11 (4.4)

13 (5.1)

8 (3.2)

Other Adverse Reactions Serotonin-associated Adverse Reactions. SSRIs, SNRIs, bupropion, tricyclic antidepressants, and MAOIs were excluded from the BELVIQ trials. Triptans and dextromethorphan were permitted: 2% and 15%, respectively, of patients without diabetes and 1% and 12%, respectively, of patients with type 2 diabetes experienced concomitant use at some point during the trials. Two patients treated with BELVIQ in the clinical program experienced a constellation of symptoms and signs consistent with serotonergic excess, including one patient on concomitant dextromethorphan who reported an event of serotonin syndrome. Some symptoms of possible serotonergic etiology that are included in the criteria for serotonin syndrome were reported by patients treated with BELVIQ and placebo during clinical trials of at least 1 year in duration. In both groups, chills were the most frequent of these events (1.0% vs. 0.2%, respectively), followed by tremor (0.3% vs. 0.2%), confusional state (0.2% vs. less than 0.1%), disorientation (0.1% vs. 0.1%) and hyperhidrosis (0.1% vs. 0.2%). Because serotonin syndrome has a very low incidence, an association between BELVIQ and serotonin syndrome cannot be excluded on the basis of clinical trial results. Hypoglycemia in Patients with Type 2 Diabetes. In a clinical trial of patients with type 2 diabetes mellitus, hypoglycemia requiring the assistance of another person occurred in 4 (1.6%) of BELVIQ-treated patients and in 1 (0.4%) placebo-treated patient. Of these 4 BELVIQ-treated patients, all were concomitantly using a sulfonylurea (with or without metformin). BELVIQ has not been studied in patients taking insulin. Hypoglycemia defined as blood sugar less than or equal to 65 mg/dL and with symptoms occurred in 19 (7.4%) BELVIQ-treated patients and 16 (6.3%) placebo-treated patients. Cognitive Impairment. In clinical trials of at least 1-year duration, adverse reactions related to cognitive impairment (e.g., difficulty with concentration/attention, difficulty with memory, and confusion) occurred in 2.3% of patients taking BELVIQ and 0.7% of patients taking placebo. Psychiatric Disorders. Psychiatric disorders leading to hospitalization or drug withdrawal occurred more frequently in patients treated with BELVIQ (2.2%) as compared to placebo (1.1%) in nondiabetic patients. Euphoria. In short-term studies with healthy individuals, the incidence of euphoric mood following supratherapeutic doses of BELVIQ (40 and 60 mg) was increased as compared to placebo. In clinical trials of at least 1-year duration in obese patients, euphoria was observed in 0.17% of patients taking BELVIQ and 0.03% taking placebo. Depression and Suicidality. In trials of at least one year in duration, reports of depression/mood problems occurred in 2.6% BELVIQ-treated vs. 2.4% placebo-treated and suicidal ideation occurred in 0.6% BELVIQ-treated vs. 0.4% placebo-treated patients. 1.3% of BELVIQ patients vs. 0.6% of placebo patients discontinued drug due to depression-, mood-, or suicidal ideationrelated events. Laboratory Abnormalities. Lymphocyte and Neutrophil Counts. In clinical trials of at least 1-year duration, lymphocyte counts were below the lower limit of normal in 12.2% of patients taking BELVIQ and 9.0% taking placebo, and neutrophil counts were low in 5.6% and 4.3%, respectively. Hemoglobin. In clinical trials of at least 1-year duration, 10.4% of patients taking BELVIQ and 9.3% taking placebo had hemoglobin below the lower limit of normal at some point during the trials. Prolactin. In clinical trials, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, occurred in 6.7%, 1.7%, and 0.1% of BELVIQ-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively. Eye Disorders. More patients on BELVIQ reported an eye disorder than patients on placebo in clinical trials of patients without diabetes (4.5% vs. 3.0%) and with type 2 diabetes (6.3% vs. 1.6%). In the population without diabetes, events of blurred vision, dry eye, and visual impairment occurred in BELVIQ-treated patients at an incidence greater than that of placebo. In the population with type 2 diabetes, visual disorders, conjunctival infections, irritations, and inflammations, ocular sensation disorders, and cataract conditions occurred in BELVIQ-treated patients at an incidence greater than placebo. Echocardiographic Safety Assessments The possible occurrence of regurgitant cardiac valve disease was prospectively evaluated in 7794 patients in three clinical trials of at least one year in duration, 3451 of whom took BELVIQ 10 mg twice daily. The primary echocardiographic safety parameter was the proportion of patients who developed echocardiographic criteria of mild or greater aortic insufficiency and/or

moderate or greater mitral insufficiency from baseline to 1 year. At 1 year, 2.4% of patients who received BELVIQ and 2.0% of patients who received placebo developed valvular regurgitation. The relative risk for valvulopathy with BELVIQ is summarized in Table 3. BELVIQ was not studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease. Table 3. Incidence of FDA-Defined Valvulopathy at Week 52 by Treatment Group1 Study 1

FDA-defined Valvulopathy, n (%) Relative Risk (95% CI) Pooled RR (95% CI) 1

Study 2

Study 3

BELVIQ Placebo BELVIQ Placebo BELVIQ Placebo N=1278 N=1191 N=1208 N=1153 N=210 N=209 34 28 24 23 6 1 (2.7) (2.4) (2.0) (2.0) (2.9) (0.5) 1.13 1.00 5.97 (0.69, 1.85) (0.57, 1.75) (0.73, 49.17) 1.16 (0.81, 1.67)

Patients

without valvulopathy at baseline who received study medication and had a post-baseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward.

DRUG INTERACTIONS Use with Other Agents that Affect Serotonin Pathways. Based on the mechanism of action of BELVIQ and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic which is a reversible non-selective MAOI), selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic antidepressants (TCAs), bupropion, lithium, tramadol, tryptophan, and St. John’s Wort. Cytochrome P450 (2D6) substrates. Use caution when administering BELVIQ together with drugs that are CYP 2D6 substrates, as BELVIQ can increase exposure of these drugs. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category X. Risk Summary. BELVIQ is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Maternal exposure to lorcaserin in late pregnancy in rats resulted in lower body weight in offspring which persisted to adulthood. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus. Clinical Considerations. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Animal Data. Reproduction studies were performed in pregnant rats and rabbits that were administered lorcaserin during the period of embryofetal organogenesis. Plasma exposures up to 44 and 19 times human exposure in rats and rabbits, respectively, did not reveal evidence of teratogenicity or embryolethality with lorcaserin hydrochloride. In a pre- and postnatal development study, maternal rats were dosed from gestation through post-natal day 21 at 5, 15, and 50mg/kg lorcaserin; pups were indirectly exposed in utero and throughout lactation. The highest dose (~44 times human exposure) resulted in stillborns and lower pup viability. All doses lowered pup body weight similarly at birth which persisted to adulthood; however, no developmental abnormalities were observed and reproductive performance was not affected at any dose. Nursing Mothers. It is not known whether BELVIQ is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of BELVIQ in pediatric patients below the age of 18 have not been established and the use of BELVIQ is not recommended in pediatric patients. Geriatric Use. In the BELVIQ clinical trials, a total of 135 (2.5%) of the patients were 65 years of age and older. Clinical studies of BELVIQ did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Since elderly patients have a higher incidence of renal impairment, use of BELVIQ in the elderly should be made on the basis of renal function. Elderly patients with normal renal function should require no dose adjustment. Renal Impairment. No dose adjustment of BELVIQ is required in patients with mild renal impairment. Use BELVIQ with caution in patients with moderate renal impairment. Use of BELVIQ in patients with severe renal impairment or end stage renal disease is not recommended. Hepatic Impairment. Dose adjustment is not required for patients with mild hepatic impairment (Child-Pugh score 5-6) to moderate hepatic impairment (Child-Pugh score 7-9). The effect of severe hepatic impairment on lorcaserin was not evaluated. Use lorcaserin with caution in patients with severe hepatic impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance. BELVIQ is listed in Schedule IV of the Controlled Substances Act. Abuse. In a human abuse potential study in recreational drug abusers, supratherapeutic oral doses of lorcaserin (40 and 60 mg) produced up to two- to six-fold increases on measures of “High”, “Good Drug Effects”, “Hallucinations” and “Sedation” compared to placebo. These responses were similar to those produced by oral administration of the positive control drugs, zolpidem (15 and 30 mg) and ketamine (100 mg). In this study, the incidence of the adverse reaction of euphoria following lorcaserin administration (40 and 60 mg; 19%) is similar to the incidence following zolpidem administration (13-16%), but less than the incidence following ketamine administration (50%). The duration of euphoria following lorcaserin administration persisted longer (> 9 hours) than that following zolpidem (1.5 hours) or ketamine (2.5 hours) administration. Overall, in short-term studies with healthy individuals, the rate of euphoria following oral administration of lorcaserin was 16% following 40 mg (n = 11 of 70) and 19% following 60 mg (n = 6 of 31). However, in clinical studies with obese patients with durations of 4 weeks to 2 years, the incidence of euphoria and hallucinations following oral doses of lorcaserin up to 40 mg was low (< 1.0%). Dependence. There are no data from well-conducted animal or human studies that evaluate whether lorcaserin can induce physical dependence, as evidenced by a withdrawal syndrome. However, the ability of lorcaserin to produce hallucinations, euphoria, and positive subjective responses at supratherapeutic doses suggests that lorcaserin may produce psychic dependence. OVERDOSAGE No experience with overdose of BELVIQ is available. In clinical studies that used doses that were higher than the recommended dose, the most frequent adverse reactions associated with BELVIQ were headache, nausea, abdominal discomfort, and dizziness. Single 40- and 60-mg doses of BELVIQ caused euphoria, altered mood, and hallucination in some subjects. Treatment of overdose should consist of BELVIQ discontinuation and general supportive measures in the management of overdosage. BELVIQ is not eliminated to a therapeutically significant degree by hemodialysis. References: 1. BELVIQ [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Thomsen WJ, Grottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther. 2008;325(2):577-587. BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH. BELV1134A © 2013 Eisai Inc. All rights reserved. Printed in USA. 10/2013

Newsline

Only ACEIs significantly reduced the doubling of creatinine levels.

being in the superior ranking positions among all three outcomes, and the treatment ranking identified ACE inhibitors combined with calcium channel blockers to have the greatest probability (73.9%) for being the best treatment in terms of reducing mortality. Another study, however, found that up to 15% of the increase in hospital admission rates in England for acute kidney injury (AKI) was potentially attributable to increased prescribing of ACE inhibitors and angiotensinreceptor antagonists (ARAs) (PLoS One. 2013;8:e78465). From 2007-2008 to 2010-2011, crude admission rates for AKI rose 51.6%, from 0.38 to 0.57 per 1,000 patients. During that time, national annual ACE inhibitor/ ARA prescribing rates increased by 15.8%, from 0.202 to 0.234. According to the researchers, strong evidence indicated that the increased prescribing of those drugs was linked with the increase in AKI admission rates. n

“How come you never want to spend time with my friends during our conjugal visits?”

CLINICIANS should acknowledge and confront the uncertainties inherent in chronic opioid treatment with their patients, advised a group of investigators who sought to characterize clinical communication regarding opioids. For the pilot study, researchers audio-recorded the primarycare visits of 30 persons with chronic pain, and interviewed each of the patients following the visits (Patient Educ Couns. 2013;93[2]:197-202). Uncertainties regarding opioid treatment in individuals with chronic pain, particularly addiction and misuse, were found to play an important role in paintreatment communication. The researchers further pointed out that three patterns of responding to uncertainty emerged in discussions between providers and patients: reassurance, avoiding opioids, and gathering additional information. In a separate statement, the investigators commented, “There is an important message here for people with chronic pain and the [clinicians] who treat them. If patients and their [clinicians] have a relationship marked by mutual trust and a strong therapeutic alliance, they are better positioned to candidly discuss all chronic pain treatment options, including risks and benefits of opioid treatment.”

ACE inhibitors were shown to protect the kidneys in persons with diabetes in one study, yet were found to be possible culprits in increased acute kidney injuries noted in another investigation. The review that uncovered renoprotective benefits of ACE inhibitors was designed to assess the effects of different classes of antihypertensive treatments on survival and renal outcomes in persons with diabetes (BMJ. 2013;347:f6008). Hon-Yen Wu and colleagues analyzed 63 randomized controlled trials that each had a follow-up period of at least 12 months. During follow-up, 2,400 of the 36,917 participants died, 766 required dialysis, and 1,099 experienced a doubling of their serum creatinine levels. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels, and only beta blockers showed a significant difference in mortality. ACE inhibitors consistently showed higher probabilities of

Unknowns ACEIs: kidney friend or foe? of opioid treatment

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

CA1213_Newsline.indd 40

11/27/13 12:46 PM

DrugUpdate New drug information from the publishers of MPR

Inhalant for agitation in schizophrenia Product: Adasuve Company: Alexza

Pharmaceuticals Pharmacologic class:

Dibenzoxazepine Active ingredient:

Loxapine 10 mg; powder for oral inhalation Indication: Acute treat-

ment of agitation associated with schizophrenia or bipolar I disorder in adults. Limitations of use: must be administered only in an enrolled health-care facility.

treatment of agitation associated with schizophrenia or bipolar I disorder was established in two short-term (24-hour), randomized, double-blind, placebocontrolled, fixed-dose trials. Study 1 (n=344) included patients who met DSM-IV criteria for schizophrenia and Study 2 (n=314) included patients who met DSM-IV criteria for bipolar I disorder, manic or mixed episodes with or without psychotic features. The primary efficacy end point in both trials was the mean change from baseline in

the Excited Component of the Positive and Negative Syndrome Scale (PANSSEC) score, assessed two hours post-dose. The key secondary endpoint was the mean Clinical Global Impression Improvement Scale score at two hours. In both studies, treatment with Adasuve was statistically significantly superior to placebo on the mean change in PANSS-EC score at two hours (Study 1: -8.7, 95% CI -2.9 [-4.2, -1.6]; P <0.0001 and Study 2: -9.2, 95% CI -4.5 [-5.8, -3.1]; P <0.0001). The decrease in agitation with Adasuve was apparent at each time point tested (10, 20, 30, 45, 60, 90, and 120 minutes post-dose). Continued pg. 46

Pharmacology: The

mechanism of action in the treatment of agitation associated with schizophrenia and bipolar I disorder is unknown. However, the efficacy of loxapine could be mediated through a combination of antagonism of central dopamine D2 and serotonin 5-HT2A receptors.

Product: Fetzima Company: Forest Laboratories Pharmacologic class:

Serotonin and norepinephrine reuptake inhibitor (SNRI) Active ingredients:

Levomilnacipran 20 mg, 40 mg, 80 mg, 120 mg; extended-release caps. Indication: Treatment

of major depressive disorder (MDD) in adults. Limitations of use: not approved for the management of fibromyalgia. The efficacy and safety for the management of fibromyalgia have not been established. Pharmacology: Although the exact mechanism of the antidepressant action of levomilnacipran is unknown, it is thought to be related to the potentiation of serotonin and norepinephrine in the central

Clinical trials: The efficacy

of Adasuve in the acute

SNRI for adults with MDD

A hand-held inhaler delivers loxapine to the deep lung for rapid absorption.

Continued pg. 46

For more products, visit www.eMPR.com

42 THE CLINICAL ADVISOR â&#x20AC;˘ DECEMBER 2013 â&#x20AC;˘ www.ClinicalAdvisor.com

CA1213_DrugUpdate.indd 42

11/27/13 12:38 PM

DrugUpdate Adasuve from pg. 42

For more clinical trial results, see full labeling. Adults: 10 mg by oral

inhalation using a singleuse inhaler. Administer only a single dose within a 24-hour period. Prior to administration, screen for current diagnosis or history of asthma, COPD, or other lung diseases, and examine for respiratory abnormalities. Monitor for signs/symptoms of bronchospasm and perform a physical exam at least every 15 minutes for at least one hour after administration. Children: Not established. Contraindications:

Current diagnosis or history of asthma, COPD,

or other lung disease associated with bronchospasm. Acute respiratory signs/symptoms (e.g., wheezing). Concomitant drugs to treat airways disease (e.g., asthma, COPD). History of bronchospasm after Adasuve treatment. Amoxapine sensitivity. Warnings/Precautions:

Risk of bronchospasm. Must be administered by health-care personnel in facility that has immediate access to manage acute bronchospasm. Increased mortality in elderly patients with dementia-related psychosis (not approved use). Monitor for neuroleptic malignant syndrome. Cardio- or cerebrovascular disease. Conditions that

predispose to hypotension (e.g., dehydration, hypovolemia, or concomitant antihypertensive drugs). History of seizures. Neonates: risk of extrapyramidal and/or withdrawal symptoms post delivery (due to exposure during third trimester of pregnancy). Pregnancy (Category C). Nursing mothers: not recommended. Interactions: Additive effects with concomitant other anticholinergics (e.g., antiparkinson drugs) or other central nervous system depressants (e.g., alcohol, opioids, benzodiazepines, tricyclic antidepressants, general anesthetics, phenothiazines, sedative/hypnotics, muscle

Fetzima from pg. 42

nervous system through inhibition of reuptake at serotonin and norepinephrine transporters. Clinical trials: The effi-

Major depressive disorder affects almost 16 million adults every year.

cacy of Fetzima was established in three eight-week, randomized, double-blind, placebo-controlled studies at doses 40 mg to 120 mg once daily in adult outpatients with MDD. Two of these studies were fixeddose (Study 1 and Study

relaxants); consider reducing dose of these drugs. Adverse reactions:

Dysgeusia, sedation, throat irritation; hypotension, syncope, lowered seizure threshold, anticholinergic effects (e.g., glaucoma, urinary retention). Note: Available only through a restricted program under Adasuve Risk Evaluation and Mitigation Strategy. Call 888.970.7367 or visit www.adasuverems.com to enroll. How supplied: Single-use,

disposable inhaler. For more information, call 800.284.0062 or visit www.Adasuve.com. 2), and one study was flexible-dose (Study 3). In Study 1 (n=713), patients received Fetzima 40 mg, 80 mg, or 120 mg once daily or placebo. In Study 2 (n=562), patients received either Fetzima 40 mg or 80 mg once daily or placebo. In Study 3 (n=434), patients received Fetzima 40 mg to 120 mg once daily or placebo. In all three studies, Fetzima demonstrated superiority over placebo in

For more products, visit www.eMPR.com

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

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DrugUpdate Fetzima from pg. 46

the improvement of depressive symptoms, as measured by the MontgomeryAsberg Depression Rating Scale total score. Fetzima also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale functional impairment total score. For more clinical trial results, see full labeling. Adults: Swallow whole. Initially 20 mg once daily for two days, and then increase to 40 mg once daily; may increase dose in 40-mg increments at intervals of >2 days; maximum 120 mg once daily. Renal impairment: moderate (creatinine clearance [CrCl] 30–59 mL/min): maximum 80 mg once daily; severe (CrCl 15–29 mL/min): maximum 40 mg once daily. End-stage renal disease: not recommended. Concomitant strong CYP3A4 inhibitors: maximum 80 mg once daily. Children: <18 years: not

established.

Contraindications:

During or within 14 days of monoamine oxidase inhibitors (MAOIs). Concomitant linezolid or

IV methylene blue (see full labeling). Uncontrolled narrow-angle glaucoma. Warnings/Precautions:

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults; monitor closely for clinical worsening and unusual changes. Monitor for serotonin syndrome; discontinue if develops. History of bipolar disorder, mania, or hypomania. Pre-existing hypertension, cardio- or cerebrovascular disease, or tachyarrhythmias. Monitor BP and heart rate; reduce dose or discontinue if elevation persists. Risk of bleeding. Controlled narrow-angle glaucoma. Obstructive urinary disorders. Seizure disorder. Volume depletion. Hyponatremia risk (especially in elderly). Re-evaluate periodically. Write prescription for smallest practical amount. Avoid abrupt cessation. Pregnancy (Category C). Nursing mothers: not studied. Interactions: See Contraindications. Allow at least 14 days after MAOI discontinuation before starting levomilnacipran; allow at least seven days after discontinuing

levomilnacipran before starting an MAOI. Increased risk of serotonin syndrome with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s wort) or with drugs that impair serotonin metabolism (e.g., MAOIs, linezolid, IV methylene blue). Increased risk of bleeding with concomitant nonsteroidal anti-inflammatory drugs, aspirin, anticoagulants; monitor. Concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir): adjust dose. Avoid alcohol. Caution with other CNSactive drugs, or drugs that can increase BP or heart rate. Adverse reactions: Nausea, constipation, vomiting, hyperhidrosis, increased heart rate, erectile dysfunction, tachycardia, palpitations; hypertension, urinary hesitation. How supplied: Caps 20

mg—30; 40 mg, 80 mg, 120 mg—30, 90 Titration Pack—1 (2 x 20 mg + 26 x 40 mg). For more information call 800.678.1605 or visit www.Fetzima.com.

Antiretroviral inhibits HIV-1 integrase Product: Tivicay Company: ViiV

Healthcare Pharmacologic class: HIV-1 integrase strand transfer inhibitor (INSTI) Active ingredient:

Dolutegravir 50 mg; tablets. Indication: In combi-

nation with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged ≥12 years and weighing ≥40 kg. Pharmacology: Dolutegravir inhibits HIV-1 integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle. Clinical trials: The effi-

cacy of Tivicay was based on analyses of data from two trials, SPRING-2 and SINGLE, in treatmentnaïve, HIV-1-infected subjects (n=1,641); from

For more products, visit www.eMPR.com

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

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Tivicay from pg. 48

one trial, SAILING, in treatment-experienced, INSTI-naïve HIV-1infected subjects (n=715); and from the VIKING-3 trial of INSTI-experienced HIV-1-infected subjects (n=183) with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance. In the SPRING-2 trial, once-daily Tivicay versus twice-daily raltegravir in 822 HIV-infected, treatment-naïve patients, both in combination with a fixed-dose dual-NRTI treatment, were evaluated. At week 48, the proportion of subjects who were virologically suppressed (HIV1 RNA <50 copies/mL) was 88% for the regimen

Tivicay is indicated for adults who have never taken HIV antiretroviral therapy.

containing Tivicay and 86% for the regimen containing raltegravir, meeting the 10% non-inferiority criteria. In the SINGLE trial, once-daily Tivicay plus fixed-dose Epzicom (abacavir and lamivudine) vs. the fixed-dose Atripla (efavirenz/emtricitabine/ tenofovir) regimen in 833 HIV-infected, treatmentnaïve patients were evaluated. At 48 weeks, the proportion of subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL) was 88% for Tivicay regimen and 81% for Atripla which was statistically significant. For more information on clinical trials, see full labeling. Adults: Aged ≥12 years and weighing ≥40 kg: treatment-naïve or treatment-experienced INSTI-naïve: 50 mg once daily. Treatment-naïve or treatment-experienced INSTI-naïve with concomitant potent UGT1A/ CYP3A inducers (e.g., efavirenz [Sustiva], fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin [Rifadin]): 50 mg twice daily. INSTI-experienced with certain INSTIassociated resistance substitutions or clinically

suspected INSTI resistance: 50 mg twice daily. Children: Aged <12 years

or weighing <40 kg, or INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir [Isentress], elvitegravir): not established.

Contraindications:

Concomitant dofetilide (Tikosyn). Warnings/Precautions:

Discontinue if hypersensitivity reactions develop. Increased risk for worsening/development of elevated transaminases in patients with hepatitis B or C; monitor liver function tests prior to starting and during therapy. Severe hepatic impairment: not recommended. INSTIexperienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with severe renal impairment: decrease in dolutegravir concentrations may result in loss of efficacy and development of resistance. Pregnancy (Category B). Nursing mothers: not recommended. Interactions: May

be affected by drugs

that induce or inhibit UGT1A1, UGT1A3, UGT1A9, BCRP, and P-gp enzymes or transporters. Avoid concomitant nevirapine (Viramune), oxcarbazepine (Trileptal), phenytoin (Dilantin, Phenytek), phenobarbital, carbamazepine, St. John’s wort. Avoid etravirine (Intelence) unless coadministered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir (Kaletra). Concomitant efavirenz, fosamprenavir/ ritonavir, tipranavir/ritonavir, or rifampin: adjust dose to 50 mg twice daily. Concomitant cationcontaining antacids, laxatives, sucralfate, oral iron/ calcium supplements, and buffered drugs: give dolutegravir two hours before or six hours after. Concomitant metformin: monitor closely and adjust metformin dose if necessary. Adverse reactions:

Insomnia, headache, immune reconstitution syndrome, lab abnormalities. How supplied: Tabs—30 n

For more information call 877.844.8872 or visit www.viivhealthcare.com.

For more products, visit www.eMPR.com

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CME CE

PROGRAM OUTLINE DECEMBER 2013

0.5 CREDITS

Page 56 FEATURE Minimizing radiation risk from diagnostic imaging Brady Pregerson, MD Brady Pregerson, MD has no relationships to disclose relating to the content of this article.

■■ LEARNING OBJECTIVES: • Describe significant predictors of intracranial injury. • Based on the PECARN study, relate conditions for which CT of the head is recommended. • Identify disadvantages of a ventilation/perfusion scan to detect pulmonary embolism. • List conditions for which abdominal ultrasound is advised in younger patients.

0.5 CREDITS

Page 113 DERMATOLOGY CLINIC Open comedones and inflammatory pustules Esther Stern, NP-C Esther Stern, NP-C has no relationships to disclose relating to the content of this article.

Linear streaks on the trunk and extremities Audrey Chan, MD Audrey Chan, MD has no relationships to disclose relating to the content of this article.

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

Page 119 DERMATOLOGIC LOOK-ALIKES Localized vesicles on the trunk 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 123 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 December 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.

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CME CE FEATURE

n LEARNING OBJECTIVES: • Describe significant predictors of intracranial injury. • Based on the PECARN study, relate conditions for which CT of the head is recommended. • Identify disadvantages of a ventilation/perfusion scan to detect pulmonary embolism. • List conditions for which abdominal ultrasound is advised in younger patients. n COMPLETE THE POSTTEST: Page 123 n ADDITIONAL CME/CE: Pages 113, 119 Turn to page 55 for additional information on this month’s CME/CE courses.

BRADY PREGERSON, MD

Minimizing radiation risk from diagnostic imaging In addition to increasing radiation exposure, CT scanning often uncovers incidental findings that may lead to emotional stress for the patient.

An axial brain CT shows a large subdural hematoma (red) in the left hemisphere.

odern diagnostic imaging provides criti cal anatomic confirmation of a vast array of disease processes and can also elucidate important functional information for many of the body’s internal organs. In mere seconds, a multi detector CT scan can obtain and generate images that diagnose acute appendicitis, pulmonary embo lism, intracranial bleeding, cervical spine fractures, and more. Unfortunately, these advantages come at a cost. In addition to the financial expense of CT screening, there are health-care costs associated with the long-term side effects of ionizing radia tion as well as with the surveillance of incidentally discovered findings that are unrelated to the clinical indication for the imaging examination performed, also known as “incidentalomas.” Observational studies have shown a significant increase in the utilization of CT over the past decades, but few of these have demonstrated an increase in diagnostic yield or prevention of disease complications. Each year, approximately 10% of U.S. citizens undergo a CT scan for detection or surveillance of

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disease, and this population has been increasing by approximately 10% per year.1 From 2001 to 2006, the overall use of diagnostic CT scans increased by 200%, with the highest relative increase for chest CT and neck CT at 600% and 500%, respectively.1 In February 2010, the FDA instituted an initiative to reduce the unnecessary use of the three types of tests that expose patients to the highest radiation doses— CT scanning, nuclear medicine studies, and fluoroscopy.1 Of these, CT scans are by far the most frequently ordered. CT is also the most likely to uncover incidentalomas, at a rate of up to 25% to 35%. Experts who have reviewed these data feel that at least 30% of these imaging tests were unnecessary.1 Although plain x-rays are probably ordered too often as well, they expose patients to much less radiation and were therefore not included in the FDA initiative. Strategies to minimize unnecessary radiation from diagnostic testing include observation without imaging, clinical decision-making instruments, alternate testing (e.g., electrocardiogram or D-dimer), and imaging that avoids or minimizes radiation exposure (e.g, plain films, ultrasound, or MRI). Risks and benefits of diagnostic imaging

The primary benefit of CT scanning is the more expeditious and accurate diagnosis of important disease processes or the ruling out of such conditions. Although no test is perfect, and the savvy clinician should always be alert for false-negative test results, CT results generally aid the clinician and can put the patient’s mind at ease. Nevertheless, exhaustive testing is not always in the best long-term health interest of the patient. Documented risks of radiation include fetal malformation, detrimental effects on brain development of children, increased risk of future cancer, and incidental findings that often require further downstream testing and may cause significant emotional distress (i.e., incidentalomas).2 The effects of diagnostic imaging on fetal development and malformation are beyond the scope of this article but are covered by guidelines from the American College of Gynecology and Obstetrics.3 Most of the data on intellectual development come from a Swedish study that followed the academic performance of teens who had previously received radiation treatment for facial hemangiomas.4 This study showed that the higher the dose of radiation received in childhood, the lower the child’s chance of passing a standardized school-entry examination. Causation could not be proven definitively because there was no randomization, but the strong dose-response correlation is highly suggestive of

TABLE 1. Comparative radiation doses from diagnostic imaging Diagnostic study

Average dose in millisieverts*

Equivalent dose in chest x-rays

Knee, ankle, elbow, wrist x-ray

0.02

Posteroanterior chest x-ray

0.02

Lateral chest x-ray

0.04

Skull x-ray

0.07

3.5

Cervical spine series

0.3

Mammogram

0.6

Kidneys, ureter, bladder x-ray

0.6

Pelvis/hip x-ray

1.2

CT – head

2.0

100

Lumbosacral spine series

2.0

100

Ventilation/perfusion scan

2.0

100

Intravenous pyelogram

3.0

150

Yearly background exposure

3.0

150

Hepatobiliary scan

3.7

185

Bone scan

4.4

220

Positron emission tomography scan

5-14

250-700

Technetium sestamibi scan

6-12

300-600

Cardiac catheterization

5-50

250-2,500

CT – chest

8-16

400-800

400

Barium enema CT – coronary

500

15-20

750-1,000

CT – urogram

1,000

Thallium scan

CT – abdomen and pelvis

12-24

600-1,200

Interventional radiology procedures

1,250

Gallium scan

2,000

Actual doses may vary (by more than tenfold for CT); higher resolution requires higher dosing.

a causal role of childhood radiation exposure in negatively impacting intellectual development. The increased risk of fatal malignancy later in life in patients exposed to ionizing radiation is most strongly supported in cases in which the degree of radiation exposure is high, such as among survivors of such nuclear disasters as the one at Chernobyl and of the atomic bombings of Hiroshima and Nagasaki. Some of these survivors experienced the disasters from a distance at which the estimated radiation exposure was extremely high, but even in survivors who were at a distance at which the radiation dose would have been similar to that of

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DIAGNOSTIC IMAGING RISK

modern CT scans, a higher rate of future malignancy was noted when compared with nonexposed persons. Other populations that have been studied and noted to have an increased rate of cancer have been radium-watch painters and patients who underwent medical radiation therapy. The magnitude of the risk of fatal cancer has been extrapolated to lower exposure levels and is thought to be as high as 1 in 1,000 for most torso CT scans. Latency is often 10 to 20 years or more but can be shorter for leukemia, thyroid cancer, and breast cancer.5,6 The degree of risk will depend on the body area imaged, the radiation dose, and the age and gender of the patient. Imaging of the head, neck, and especially the torso carries a higher risk than imaging of the extremities.7 Younger patients are at much higher risk due to more rapidly dividing cells and a longer life expectancy over which they may manifest disease. Risk can be up to 10 times higher in childhood than it is in late adulthood.7 Risk related to chest CT is significantly higher in women than in men because of the risk of breast cancer. Finally, and most important, certain types of imaging use higher doses of radiation than do others (Table 1). Ultrasound and MRI are radiation-free. Standard x-rays use much lower doses of radiation than do nuclear medicine studies, which tend to use lower doses than do CT scans. It is estimated that the average person living in the United States is exposed to 3.0 millisieverts of natural background radiation per year. Imaging tests, CT scans in particular, may occasionally reveal positive findings unrelated to the patient’s symptoms. These incidentalomas are often small nodules or cysts in the thyroid, lung, liver, kidneys, or adrenal glands. Like freckles, bumps, and moles on the outside of the body, these internal nodules tend to be more common with increasing age and can be found in up to 15% to 30% of CT scans.8 Fortunately, the vast majority are benign, but because a small percentage TABLE 2. Predictors of significant intracranial injury (BEAN BASH) Behavior abnormal Emesis intractable Age >65 years Neurologic deficit Bleeding disorder Altered mental status Skull fracture Hematoma scalp Adapted from Mower WR, Hoffman JR, Herbert M, et al. Developing a decision instrument to guide computed tomographic imaging of blunt head injury patients. J Trauma. 2005;59:954-959.

eventually turn out to be malignant, surveillance imaging is often recommended. Unfortunately, this leads to added medical costs and, in many cases, additional radiation exposure and increased patient stress and anxiety. Most of this is all for naught, as the number of cancer “saves” from this process is quite low. Given the scope of the problem, how can clinicians reduce the use of diagnostic imaging without seeing an increase in missed diagnoses? What follows is a top-down approach for minimizing unnecessary use of CT scanning. This discussion will cover the evaluation of head injury; chest pain; and abdominal, flank, and pelvic pain. Additional topics that should warrant your attention but are beyond the scope of this article include nontraumatic headache, neck injury, and abdominal pain in pregnancy. Head injury

Head injuries are a common reason for patients to present for medical evaluation. Fortunately, most patients with a normal neurologic exam will not have a brain injury that requires any significant intervention. However, some will. Such clinical factors as the age of the patient, the mechanism of injury, the presence of vomiting, and the use of blood thinners help to risk-stratify these head-injured patients with a normal neurologic exam. Although clinical information can help providers minimize the use of CT scan without missing any significant injuries, there is no simple rule that can be used to do this effectively. A variety of clinical information, along with provider judgment, must come into play. A number of large clinical studies have addressed the minimization of CT in patients with head injury, the best known of which have led to the development of the New Orleans Criteria, the Canadian Head CT Rule, and NEXUS-2.9,10,11 All of these are useful, but none is perfect. The issue is too complex to be encompassed by a simple rule. The NEXUS2 researchers concluded that providers must know the red flags for brain injury and integrate these warning signs with other clinical information to decide whether CT-scanning of the brain is warranted. The authors use the mnemonic BEAN BASH to identify predictors of significant intracranial injury (Table 2).11 Other factors to consider are the presence of a headache, its severity, and whether it is improving or worsening, or aggravated by the Valsalva maneuver. What was the mechanism of injury, and is the trauma confined to the front of the head or does it extend to other areas that are higher risk, such as the occiput? Was there loss of consciousness, and if so, how

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long did it last? Is short-term memory intact? Does the patient have a reliable person who can wake him or her every two to three hours overnight and in the morning for status checks? More red flags indicate higher risk of a significant brain injury. Patients with normal exams and no red flags probably do not need any imaging at all. Patients who only have a mild or improving headache or who report a loss of consciousness of fewer than 60 seconds and have no other red flags likely do not need imaging. On the other hand, patients who are on blood thinners but have normal brain imaging may still not be safe for discharge home. The issues involved are complex, but clinicians should not order indiscriminant CT scanning on all head-injured patients. The clinical information provided by the previously cited head-injury studies provides a viable plan for selective imaging and a reduction in the radiation exposure in adults.9,10,11 Although the risks of radiation are significantly higher in children with head trauma, the clinical issues are somewhat simpler. In general, young children do not drink alcohol, do not have brain atrophy, and do not use blood thinners. Separate studies have addressed the issue of CT scanning after head trauma in children, the most important of which is the PECARN study.12 Researchers looked at more than 42,000 children younger than age 18 years with Glasgow Coma Scale scores of 14-15. Patients were excluded if they presented more than 24 hours after injury, had a prior neurologic injury, or had a nonsevere injury mechanism (e.g., a ground-level fall or walking into an object). For children younger than age 2 years, red flags for brain injury included changed mental status, concerning or unknown mechanism of injury, loss of consciousness for more than five seconds, palpable skull fracture, or a nonfrontal hematoma. For children aged 2 to 18 years, red flags for brain injury included changed mental status, concerning or unknown mechanism of injury, loss of consciousness, signs of a basilar skull fracture, vomiting, or a severe headache. Concerning mechanisms were considered to be bike accidents with no helmet, a fall greater than five stairs or 3 ft (>5 ft if older than age 2 years), or being hit with a projectile. Recommendation was for no CT scan in cases without any red flags, CT in all cases with abnormalities on neurologic assessment or signs of a fracture, and selective scanning in cases where there was only one red flag. In the selective scanning cases, the decision to use CT was based on whether symptoms were getting better or worse, clinician experience, and parental preference.12 When suspicion of intracranial injury is low with only a single red flag present, the clinician should discuss the risks and benefits of CT with radiation vs. home observation

with return precautions. Advise the parent or patient that it is always safer for the clinician to order more testing, but that the clinician has a duty to recommend what is safest for the patient. This will help create a therapeutic alliance rather than a confrontation. Letting the patient or parent decide in equivocal cases may take a little more time, but it is the right thing to do. Dyspnea and/or pleuritic chest pain

Many patients with pleuritic chest pain have only pleurisy or bronchitis, but some have pulmonary embolism (PE), a potentially fatal diagnosis. Again, the goal is to avoid unnecessary testing without missing the diagnosis. Patients with no dyspnea, no pleuritic component to their pain, or no tachypnea have a very low pre-test probability of PE and likely need no testing at all. Low-risk patients that do not fit these criteria should be initially screened using either the PE rule-out criteria (PERC) tool or a highly sensitive D-dimer, as both tools avoid radiation.13 In such cases, it is critical to consider whether there is a more likely diagnosis than PE. Small PEs can be difficult to detect in otherwise healthy patients presenting with pleuritic pain but no dyspnea or alteration in vital signs. If the clinical scenario is classic for bronchitis or a muscle strain, no testing may be required, but the provider should be alert for anything in the clinical picture that does not fit. When used properly, D-dimer testing can prevent unnecessary advanced imaging and its attendant radiation. When D-dimer is used improperly to screen no-risk patients, the many false-positive results produced can lead to increased imaging. D-dimer testing should not be ordered in a patient with chest symptoms that are not suggestive of PE. D-dimer should only be ordered when the provider would otherwise order a ventilation/perfusion (VQ) or CT scan due to clinical concern. If the D-dimer is negative, the workup can usually be stopped and the patient spared the risks of radiation and/or IV contrast. Up to 50% of D-dimers will be false-positives. The following conditions can cause an elevated D-dimer; in such cases, it may be advisable to skip directly to imaging.14 • Traumatic: postoperative (for up to 10 days), bruise, pregnancy/peripartum period • Thrombotic: myocardial infarction, cerebrovascular accident, dissection, abdominal aortic aneurysm (AAA) • Chronic: liver disease, renal disease, malignancy, collagen vascular disease, sickle-cell disease • Infectious/inflammatory: pericarditis, infection, sepsis, disseminated intravascular coagulation. Continues on page 60

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DIAGNOSTIC IMAGING RISK

FIGURE 1. VQ scan shows right-sided pulmonary embolism.

FIGURE 2. CT shows acute embolism in both pulmonary arteries.

Factors that can cause-false negative D-dimer results are even more important to be aware of and require advanced imaging with either VQ or CT angiogram.14 These factors include symptoms lasting longer than one week and current use of heparin (Lipo-Hepin, Liquaemin, Panheparin) or warfarin (Coumadin, Jantoven). D-dimer can be used to rule out PE in low-risk patients; if combined with a high-sensitivity assay, it can also rule out PE in intermediate-risk patients.15 The better D-dimer tests have sensitivities in the mid- to high-90s, which is comparable to or better than CT angiogram. Another advantage of D-dimer is added sensitivity when VQ or CT gives nondefinitive or suboptimal results. Benefits of D-dimer include rapid turnaround, low cost, and no radiation. The main disadvantage is the test’s low specificity, which is around 50% in most studies. If a patient is considered high-risk clinically, or if a D-dimer is positive or not an optimal test, a VQ scan or CT angiogram is advised. Although CT has gained popularity, VQ remains the test of choice for most patients when available (Figure 1). Benefits of VQ compared with CT include better sensitivity (96% to 98% for a normal scan),16 less radiation (one-eight to one-fourth the dose), and no need for IV contrast or a large proximal IV.14 Disadvantages of VQ include the need for a normal screening chest x-ray to minimize the chance of an indeterminate study, the tests’s inability to detect such other conditions as pneumonia or dissection, and limited availability.14 One disadvantage of VQ that is

more perceived than real is the way that results are reported back to the clinician as normal, low, intermediate, or high probability. This should not prevent its use when the chest x-ray is normal, as fewer than 10% of VQ scans will be read as indeterminate or intermediate probability in such cases. Advantages of CT scan for evaluation of PE (Figure 2) include superiority when the chest x-ray is abnormal, rapid scanning time for unstable patients, 24-hour availability in most institutions, high specificity (96%),17 and the ability to find alternate diagnoses.14 Disadvantages of CT include lower sensitivity (77% to 83%),17 much higher radiation exposure (especially to breast tissue), need for IV contrast, and incidental findings that occur in approximately 30% of cases.14 The recommended strategy for evaluation of PE begins with avoiding initiating the workup in no-risk patients (i.e., those with no dyspnea, no pleuritic pain, and no tachypnea). Next, avoid indiscriminant use of D-dimer testing, as the high rate of false-positives may lead to increased use of radiation. In patients at low to intermediate risk in whom CT or VQ would be indicated, start with a high-sensitivity D-dimer test whenever available. A negative D-dimer can be considered as sensitive as VQ and more sensitive than CT as long as it is not one of the older assays and there are no conditions present that would cause a false-negative result. If D-dimer is positive or deemed inappropriate, use VQ first when available, especially in younger patients who have normal chest x-ray and for whom alternate diagnoses are not a concern, or when there is a contraindication to

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IV contrast. A CT scan is advised when the patient is semiunstable, when the chest x-ray is abnormal, or when such alternate conditions as aortic dissection are a consideration. Abdominal, flank, and pelvic pain Advances in CT scanning of the abdomen have revolutionized diagnosis of abdominal pain over the past few decades, most notably with improved sensitivity for important pathology (Table 3). Unfortunately, these advances, combined with the practice of defensive medicine, have led to inappropriate overuse of CT in patients with nonspecific abdominal pain, gastroenteritis, and dyspepsia. This overuse has led to increased cost, increased exposure to iodinated IV contrast, increased exposure to ionizing radiation, and delay in patient disposition. Making a diagnosis with CT scan is often relatively straightforward. Clinicians should be looking for instances in which the CT can be skipped. Consider three alternate approaches: ultrasound only, plain films only, and observation or therapeutic trials with no imaging. Ultrasound only. Abdominal ultrasound, an imaging modality that lacks any ionizing radiation, already outperforms CT in a few scenarios. Ultrasound should be used preferentially—or at least initially—for right-upper-quadrant pain, pelvic pain, and abdominal pain in the pregnant patient. Ultrasound should also be considered initially in younger patients in whom ureteral stones or acute appendicitis is suspected. In ureteral stone disease, ultrasound is 65% to 95% sensitive. Although not great, this sensitivity is acceptable as long as there is no concern for more serious conditions (i.e., AAA), as most stones pass on their own with time.14 If hematuria is present and the patient history is classic for a ureteral stone, imaging may be omitted altogether provided there is no suspicion for more serious disease based on risk factors and/ or prior imaging showing a normal aorta. For right-lower-quadrant pain, abdominal ultrasound is 80% to 95% sensitive and 86% to 98% specific for acute appendicitis in nonobese children.18 Abdominal ultrasound requires no IV, no prep time, and no radiation. It is the initial test of choice in children’s hospitals and should be the required initial test for evaluation of pediatric right-lowerquadrant pain when the primary rule-out is appendicitis. Adequately trained sonographers and buy-in from hospital surgeons are critical for successful implementation of such a plan, but lack of either should by no means be seen as a reason to go straight to CT. Emergency and primary-care providers can use their influence to encourage technicians and general surgeons to use ultrasound to rule out appendicitis in children with right-lower-quadrant pain.

TABLE 3. CT sensitivity for common abdominal conditions Abdominal aortic aneurysm: 99% Bowel obstruction: 97% Renal stones: 97% Diverticulitis: 95% Appendicitis: 92%-97% Biliary disease: 88% Ischemic bowel: 80% Adapted from Pregerson DB. Tarascon Emergency Department Quick Guide. Sudbury, Mass.: Jones & Bartlett Learning; 2012:45-47.

Plain films only. Plain films may be used instead of CT in a few fairly common emergency scenarios featuring bowel obstruction or perforation. If the patient appears acutely ill and may need to be rushed to the operating room, an abdominal series may be safer than CT since x-ray results are available more rapidly. If there is no CT queue and the clinician prefers noncontrast CT for this indication, CT may be almost as rapid. Plain films may also be the study of choice when the patient is stable and suspicion for bowel obstruction is low, but vomiting and/or pain is present. Examples of such a scenario include suspected gastroenteritis in a patient who has had prior abdominal surgery and/or not much diarrhea, or a young patient with Crohn disease who has had multiple prior CTs for abdominal pain and vomiting. Plain films can help minimize radiation exposure without increasing the risk of missing a potentially surgical condition. Observation or therapeutic trials with no imaging. Home observation for nonspecific abdominal pain with no or few red flags is a wise option in a majority of cases. A trial of antacids combined with carefully worded verbal and written aftercare instructions can prevent unnecessary radiation exposure and prolonged visits in most patients with nonspecific abdominal pain. Conclusion

There are three relevant aspects of the Hippocratic Oath to consider in radiation stewardship: • Place your patient’s interests before your own: It may be in the provider’s interest to do more testing, but not necessarily the patient’s. • Respect the patient’s right to make decisions: Always discuss risks and benefits, which will help prevent legal problems if something is missed. • Try to prevent as well as cure disease: Avoid unnecessary radiation, especially CT scanning, in younger low-risk patients. Continues on page 62

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CME CE

DIAGNOSTIC IMAGING RISK

Disadvantages of CT include increased costs, increased visit times, increased waiting-room times, and increased radiation exposure. CT scanning provides excellent imaging information that can help rule in or rule out a number of emergency medical conditions. On the other hand, disadvantages of CT include increased costs, increased visit times, increased waiting-room times, and increased radiation exposure that puts patients at higher risk for future cancers. Clinical decision-making tools can help providers determine which patients require imaging. Alternate imaging modalities that use less radiation than CT (or no radiation at all) may be preferable under certain circumstances. Home observation may be a viable option for the right situation, but to minimize legal risks and maximize patient satisfaction, try to involve the patient in the decision-making process. n

10. Stiell IG, Wells GA, Vandemheen K, et al. The Canadian CT Head Rule for patients with minor head injury. Lancet. 2001;357:1391-1396. 11. Mower WR, Hoffman JR, Herbert M, et al. Developing a decision instrument to guide computed tomographic imaging of blunt head injury patients. J Trauma. 2005;59:954-959. 12. Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009;374:1160-1170. 13. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008;6:772-780. 14. Pregerson DB. Tarascon Emergency Department Quick Guide. Sudbury, Mass.: Jones & Bartlett Learning; 2012:45-47. 15. Turkstra F, van Beek EJ, ten Cate JW, Büller HR. Reliable rapid blood

Dr. Pregerson is a staff emergency physician at Cedars-Sinai Medical Center in Los Angeles and the editor-in-chief of EMresource.org.

test for the exclusion of venous thromboembolism in symptomatic outpatients. Thromb Haemost. 1996;76:9-11. 16. PIOPED Investigators. Value of the ventilation/perfusion scan in acute

References

pulmonary embolism. Results of the prospective investigation of pulmo-

1. Smith-Bindman R. Is computed tomography safe? N Engl J Med.

nary embolism diagnosis (PIOPED). JAMA. 1990;263:2753-2759.

2010;363:1-4.

17. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed

2. Picano E. Informed consent and communication of risk from radiological

tomography for acute pulmonary embolism. N Engl J Med. 2006;354:2317-

and nuclear medicine examinations: how to escape from a communication

2327. Available at www.nejm.org/doi/full/10.1056/NEJMoa052367.

inferno. BMJ. 2004;329:849-851. Available at www.ncbi.nlm.nih.gov/pmc/

18. Neufeld D, Vainrib M, Buklan G, et al. Management of acute appendici-

articles/PMC521582/.

tis: an imaging strategy in children. Pediatr Surg Int. 2010;26:167-171.

3. ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995).

All electronic documents accessed November 15, 2013.

4. Hall P, Adami HO, Trichopoulos D, et al. Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study. BMJ. 2004;328:19. Available at www.ncbi.nlm.nih.gov/ pmc/articles/PMC313898/. 5. National Research Council. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, D.C.: The National Academies Press, 2006. 6. Lockwood D, Einstein D, Davros W. Diagnostic imaging: radiation dose and patients’ concerns. Cleve Clin J Med. 2006;73:583-586. Available at www.ccjm.org/content/73/6/583.long. 7. Picano E. Sustainability of medical imaging. BMJ. 2004;328:578-580. Availble at www.ncbi.nlm.nih.gov/pmc/articles/PMC381057/. 8. Hillman BJ, Goldsmith JC. The uncritical use of high-tech medical imaging. N Engl J Med. 2010;363:4-6. 9. Haydel MJ, Preston CA, Mills TJ, et al. Indications for computed tomography in patients with minor head injury. N Engl J Med. 2000;343:100-105. Available at www.nejm.org/doi/full/10.1056/NEJM200007133430204.

“I didn’t get where I am by trying to please.”

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FEATURE: AMBER WHITMORE, PA-C

Understanding the changes in DSM-5 The latest revision of the diagnostic manual does away with the complex multiaxial organization in favor of a simpler chapter listing of disorders.

The latest version of the DSM is the first full revision since 1994.

he fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was unveiled at the annual American Psychiatric Association (APA) meeting in San Francisco in May 2013. After nearly a decade of multilevel scientific, clinical, and public-health review, the new guidelines are ready for immediate use by the APA and in your own clinical practice. The original DSM was published in 1952, with a fourth revision in 1994, and a text revision in 2000. To incorporate new research and advances in knowledge since the last revision, the APA recruited a task force and various study groups consisting of top researchers and clinicians worldwide. The new guidelines became eligible for application in May 2013. The complete transition is slated for December 31, 2013, allowing for delays as insurance companies update claim forms and reporting diagnoses and codes. DSM-5 is compatible with the World Health Organization’s International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for immediate use. Transition to use of the ICD10-CM is currently set for October 1, 2014. The transition to ICD-10-CM is required by the Health Insurance Portability and Accountability Act of 1996. To accommodate differing DSM-5 and ICD-10-CM disorder names, the DSM diagnosis should always be documented in medical records in addition to the ICD code. National board examinations generally take two to three years to incorporate new guidelines. Continues on page 69

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DSM-5 has been restructured to consist of three sections in addition to the preface, the classification of coding portion, and the appendix. The new manual has removed the multiaxial organization (Axes I-V) of disorders by combining the first three DSM-IV-TR axes into a single developmental list. The nonaxial documentation includes all mental and personality disorders, including intellectual disability, with separate scales for measuring symptom severity and disability. The noteworthy changes address the names of disorders, enhance criteria to align all providers in accurately assessing patients, and identify the impact a diagnosis has on daily functioning. This brief review of the new three-part structure outlined below contains some of the key changes in DSM-5 that may impact your clinical practice. Section 1: DSM-5 basics

The introductory section of the new volume outlines the changes in the order in which they appear. Section 2: Diagnostic criteria and codes

The previous multiaxial structure is now divided into topics with subtopics. The nonaxial documentation for diagnosis will combine the former Axes I, II, and III, with separate notations for psychosocial and contextual factors (formerly Axis IV) and disability (formerly Axis V). Substantial changes were made to the following disorders: Intellectual disability. The federal law (Rosa’s Law) signed by President Obama on October 5, 2010, replaced the term “mental retardation” with “intellectual disability.” DSM-5 will adopt this diagnostic term to align with the rest of the medical, educational, and advocacy communities. Intellectual disability is based on clinical assessment and standardized testing

POLL POSITION

How concerned are you about the possibility of overmedicaton caused by changes in diagnostic criteria? n=109

27% n Extremely: 28% n Somewhat: 45% n Not at all: 27%

28%

45%

For more polls, visit CliniAd.com/10TDwDb.

of intelligence. DSM-5 emphasizes that intelligence should be assessed across three domains of adaptive functioning: (1) conceptual domain (language, reading, math); (2) social domain (social judgment, interpersonal communication); and (3) practical domain (personal care, job responsibilities). The intelligence quotient (IQ) will no longer be used as a diagnostic criterion but is still recommended for assessment. Intellectual disability is suggested for individuals with an IQ score of approximately 70 or below (two standard deviations below the population). Severity can be specified as mild, moderate, severe, or profound. Severity is determined by adaptive functioning rather than cognitive capacity (i.e., IQ). Autism spectrum disorder (ASD). A graded scale now combines the former four autism-related disorders: autistic, Asperger, childhood disintegrative, and pervasive developmental. In DSM-5, ASD is a collective condition that reflects severity of symptoms encompassing deficits in social communication and interaction and restricted repetitive behaviors (RRBs), interests, and activities. (Note: If RRBs are not present, the diagnosis of social communication disorder is suggested.) The new criteria will allow for variation in symptoms and behaviors between individuals. Placing a patient on a spectrum rather than providing an individual diagnosis prevents inconsistency between clinicians and reduces the risk of misdiagnosis. DSM-5 requires symptoms to be present from early childhood even if ASD is not assessed or diagnosed until later in life. A recent study found that 91% of children diagnosed with ASD using DSM-5 criteria were also diagnosed with one of the four DSM-IV autism-related disorders.1 This study shows that most children will retain a diagnosis of ASD when converting to the new guidelines. Attention deficit hyperactivity disorder (ADHD). The DSM-5 criteria divide the 18 diagnostic symptoms from DSM-IV into inattention and hyperactivity. Key changes include the addition of examples to help identify the disorder across the life span and the facts that: symptoms are now required to be present before age 12 years rather than age 7 years; a diagnosis of both ADHD and ASD is now permitted; the symptom threshold for ADHD in adults has been lowered to five symptoms (six for those younger); and ADHD is now listed as a neurodevelopmental disorder rather than a disruptive disorder. Specific learning disorder. All previous learning disorders are now combined into a single diagnosis, which acknowledges the fact that academic deficits commonly occur together. A coding specifier can be added to designate deficits in reading, mathematics, written expression, and learning disorder not otherwise specified. Continues on page 74

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Critics question the methodology and transparency of DSM-5 WALKER HARRISON

The release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) this in May 2013 was met with criticism within the mental health profession. Modifications in diagnostic criteria for autism, bipolar disorder, attention-deficit hyperactivity disorder (ADHD), and other conditions have been questioned by experts. Many suspect that the manual has been influenced by the pharmaceutical industry, which could benefit from an increase in drug prescriptions for people with the aforementioned conditions. Among the detractors are two authors of previous versions of the manual. Robert L. Spitzer, MD, head of the task force for DSM-3, expressed outrage over the fact that the creators of DSM-5 signed a nondisclosure agreement, allowing them to operate confidentially. “When I first heard about this agreement, I just went bonkers. Transparency is necessary if the document is to have credibility,” said Dr. Spitzer. Allen Frances, MD, chair of the DSM-IV task force, was also skeptical, pointing to the increasingly mild and ambiguous signs for such disorders as ADHD proposed by DSM-5 that could add to the widespread overdiagnosis of these conditions. “The DSM-5 should buck the trend and its inclinations—it should be ending false epidemics, not starting them,” said Dr. Frances, who also called the work a “most unhappy combination of soaring ambition and weak methodology.” In an effort to quantify the concern over the then upcoming DSM-5, the Massachusetts General Hospital Psychiatry Academy partnered with myCME (myCME.com) to conduct a survey of medical professionals’ opinions on the matter. The survey was sent to clinicians in December 2012 and January 2013 and received 144 responses. Responses were split into physicians (36.8%) and nonphysicians (63.2%). Almost all nonphysicians (94.6%) were nurse practitioners or physician assistants. More than 75% of respondents had more than 10 years of practice experience, and 91.6% were in the field of psychiatry.

Catatonia. This diagnosis now requires three out of 12 catatonic symptoms for all contexts. Diagnosis can be made separately or as a specifier for bipolar, psychotic, or depressive disorder. Disruptive mood dysregulation disorder. This new diagnosis identifies children experiencing persistent irritability and extreme changes in mood without bipolar disorder. This change addresses and prevents overdiagnosis and treatment

Nonphysicians appeared to be more interested in the release of DSM-5 than were physicians: 88% of the former expressed at least moderate anticipation about the new manual, compared with 70.6% of the latter. Meanwhile, 11.3% of physicians were indifferent to the release, and 15.1% said they would only pay attention once it impacted their practice, compared with 4.4% and 6.6%, respectively, for nonphysicians. In general, clinicians expressed anxiety about understanding the changes made to diagnostic criteria. A large majority (84%) were at least “somewhat concerned” that implementing the revisions would be complicated, with just over half (50.7%) reporting high levels of concern. Moreover, only 14.6% of participants felt “very confident” that they would be able to put the changes into practice. Nonphysicians were more optimistic than physicians about the prospects of DSM-5, as 67% reported at least moderate confidence in incorporating the changes, compared with 47.2% for physicians. When clinicians were asked to specify what exactly concerned them about DSM-5, the most common answers were the time required and available to understand the new manual, access to education on the new guidelines, and insurance- and reimbursement-related issues. Therapeutic areas of DSM-5 that troubled clinicians most were bipolar disorder (59.0%), autism spectrum disorders (47.9%), depression (47.2%), substance abuse disorders (45.8%), and posttraumatic stress disorder (41.0%). With regard to actually educating themselves, 87.8% of participants said they would seek to do so either right away or soon after the release of DSM-5, while almost half (49.3%) planned on primarily using the Internet to learn about the revised manual. While there are certainly some clinicians who are not fretting about DSM-5, the general trends of the survey seem to indicate high levels of doubt surrounding the manual and reflect the overall anxious mood of practitioners in the related fields. Mr. Harrison is a freelance medical writer in New York City.

of bipolar in patients aged 6 to 18 years. Diagnostic criteria include persistent irritability and frequent behavior outbursts occurring at least three times per week for over a year. Major depressive disorder (MDD). No modifications have been made to the core symptom criteria or length of symptoms for diagnosis (at least two weeks). However, a bereavement exclusion modification removes the exemption of diagnosing MDD when grief is present within two months of the death

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Symptoms of premenstrual dysphoric disorder must cause clinically significant distress affecting work, school, social activities, or relationships. of a loved one. This change reflects the belief that bereavement can be a stressor precipitating depression soon after a loss and that grief can last up to two years. Bereavement now does not exempt one from being diagnosed with MDD, and guidance is given regarding how to differentiate grief from depressive disorders. In cases of grief, self-esteem is usually preserved, and painful feelings present in waves mixed with positive memories. Cases of depressive disorders commonly feature feelings of worthlessness and self-loathing and constant negative thoughts. Depression both related and unrelated to bereavement responds to the same or similar treatment options. Persistent depressive disorder. This new diagnosis, which includes chronic MDD and the previous dysthymic disorder, was formed after an inability to scientifically find meaningful differences between dysthymia and chronic depression. Suicide risk assessment scales. Two new suicide risk assessment scales—one for adolescents and one for adults—help identify individuals with suicidal risk factors, gives clinical guidance, and recommend assessment of suicidal thinking and plans. The goal is to implement suicide prevention while devising treatment plans. Premenstrual dysphoric disorder (PMDD). PMDD is a state of extremely high tension, anxiety, and aggression. Criteria for this diagnosis include five or more symptoms during most menstrual cycles with presence in the week prior to menses onset, improvement of symptoms a few days after menses, and absence in the week following menses. The symptoms must cause clinically significant distress affecting work, school, social activities, or relationships. Obsessive-compulsive and related disorders. This new chapter adds hoarding disorder (including specifiers for personal insight into the problematic nature of the hoarding-related beliefs [i.e., good/fair, poor, or absent insight]), excoriation (i.e., skin picking), substance- or medication-induced obsessive-compulsive and related disorder including specifiers for onset of the disorder (i.e., during intoxication, withdrawal, or after medication use), and obsessive-compulsive and related disorder due to another medical condition.2

Other specified and unspecified obsessive-compulsive and related disorders. This diagnosis is reserved for conditions that do not fit into a designated category. Such conditions include bodyfocused repetitive behavior disorder—such recurrent behaviors as cheek-chewing, lip-biting, and nail-biting that the patient has repeatedly and unsuccessfully tried to stop—and obsessional jealousy (nondelusional obsessions of a partner’s infidelity). Body dysmorphic disorder. Preoccupation with physical appearance resulting in such repetitive behaviors or acts as looking in a mirror and reassurance-seeking is now added to the manual. Specifiers include degree of insight into the individual’s beliefs of appearing “ugly or deformed” and the option to add “with muscle dysmorphia” for individuals preoccupied with insufficient muscularity. Post-traumatic stress disorder (PTSD). Stressor criteria have become more explicit in DSM-5, and symptom clusters have been increased from three to four. These clusters include: • Re-experiencing the traumatic event (memories, dreams, flashbacks) • Persistent avoidance of stimuli associated with the event • Persistent negative alterations in cognitions and mood • Marked alterations in arousal and reactivity (aggressive, reckless, or self-destructive behavior). By lowering the threshold of criteria, DSM-5 is more sensitive for diagnosing PTSD in children and adolescents. A new subtype with separate criteria has been included for children aged 6 years or younger. Feeding and eating disorders. This category now includes the diagnosis of binge-eating disorder, which is specified as binging on food one or more times per week for three months. The criterion for bulimia nervosa has been reduced to one or more episodes of binge-eating per week (in DSM-IV, it was two episodes per week). Anorexia no longer includes the criterion of amenorrhea to prevent excluding men, women in pre-menarche, women who use contraception, and women in post-menarche. Gender dysphoria. A transition from the previous “Sexual and gender identity disorders” reflects the variations in

For more news, opinion, and clinical features on depression and other mental illnesses, visit our Psychiatry Information Center at

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The independent sleep-wake disorders include rapid eye movement sleep behavior disorder and restless leg syndrome. criteria and experiences regarding the diagnosis of gender dysphoria. Identifying with a gender different from what an individual was assigned at birth does not constitute a mental disorder; it is the stressors resulting from this dysphoria that meet the criteria for diagnosis. Removing the term “disorder” indicates a movement toward eliminating stigma surrounding affected individuals by modifying the terminology that previously suggested the patient is “disordered.”3 Gender dysphoria was included in the manual to facilitate clinical care and allow access to insurance coverage that supports mental health. The concern with complete omission of gender dysphoria would be denial of medical treatments that include counseling, cross-sex hormones, gender reassignment, and legal transition. Separate criteria are provided for children and must also be present for at least six months. A post-transition specifier can be applied when an individual’s post-gender transition no longer meets criteria and treatment is still needed, whether surgical, endocrinologic, or psychotherapeutic. Substance-related and addictive disorders. The diagnosis of gambling disorder is now included under the chapter related to substance disorders, reflecting evidence that addictive behaviors (i.e., gambling) activate the brain’s reward system in a manner similar to that of drugs or alcohol. DSM-5 also combines substance abuse and dependence into the overall diagnosis of substance use disorder. Criteria changes include the removal of “recurrent legal problems” and addition of “craving or a strong desire or urge to use a substance.” A new diagnosis is included for cannabis withdrawal. Severity of substance use disorder is ranked by the number of symptom criteria: mild disorder (2-3); moderate disorder (4-5); severe (6 or more). Communication disorders. Phonological disorder is referred to as speech sound disorder in DSM-5, and stuttering is referred to as childhood-onset fluency disorder. Social (pragmatic) communication disorder is a new diagnostic category in DSM-5. This diagnosis was created to more accurately recognize individuals who have significant problems using verbal and nonverbal communication for social purposes. This difficulty can cause impairments in the individual’s ability to communicate effectively, participate socially, maintain social relationships, or otherwise perform at school or at work. Anxious distress specifier. Individuals with the diagnosis of a depressive or bipolar disorder can have the specifier “with anxious distress” added.

Social anxiety disorder (SAD). The features of SAD, formerly termed “social phobia,” are essentially the same. Changes include removing the requirement of individuals older than age 18 years to recognize their anxiety and now require all ages to have duration of symptoms for six months or longer. The only specifier offered is “performance only,” which is used to identify fears regarding speaking or performing in front of an audience. Panic attack. The optional features of describing a panic attack are replaced with the diagnosis of expected or unexpected panic attacks. A panic attack specifier can be added to all DSM-5 disorders. Somatic symptoms and related disorders. Previously, somatoform disorders had overlapping symptoms and lacked well-defined boundaries for diagnosis. Removal of individual disorders now falling under this diagnosis includes hypochondriasis, pain disorder, somatization disorder, and undifferentiated somatoform disorder. Parasomnias. The independent sleep-wake disorders in DSM-5 include rapid eye movement sleep behavior disorder and restless leg syndrome. Previous research suggested that these disorders should no longer fall under the DSM-IV category “not otherwise specified.” Section 3: Emerging measures and models

Section 3 of DSM-5 includes the chapters Assessment Measures, Cultural Formulation, and Conditions for Further Study. Assessment Measures. The World Health Organization Disability Assessment Schedule (WHO-DAS 2.0) is considered the best current measure for disability based on the International Classification of Functioning, Disability, and Health. Conditions for Further Study. Continued research is recommended in determining whether criteria should be made for formal diagnosis of: • Attenuated psychosis syndrome: This syndrome could identify an individual who shows relevant psychotic symptoms suggesting an increased risk for developing a psychotic disorder without meeting criteria for a formal diagnosis. • Caffeine use disorder: Research indicates that the drinking of as few as two or three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness.4,5 The extent of clinical impact on an individual has not been identified. Continues on page 91

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2. Psychiatric News. DSM-5 updates depressive, anxiety, and OCD

CLINICAL SLIDESHOW

criteria. Available at psychnews.psychiatryonline.org/newsArticle. aspx?articleid=1653568.

For more information on understanding post-traumatic stress disorder, view the slideshow at CliniAd.com/172v86r.

3. Kuhl EA, Kupfer DJ, Regier DA. Patient-centered revisions to the DSM-5. Virtual Mentor. 2011;13:873-879. Available at virtualmentor .ama-assn.org//2011/12/stas1-1112.html. 4. Monthly Prescribing Reference. Caffeine withdrawal syndrome —an official diagnosis? Available at www.empr.com/caffeine-withdrawal -syndrome--an-official-diagnosis/article/296408/. 5. Medscape. Caffeine withdrawal recommended for inclusion in DSM-5.

• Internet gaming disorder: This disorder reflects research and scientific findings that identify preoccupation with online gaming that causes significant clinical distress and impairment. Currently, the condition only applies to gaming and does not include online gambling, general Internet use, or social media. Studies have shown evidence in Asian countries, primarily among young males. • Nonsuicidal self-injury: This category includes skin cutting, burning, scratching, and banging when suicide is not the intention.

Available at www.medscape.com/viewarticle/755557. 6. Kraemer HC, Kupfer DJ, Narrow WE, et al. Moving toward DSM-5: the field trials. Am J Psychiatry. 2010;167:1158-1160. Available at ajp.psychiatryonline.org/article.aspx?articleid=102483. 7. Kupfer DJ, Regier DA. Why all of medicine should care about DSM-5. JAMA. 2010;303:1974-1975. All electronic documents accessed November 15, 2013.

The authors of the DSM-5 still have a great deal of work left to do in refining the new guidelines and continuing with research in the field of psychological disorders.6 This edition was drafted to reduce the stigma of mental illnesses, more accurately label and clarify diagnoses, and improve medical understanding. Critics believe that the new version is too broad and are concerned that nearly half of the U.S. population will meet the criteria for at least one DSM-5 diagnosis at some point7 (see “Critics question the methodology and transparency of DSM-5,” on page 74). The DSM-5 changes aim to create access to clinical treatment for patients who may lack well-defined symptoms for a diagnosis. The manual is used to help determine an accurate diagnosis and represents only one part of the overall care delivered to patients. Ultimately, the clinician is the key to identifying, screening, treating, and following the individual. n

“I hear it’s because we’re right and they’re wrong.”

Ms. Whitmore is an assistant professor at the University of Florida School of Physician Assistant Studies in Gainesville. References 1. Huerta M, Bishop SL, Duncan A, et al. Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am J Psychiatry. 2012;169:1056-1064. Available at ajp.psychiatryonline.org/article. aspx?articleid=1367813.

“Being falsely accused on social media has left my life largely unchanged.”

What is the controversy?

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FEATURE: TERI CAPRIOTTI, DO, MSN, CRNP, AND BRIAN HARTMANN

What you should know about medical marijuana Federal criminalization of this drug—most commonly used in the treatment of HIV, pain, and glaucoma—has limited research into its effectiveness.

edical marijuana is legal in 20 states and the District of Columbia, but it is still considered a federal offense to grow, sell, or purchase marijuana. Because of its therapeutic potential, medicinal marijuana is being prescribed by an increasing number of clinicians for various disorders. However, because of the federal criminalization of marijuana, evidence-based research into its effectiveness has been hindered, and many clinicians still question its scientific legitimacy.1,2 Marijuana, also known as Cannabis sativa, has been used since ancient times for therapeutic, spiritual, and recreational purposes. Clinicians in the United States prescribed marijuana for many different conditions until it was declared illegal and removed from the U.S. Pharmacopeia in 1942. The Controlled Substance Act of 1970 placed marijuana in the Schedule I category as a substance with high potential for abuse, the same as illicit street drugs.2 Although many anecdotal reports and research studies show its therapeutic value for a number of different disorders, the use of medicinal marijuana has been a controversial topic. Constituents

Marijuana is used to reduce intraocular pressure in persons with glaucoma.

The two primary compounds that contribute to marijuana’s therapeutic value are tetrahydrocannabinol (THC) and cannabidiol (CBD). Natural marijuana plants contain 5% to 15% THC, the most active ingredient. The variability in THC-to-CBD ratio in different marijuana

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MEDICAL MARIJUANA

The long-term effects of inhaled marijuana on the respiratory system are similar to those associated with chronic obstructive pulmonary disease. plants makes dosage standardization difficult.3 THC, the primary psychoactive component of marijuana, binds to cannabinoid receptors in the brain and produces feelings of euphoria, altered sense of time, analgesia, increased appetite, and impaired memory. CBD is a nonpsychoactive compound that is a serotonin receptor agonist with antiinflammatory and neuroprotective effects.4 Pharmacokinetics

The pharmacokinetics of THC vary depending on the route of administration. Medical marijuana can be administered by inhalation or orally. Inhaled THC causes maximum plasma concentration after 15 to 30 minutes, with a duration of two to three hours. Following oral ingestion, effects begin in 30 to 90 minutes and can last up to 12 hours. The duration of marijuana’s effects depends on dosage; however, it is unclear how to deliver a specific dose of marijuana by smoking.3 Patients report that the inhalation route is the most effective mode of delivery. The FDA has approved two oral forms of synthetic THC: dronabinol (Marinol) and nabilone (Cesamet). Patients report that these agents are slow-acting and less effective than inhaled forms of marijuana. Nabiximol (Sativex), an oral mucosal spray, has been approved for medicinal use in Europe only.2 As a Schedule I drug, the marijuana plant has great potential for abuse and dependence, and use of it is restricted. Nabilone is a Schedule II drug, and dronabinol is a Schedule III drug, which indicate that these medications have less abuse potential, do not usually lead to dependence, and are approved for restricted use.2

Medical marijuana has been shown to be particularly effective in pain management. Marijuana potentiates analgesic effects when used with narcotics, thereby diminishing the dosage of opioids needed for pain relief.6 Currently, studies are being conducted to evaluate the use of medical marijuana in rheumatoid arthritis, multiple sclerosis and spinal cord injury, Crohn disease, endometriosis, epilepsy, and fibromyalgia. Marijuana’s anxiety-reducing effects are being studied for use in the treatment of post-traumatic stress disorder.7 Adverse effects and safety issues

A significant part of the debate surrounding the use of medical marijuana relates to its possible adverse effects, which include hypotension, sedation, dizziness, decreased reaction time, reduced motor skills, diminished cognitive ability, and impaired memory. Some patients report increased anxiety or paranoia after using inhaled marijuana. Studies have shown increased symptoms of psychosis in patients with schizophrenia after smoking marijuana.2 The long-term effects of inhaled marijuana on the respiratory system are similar to those associated with chronic obstructive pulmonary disease. Inhaled marijuana is believed to contain as much as three times the amount of carcinogens as cigarettes. Some studies suggest that there is a withdrawal syndrome when chronic marijuana use is abruptly discontinued. The symptoms of withdrawal syndrome includes restlessness, agitation, and insomnia.8 The use of marijuana by adolescents has also raised concerns, as some regard marijuana use as a gateway to more serious drugs, such as heroin or cocaine.9 Implications for health-care providers

Therapeutic uses

Studies show that the most common conditions for which medical marijuana is being prescribed include HIV/AIDS wasting syndrome, cancer chemotherapy, and pain. The American College of Physicians (ACP) recommends medicinal marijuana for the following therapeutic uses:5 • As an appetite stimulant in HIV/AIDS wasting syndrome • As an antiemetic agent in chemotherapy treatment of cancer • As an analgesic for cancer pain • As an agent in reducing intraocular pressure in glaucoma (however, there is no increased benefit compared with available established drugs) • As an antispasmodic agent in such neuromuscular disorders as multiple sclerosis and spinal cord injury.

There is widespread agreement among health-care providers as to the need for further studies and medical education regarding medicinal marijuana. Many providers feel unprepared to prescribe marijuana and want formalized training regarding its medical uses. Kondrad reported that most surveyed physicians are receiving information about medicinal marijuana from the media or from other clinicians.10 Before a patient can receive marijuana for medicinal use, he or she must apply for a state-issued identification card.11 The patient needs to be evaluated for the need for medical marijuana by a health-care provider. The application is reviewed by a public-health board that assesses the patient’s eligibility for the treatment.7 Once a patient is approved to receive the medication, he or she receives the marijuana from a state-approved

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MEDICAL MARIJUANA

Many believe that medicinal marijuana is being predominantly used by those who are not ill but want legal protection for recreational use. 2. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012;87:172-186. Available at www.ncbi.nlm. nih.gov/pmc/articles/PMC3538401/. 3. Greenwell GT. Medical marijuana use for chronic pain: risks and benefits. J Pain Palliat Care Pharmacother. 2012;26:68-69. 4. Aggarwal SK, Carter GT, Sullivan MD, et al. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag. 2009;5:153-168. 5. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33:195-209. 6. Nussbaum AM, Boyer JA, Kondrad EC. “But my doctor recommended pot”: medical marijuana and the patient-physician relationship. J Gen Intern Med. 2011;26:1364-1367. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3208453/. 7. Trossman S. Exploring the science of medical marijuana. Am Nurse. 2010;42:1, 7. 8. Lamarine RJ. Marijuana: modern medical chimaera. J Drug Educ. 2012;42:1-11. 9. Joffe A, Yancy WS; American Academy of Pediatrics Committee on Substance Abuse, American Academy of Pediatrics Committee on Adolescence. Legalization of marijuana: potential impact on youth. Pediatrics. 2004;113:e632-e638. Available at pediatrics.aappublications.org/ content/113/6/e632.long. 10. Kondrad E. Medical marijuana for chronic pain. N C Med J. 2013;74:210-211. 11. Lynne-Landsman SD, Livingston MD, Wagenaar AC. Effects of state medical marijuana laws on adolescent marijuana use. Am J Public Health. 2013;103:1500-1506. 12. Adams D, Desharnais C, Johnston S, et al. Demystifying medical marijuana: The economic implications of medical marijuana. Nursing News. 2013;37:13. 13. State of New Jersey Department of Health. Medical Marijuana

Conclusion

Although growing, possessing, and smoking marijuana remain illegal at the federal level, individual states have been legalizing it for medical use since 1986. The drug has been shown to have therapeutic effects in patients, but further research is needed regarding the safety and efficacy of marijuana as a medical treatment for various conditions. n

Program. Available at www.state.nj.us/health/medicalmarijuana/. All electronic documents accessed November 15, 2013.

Dr. Capriotti is a clinical associate professor, and Mr. Hartmann is a third-year honors student, at Villanova University College of Nursing in Villanova, Pa. References 1. ProCon.org. Medical marijuana. Available at medicalmarijuana.procon. org/view.resource.php?resourceID=000881.

dispensary and is eligible to receive the maximum amount permitted per month.12 In New Jersey, for example, clinicians and patients must be registered with the state health department’s Medical Marijuana Program (MMP) for the patient to obtain the treatment. Patients can only apply to register after a clinician registered with the program has completed a formal statement advocating the MMP for the patient.The patient must have a diagnosis of one of the debilitating conditions that the MMP has approved for treatment with medical marijuana. Once approved, the clinician can prescribe up to 2 oz. of marijuana per month, to be dispensed in one-eighth or one-quarter-ounce packages.13 Many clinicians are concerned about the lack of consistency in composition of marijuana and the side effects. There is a widely held belief that medicinal marijuana is being predominantly used by those who are not ill but want legal protection for recreational use of the drug. Clinicians and patients need to be aware that growing, selling, buying, or producing marijuana in any way is a federal offense. The ACP strongly encourages more research and funding for rigorous scientific evaluation of the potential therapeutic benefits of medical marijuana. In addition, the ACP urges evidence-based review of marijuana as a Schedule I drug to determine if it should be reclassified. The ACP strongly promotes protection from criminal or civil penalties for patients who are legally prescribed medical marijuana under state law; the association also supports exemption from criminal prosecution, civil liability, or professional sanctioning of clinicians who prescribe the drug in accordance with state laws.2

“The guy with the weird skin disease forgot to sign the privacy forms.”

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FEATURE: CARL SHERMAN

Treating hypertension in older patients In those older than age 65 years, high BP heightens risk for various forms of heart disease as well as for chronic kidney disease and diabetes mellitus.

he age-adjusted prevalence of hypertension among U.S. adults aged 18 years and older was recently found to be 29.1% in 2011-2012.1 Prevalence increased with age, from 7.3% in persons aged 18 to 39 years, to 32.4% in persons aged 40 to 59 years, to 65% among persons aged 60 years and older. Special considerations are associated with the treatment of hypertension in older persons. Clinicians who are faced with managing this highly prevalent condition in this extremely vulnerable group can always consult the expert consensus document from the American College of Cardiology and the American Heart Association.2 “There is very little difference in treating older versus younger patients,” commented Wilbert S. Aronow, MD, professor of medicine at New York Medical College/Westchester Medical Center and co-chair of the committee that wrote the document. “You use the same drugs, with the same indications.” But comorbidities and interactions with other drugs are likely to play a larger role in medication choice, and the risk of adverse effects— particularly orthostatic hypotension—require particular attention, Dr. Aronow advised. Evaluation and diagnosis

White-coat hypertension tends to be more pronounced in older patients.

As with younger patients, hypertension in the elderly is diagnosed on the basis of three measurements on at least two separate occasions. But in the older patient population, it is important for both initial diagnosis and subsequent monitoring to include a measurement taken www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2013 97

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ELDERLY HYPERTENSION

The guideline authors recommend home BP monitoring, which has better prognostic and diagnostic accuracy than clinical measurement. while the individual is standing for one to three minutes to screen for orthostatic hypotension. Orthostatic hypotension is linked to a heightened risk of falls and makes it essential that clinicians avoid overestimation of BP due to such sources of error as pseudohypertension (systolic BP that appears increased due to noncompressible brachial arteries) and the “white-coat effect” of transient elevation in the medical office, which tends to be more pronounced in older patients. The guideline authors recommend home monitoring, which has better prognostic and diagnostic accuracy than clinical measurement. Ambulatory 24-hour monitoring provides even more detailed information, including the possibility of postprandial hypotension, and should be considered when there are strong reasons to suspect the diagnosis (e.g., the absence of target-organ damage). The document notes that while there is little evidence of the need for routine laboratory testing as part of the evaluation, information relevant to organ damage and additional risk factors should be available through urinalysis, blood chemistry (including potassium and creatinine), blood lipids, fasting blood glucose or hemoglobin A1c, and electrocardiography. Target pressures

Although the goal of 140/90 mm Hg is generally recommended for patients at any age with uncomplicated hypertension, it is unclear that this target is appropriate for those aged 80 years and older, wrote the guideline authors. Taking existing data into account—including the only randomized controlled trial of treatment for patients in this age range3 —“The goal for people aged 79 years and younger should be 130-139 systolic; and for those 80 years and older, 140-145 if tolerated,” Dr. Aronow affirmed. In this older group, systolic pressures <130 should be avoided. As for diastolic pressure, “We do not have enough data, but based on what is available, we would not want to get below 65 in an older individual.” In reality, very few elderly patients have diastolic hypertension—fewer than 1% of those older than age 80 years, according to Dr. Aronow. Although existing guidelines suggest lower target pressures for individuals of all ages with diabetes and coronary artery disease (CAD), there is reason to question this recommendation for older patients. What limited data exist for this population indicate that risk is lowest at 135/75 for CAD

patients aged 70 to 80 years and at 140/70 for those who are older. Random controlled trial data for elderly individuals with diabetes found no benefit with systolic pressures <120 compared with <140. Lifestyle management

As with younger patients, lifestyle modification should be part of hypertension management and may be sufficient when hypertension is mild. Key factors include smoking cessation, weight control, sodium restriction, increased potassium intake, moderation in alcohol consumption, and exercise. The guideline authors pointed out that Medicare benefits for smoking-cessation counseling and medication have expanded and that weight loss has been shown to be effective for BP reduction in older individuals. Sodium restriction appears to have greater BP benefits for older persons than for younger. There is evidence that aerobic training reduces BP in individuals aged 60 to 69 years and 70 to 79 years. In addition, the finding that increasing exercise intensity beyond the moderate level carries no additional benefit “is especially meaningful for the elderly,” the authors reported. Drug treatment

Hypertension is treated with the same drugs for older and younger patients, but extra caution must be taken to account for age-related changes in metabolism and pharmacodynamics. Clinicians are advised to start at the lowest dose and increase gradually to the highest tolerated dose. Most older patients will require two or more medications to achieve adequate BP control. Cardiovascular and other benefits are a function of BP reduction, regardless of the medication. “It does not matter if you use an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), calcium channel blocker, beta blocker, or diuretic. The choice will depend on comorbidities, adverse effects, and cost,” Dr. Aronow explained. A diuretic is frequently indicated as the initial or second drug, according to the consensus document. Diuretics should be avoided in patients with or at high risk for diabetes, however, because these agents increase hyperglycemia and diabetes incidence. As an alternative, Dr. Aranow recommended prescribing an ACE inhibitor or an ARB instead. For hypertensive patients who have suffred a recent MI, the drug regimen should include a beta blocker—usually in

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For older patients with a history of stroke or transient ischemic attack, treatment with a diuretic and an ACE inhibitor is recommended. combination with a calcium channel blocker, diuretic, or ACE inhibitor—and an aldosterone antagonist if needed. For older individuals with heart failure, the recommended choice is diuretics, beta blockers, or ACE inhibitors or ARBs, to which an aldosterone antagonist may be added. BP control is particularly important for older patients with a history of stroke or transient ischemic attack. For such individuals, the authors advocate treatment with a diuretic and an ACE inhibitor, while noting that the magnitude of pressure reduction is probably more important than the agent used. A regimen that includes an ACE inhibitor or an ARB is indicated for older patients with chronic kidney disease.

medications’ antihypertensive effects, and may accentuate hypertension-associated risks of heart failure, renal failure, and cardiovascular events. n Mr. Sherman is a freelance medical writer in New York City. References 1. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: national health and nutrition examination survey, 2011-2012. NCHS Data Brief. 2013;133:1-8. Available at www.cdc.gov/nchs/data /databriefs/db133.htm. 2. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert

Interactions

Consensus Documents developed in collaboration with the American

Whatever the regimen, the danger of drug-drug interactions must be kept in mind. The average elderly patient takes more than six prescription medications as well as OTC preparations. The BP-elevating effects of such drugs should be assessed, particularly in cases of apparent treatment resistance. Common culprits include corticosteroids, sympathomimetics, and, perhaps most insidiously, nonsteroidal antiinflammatory drugs (NSAIDs). Dr. Aronow stated that in addition to increasing BP, NSAIDs interfere with other

Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Soc Hypertens. 2011;5:259-352. Available at www.medscape.com/viewarticle/742637. 3. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):188798. Available at www.nejm.org/doi/full/10.1056/NEJMoa0801369.

All electronic documents accessed November 15, 2013.

“Your dish will be out just as soon as it clears legal.”

“It says, ‘There are people waiting for your table.’”

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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 DECEMBER 2013

Consultations Is estrogen plus progesterone necessary for vaginal atrophy?. . . . . . . . . . . . 101 Administering medication to an NPO patient. . . . . . . . . . . . . . . . . 101 Stopping medications before knee or hip surgery. . . . . . . . . . . . 101 Breathing difficulty despite adherence to COPD guidelines . . . . . . . . . . . 102 Reliable sources of safety information on vitamins and supplements. . . . . 102

Clinical Pearls Is it a wart or a callus? . . . . . . . . . . . 103 Quick relief of oral mucositis. . . . . . 103 What aortic stenosis sounds like. . . . 103 Remembering side effects of antipsychotic medications. . . . . . . . 103

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 TESTING FOR MULTIPLE STDs How do I explain to a patient that he or she has chlamydia and gonorrhea if I only have lab results for the positive chlamydia? The lab called to let me know that while both tests were positive, they could not complete the gonorrhea testing because of insufficient specimen quantity.—ANNIE M. CLAVON, NP, Lauderhill, Fla. Simply be honest and tell the patient that he or she has chlamydia and most likely gonorrhea. Even in the face of incomplete testing, recommend treatment for both infections, as well as partner notification, treatment, and follow-up testing for cure.—Julee B. Waldrop, DNP (182-1)

THE LIFESPAN OF MONONUCLEOSIS Can a person have mononucleosis more than once? Will monospot or heterophile antibody tests stay positive for life?— DAVID COOPER, PA-C, Fayetteville, Pa. Mononucleosis is caused by Epstein-Barr virus (EBV), a human herpesvirus (HHV4). Like all HHV infections, mononucleosis consists of a primary phase, latency, and reactivation. Most infections with EBV are asymptomatic (95% of young adults will test positive for exposure to EBV). The monospot test is a nonspecific test

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.

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.

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for heterophile antibodies and is used for initial screening in suspect individuals. If an individual is negative for monospot, more specific testing for EBV is required. False-positive monospot results occur in cytomegalovirus and varicella-zoster virus infections, leukemia, lymphoma, hepatitis, influenza, rubella, and autoimmune disorders (namely systemic lupus erythematosus). Up to 85% of patients with infectious mononucleosis will have positive monospot results, although they may be delayed for up to two weeks. Patients are typically well within one to two months, but the virus remains inactive in a few cells for life. Periodically, the virus can reactivate, usually without symptoms. The likelihood of infection is increased by the presence of immunoglobulin M antibodies or a fourfold increase in immunoglobulin G over four weeks.—Claire Babcock O’Connell, MPH, PA-C (182-2)

IS ESTROGEN PLUS PROGESTERONE NECESSARY FOR VAGINAL ATROPHY? Does a woman with an intact uterus and ovaries being treated with topical vaginal estrogen need to be covered with oral progesterone as well?—MICHELLE OWENS, FNP, New Ulm, Minn. Vaginal estrogen is used to treat vaginal atrophy in peri- and postmenopausal women. The most common complaints that indicate vaginal atrophy are vaginal dryness, itching, irritation, burning, and dysparunia. Treatment options include creams, pills, and rings. At low-dose regimens, these estrogens have not been shown to cause endometrial hyperplasia, so an opposing progesterone is not required, provided that the following doses are not exceeded: (1) estradiol tablet (Vagifem) 10 µg (one tablet per vagina every night at bedtime for 14 days, then one tablet per vagina twice a week); (2) estradiol ring (Femring) 7.5 µg (place one ring per vagina for 90 days, repeat); and (3) estradiol cream (Estrace, Ogen, Premarin)

Debra August King, PhD, PA,

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

Mary Newberry, CNM, MSN,

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

1 g cream (100 mg estradiol) (1 g cream per vagina every night at bedtime for two weeks, then 0.5 g twice a week thereafter). If a woman still has her uterus and requires more estrogen than the low-dose regimens, she will need progesterone as well to protect from endometrial hyperplasia and cancer. I recommend micronized progesterone (Prometrium)100 mg every night at bedtime. Another option is to cycle in micronized progesterone 200 mg for 12 days of every month, after which she may experience a withdrawal bleed. I advise against medroxyprogesterone (Provera), as this synthetic progesterone may increase risk of breast cancer as well as blood clot. Be aware that a woman with a history of breast cancer should not be given estrogen at any dosage without consultation with her oncologist.—Mary Newberry, CNM, MSN (182-3)

ADMINISTERING MEDICATION TO AN NPO PATIENT A man who has been taking baclofen (Lioresal) 20 mg four times a day for spasticity from a spinal cord injury developed an ileus. He had to have a nasogastric tube inserted and is obviously NPO. Do you have any suggestions for administering the baclofen to prevent withdrawal?—MARY ANN JACOBS, RN, MSN, NP, St. Louis, Mo. I suggest trying a short course of baclofen administered via a temporary intrathecal catheter in addition to augmentation of antispasticity with parenteral benzodiazepines.—Sherril Sego, FNP-C, DNP (182-4)

STOPPING MEDICATIONS BEFORE KNEE OR HIP SURGERY How long should the following drugs be stopped prior to knee or hip replacement: raloxifene (Evista), anastrozole

Claire O’Connell, MPH, PA-C,

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

Sherril Sego, FNP-C, DNP,

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

Julee B.Waldrop, DNP,

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

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Advisor Forum

itself is thought to be a prothrombotic drug, and anoatrozole reduces estrogen levels, there is no increased risk for embolic events with this drug. The primary side effects with anastrozole are decreased bone density (caused by a dramatic drop in sex steroid levels) and elevation of LDL cholesterol.—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, Family Nurse Practitioner Program, Duke University School of Nursing, Durham, N.C. (182-5)

Medications that increase risk of embolic events may need to be discontinued before hip- or knee-replacement surgery (shown).

(Arimidex), and tamoxifen (Nolvadex, Soltamox)?—VAL CANTAGALLO, MD, Philadelphia, Pa. All of these drugs affect hormone action, but they have differing clinical uses and risk for embolic events. Raloxifene and tamoxifen are selective estrogen-receptor modulators, meaning that they affect estrogen action selectively throughout the body. Each drug works a bit differently and therefore they have differing clinical indications. Raloxifene works as an estrogen agonist in bones, reducing bone resorption and fracture risk, and as an estrogen antagonist in the breast and uterus, reducing the risk for breast cancer. Raloxifene is used primarily as a second-line agent for osteoporosis. Similar to raloxifene, tamoxifen works as an estrogen antagonist in breast tissue and bone but as an estrogen agonist in the female lower genital tract. Tamoxifen is used primarily for treatment of breast cancer. Raloxifene and tamoxifen exert estrogen-like prothrombotic effects, and it is thought that these medications cause reduced antithrombin activity. A large trial of postmenopausal women noted that taking raloxifene caused a hazard ratio of 1.49 for stroke and 1.95 for DVT when compared with placebo (N Engl J Med. 2006;355:125-137, available at www.nejm.org/doi/full/10.1056/NEJMoa062462, accessed November 15, 2013). Tamoxifen has been associated with an increased risk for embolic events, especially in the first two years of treatment and in those undergoing chemotherapy (Lancet. 2002;360:817-824). This increased risk has led to a recommendation to discontinue these drugs 72 hours before prolonged immobilization. Anastrozole is a selective nonsteroidal aromatase inhibitor that works by blocking the conversion of androstenedione to estrone as well as the conversion of testosterone to estradiol, thus dramatically reducing estrogen levels and exposure to estrogen in hormone-receptive tumors (e.g., estrogen-receptor-positive breast cancer). Since estrogen

BREATHING DIFFICULTY DESPITE ADHERENCE TO COPD GUIDELINES I often care for individuals with moderate-to-severe chronic obstructive pulmonary disease (COPD). These patients report that they follow the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines but insist that they continue to have difficulty breathing. Typically, the oxygen saturation levels by pulse oximetry in these individuals are in the high 90s, and the patients report no improvement with an albuterol nebulizer. These patients are almost always smokers who have had pulmonary consults. What therapeutic option do you advise?—CYNTHIA SMITH, FNP, South Charleston, W. Va. Is pulmonary rehabilitation included in the patients’ recommended regimen? If not, consider referral for this treatment. Also, many COPD patients become very anxious because of their constant subjective shortness of breath and benefit greatly from low doses of such anxiolytics as benzodiazepines. Once these patients relax, the feeling of air hunger dissipates.—Sherril Sego, FNP-C, DNP (182-6)

RELIABLE SOURCES OF SAFETY INFORMATION ON VITAMINS AND SUPPLEMENTS Where is the best place to look up information on vitamins and supplements for children? A number of parents have asked for my approval to administer specific brands to their toddlers, and I am finding inconsistent reports.—JANET NAZARIO, CPNP, Phoenix The Nutrition.gov website is the best source of information on vitamins and supplements with specific information on recommended dietary allowance and upper tolerable limits (available at www.nutrition .gov/smart-nutrition-101/dietary-reference-intakes-rdas, accessed November 15, 2013). The National Institutes of Health Office of Dietary Supplements also has an iPhone app called “My Dietary Supplements” that provides fact sheets on all vitamins and minerals; dosing and safety information can also be accessed online (available at

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ods.od.nih.gov/factsheets/list-VitaminsMinerals, accessed November 15, 2013). To assess specific brands of vitamins or supplements, visit www.consumerlab.com (accessed November 15, 2013). They have tested more than 400 brands, and any problem with contamination or other issues related to content of the products can be found there.— Julee B. Waldrop, DNP (182-7)

CLINICAL PEARLS IS IT A WART OR A CALLUS? It can be difficult to differentiate between a wart and a callus. If the pain is greater with transverse compression (squeezing the lesion) than with direct pressure (pushing the lesion), the lesion is likely a wart.—TONYA KHAN, MPH, PA-C, Fort Worth, Tex. (182-8) QUICK RELIEF OF ORAL MUCOSITIS Intense chemotherapy or radiation therapy can cause oral mucositis (tissue swelling) to develop in the mouth of a cancer patient. To treat these sores, have the patient place ice chips in his or her mouth and repeat for up to 30 minutes. This oral cryotherapy will immediately relieve

acutely painful symptoms and plays a part in reducing the intensity of future oral mucositis when performed on a regular basis.—KAREN GRANT-ANDREWS, APRN, FNP-BC, New Orleans (182-9)

WHAT AORTIC STENOSIS SOUNDS LIKE Differentiating systolic heart murmurs can be challenging. The murmur associated with aortic stenosis is transmitted to the neck, whereas the murmur of mitral regurgitation is not.—DONNA BERTHOFF, PA-C, FNP-BC, Syracuse, N.Y. (182-10) REMEMBERING SIDE EFFECTS OF ANTIPSYCHOTIC MEDICATIONS Antipsychotic medications with lower prescribing doses (e.g., haloperidol [Haldol], aripiprazole [Abilify]) are more likely to cause extrapyramidal symptoms; medications with higher prescribing doses (e.g., quetiapine [Seroquel], clozapine [Clozaril]) typically cause weight gain and sedation. There is more to be said regarding neurotransmitters, but this is a useful general tip for beginning practitioners.—EMALENE COOK, FNP, Lebanon, Va. (182-11) n

Statement of Ownership, Management and Circulation 1. Publication Title: The Clinical Advisor 2. Publication Number: 017-546 3. Filing Date: Sept. 30, 2013 4. Issue Frequency: Monthly 5. Number of Issues Published Annually: 12 6. Annual Subscription Price: U.S.: United Stated $75.00 7. Complete Mailing Address of Known Office of Publication: 114 West 26th Street, 4th Floor New York, NY 10001 8. Complete Mailing Address of Headquarters or General Business Office of Publisher: 114 West 26th Street, 4th Floor New York, NY 10001 9. Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Editor: Publisher: Thomas Hennessy, 114 West 26th Street, 4th Floor, New York, NY 10001; Editor: Joe Kopcha 114 West 26th Street, 4th Floor, New York, NY 10001; Managing Editor: Marina Galanakis 114 West 26th Street, 4th Floor, New York, NY 10001 10. Owner: Haymarket Media Group, LTD. 174 Hammersmith Road, London, UK W6J7P 11. Known Bondholders, Mortgages, and Other Security Holders Owning or Holding 1 percent or More of Total Amount of Bonds, Mortgages, or Other Securities: None 12. Tax Status: The purpose, function, and nonprofit status of this organization and the exempt status for federal income tax purposes: Has Not Changed During Preceding 12 Months. PS Form 3526-R. August 2012 13. Publication Title: The Clinical Advisor 14. Issue Date for Circulation Data Below: Sept. 2013 15. Extent and Nature of Circulation [i] Average No. Copies Each Issue During Preceding 12 Months [ii] No. Copies of Single Issue Published Nearest to Filing Date a. Total Number of Copies (Net press run) [i] 135,420 [ii] 137,441 b. Paid and/or Requested Circulation (1) Paid/Requested Outside—County Mail Subscriptions Stated on Form 3541 [i] 69,834 [ii] 69,044 (2) Paid In-County Subscriptions Stated on Form 3541 [i] 0 [ii] 0 (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and Other Non-USPS Paid Distribution [i] 0 [ii] 0 (4) Other Classes Mailed Through the USPS [i] 0 [ii] 0 c. Total Paid and/or Requested Circulation [i] 69,834 [ii] 69,044 d. Free Distribution by Mail (1) Outside-County as Stated of Form 3541 [i] 0 [ii] 0 (2) In-County as Stated on Form 3541 [i] 0 [ii] 0 (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail [i] 0 [ii] 0 (4) Nonrequested Copies Distribution Outside the Mail [i] 263 [ii] 550 e. Total Nonrequested Distribution [i] 64,600 [ii] 65,586 f. Total Distribution [i] 134,697 [ii] 135,180 g. Copies not Distributed [i] 723 [ii] 2,261 h. Total [i] 135,420 [ii] 137,441 i. Percent Paid and/or Requested Circulation [i] 51.85% [ii] 51.08% 16. Total Circulation includes electronic copies: No 17. Publication of Statement of Ownership for a Requestor Publication is required and will be printed in the December 2013 issue of this publication 18. Manager or Owner: John Crewe, Chief Operations Officer 09/30/2013 I certify that all information furnished on this form is true and complete. I understand that anyone who furnishes false or misleading information on this form or who omits material or information requested on the form may be subject to criminal sanctions (including fines and imprisonment) and/or civil sanctions (including civil penalties).

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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.

Skin-colored papules on the lower eyelids An Asian man, aged 55 years, presents requesting an evaluation of skin-colored papules on his bilateral lower eyelids. WHAT IS YOUR DIAGNOSIS?

• Syringoma • Fibrofolliculoma • Xanthelasma • Angiofibroma

● See the full case at CliniAd.com/I4IN34

Sudden-onset hair loss on the top and side of the head An otherwise healthy 45-year-old patient presents with complaints of several patches of hair loss on the top and side of the head. WHAT IS YOUR DIAGNOSIS?

• Secondary syphilis • Trichotillomania • Lichen planopilaris • Alopecia areata ● See the full case at CliniaAd.com/HNgaaI

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.

Smelly feet with depressions

A red bump on the jaw

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LEGAL ADVISOR CASE

Negligence in the pharmacy When a prescription is unclear, supporting clinicians engage in guesswork to decipher the dosage. BY ANN W. LATNER, JD

Ms. Q, aged 28 years, looked down at the prescription in her hand, sighed, and shook her head. It was not the first time she had been confronted with an illegible prescription: In the past eight months since she had taken a job as a nurse practitioner at a mid-size hospital, she had seen plenty of them. When she first graduated from school, Ms. Q had accepted a job with a local pediatrician. For the first year the job was an interesting learning experience, but by the third year, she was tired of sore throats and stomach viruses and wanted to experience more challenging clinical work. Her new position at the hospital certainly provided that. It was much different than working with one pediatrician in a small office. Ms. Q’s current patients had far more serious issues than head colds and stomach flu. With the more challenging work came longer hours, more patients, more responsibility, and the need to learn the habits and practices of many more physicians. The patient for whom the illegible prescription had been written was Mrs. D, a 72-year-old

Ms. Q took the prescription to the pharmacy, and she and the pharmacist both tried to interpret it.

woman who was on kidney dialysis. Mrs. D’s condition was poor, and she had been admitted to the hospital for the amputation of her right foot. Her nephrologist, Dr. F, had been to see his patient earlier. Ms. Q walked in while he was writing a prescription for Mrs. D, and the physician interrupted what he was doing to discuss the patient with her. Unbeknownst to Ms. Q, Dr. F had been writing a prescription for 10 millimoles of potassium. However, after Ms. Q left the patient’s room, Dr. F reconsidered the dosage and decided to make it 20 millimoles rather than 10. Instead of starting with a fresh prescription, or crossing out what he had already written, Dr. F attempted to write the number “2” over the number “1,” thereby changing it to 20 millimoles. When he was done, Dr. F left the prescription in the patient’s file for Ms. Q. Continues on page 106

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.

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LEGAL ADVISOR When Ms. Q later returned to the patient’s room, she found the prescription and had trouble making out what it said. Ms. Q took the prescription to the pharmacy, and she and the pharmacist both tried to interpret it. “I see a 1,” said the pharmacist. “So do I,” said Ms. Q. “But I also see a 2.” “I do as well,” said the pharmacist. “What is it with doctors and their handwriting? They should have to take a class.” They both looked at the prescription for a few minutes more, until Ms. Q said “It says 120.” The pharmacist agreed that it appeared to be 120 millimoles, and the prescription was filled and administered to Mrs. D. Ms. Q’s shift was over at that point, and she went home. When she returned the next day, she found out that the patient had died. Both Ms. Q and the pharmacist were suspended from work while the hospital conducted an internal investigation. As part of the investigation, Dr. F was called in to discuss the patient’s death and the circumstances surrounding it.

Both Ms. Q and the pharmacist were asked why they hadn’t contacted the physician to clarify what was written. “I may have been a little messy when I wrote the prescription,” Dr. F admitted, “but it went through a pharmacist and a nurse before the patient received it. How could the nurse and pharmacist not have realized that a 120-millimole dose of potassium is fatal?” Both Ms. Q and the pharmacist were asked why they hadn’t contacted Dr. F to clarify what was written, since they had trouble reading his handwriting. Neither practitioner had a good answer. “It was after midnight by then,” said Ms. Q. “I did not want to bother Dr. F at that point.” “Ms. Q and I both agreed that it appeared to both of us to be 120 millimoles,” said the pharmacist. The patient’s family hired a plaintiff’s attorney and filed a malpractice lawsuit against the hospital (the employers of Ms. Q and the pharmacist) and Dr. F. The hospital’s attorneys met numerous times with Ms. Q and the pharmacist and made them repeat their story several times. Eventually, the hospital’s attorneys suggested to the hospital administrators that it would be in their best interests to settle the case before it reached the trial stage. The case against the hospital was settled out of court for an undisclosed sum. Both Ms. Q and

the pharmacist were terminated from their positions. Dr. F’s case now proceeded to trial. The physician’s attorneys argued that even if Dr. F had erred by writing the prescription sloppily, the nurse and pharmacist should have noticed and called him for clarification. He argued that their superseding error was the cause of the patient’s death. The jury both agreed and disagreed: After deliberations, the jury found Dr. F negligent, but it also determined that the hospital was 90% at fault, and Dr. F was only 10% at fault. Legal background

Because Ms. Q and the pharmacist were hospital employees, the plaintiff’s attorneys opted to sue the hospital, rather than Ms. Q or the pharmacist as individuals. This is quite common. For one thing, a large hospital is going to have deeper pockets than will individual clinicians. Also, as employees of the hospital, their employer bears responsibility for actions carried out while on the job. Once the hospital settled, the plaintiffs could only try the weaker case against the doctor. While Dr. F had been negligent in his careless writing of the prescription, the acts (or in this case, lack of acts) by the nurse and pharmacist were what allowed the error to reach the patient. Therefore, the jury apportioned the greatest part of the blame for the incident on the nurse and pharmacist. Had the case gone to trial, the hospital would have been responsible for 90% of the jury’s award. Since it settled out of court (a common occurrence), Dr. F was responsible for only 10% of the fault. Protecting yourself

Leaving aside the question of why the hospital’s pharmacy software didn’t alert the pharmacist to the fatal dose of potassium, what should have happened is quite clear. Ms. Q or the pharmacist should have called Dr. F to have him clarify what was written on the prescription. There is absolutely no excuse not to call an attending physician—regardless of the time of day—when there is a question about a patient’s medication. A clinician’s job is to act as the patient’s advocate, and if that means waking a physician with a middle-of-the-night phone call, then so be it. Guessing what a dosage might be or making a conjecture is completely unacceptable when it comes to patient care. There is never a good excuse for not picking up that phone. Had Ms. Q realized that, she might still have her job, and her patient might still be alive. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Clinical Challenge Young man presents with findings suspicious for occult fracture CHARLES D. FROST, DHSc , MPAS, PA-C

A teenager complains of pain in the left wrist, yet manifests no localized swelling and exhibits symmetric bilateral range of motion.

A 17-year-old right-handdominant male, Mr. B, presented to our pediatric fracture clinic with a complaint of left wrist pain. He had a history of an undocumented scaphoid fracture three years earlier with an increase in pain levels in the three weeks prior to presentation. Mr. B was an athletic young man with a history of boxing as a sport and had been increasing his training prior to the onset of his current symptoms.

CASE

1. HISTORY On presentation, Mr. B was a well-developed male who appeared his stated age. His medical history was significant for mild, controlled asthma and an atypical depressive disorder, which was in remission. Examination of his extremities—with particular attention to the affected left wrist—showed a symmetric range of motion bilaterally with no obvious skin lesions. The patient’s left wrist demonstrated no effusion or edema; tenderness was noted in the anatomic snuff box, at the scapholunate junction, and in the lunate fossa. Results of a neurovascular exam were normal.

2. EXAMINATION AND INITIAL TREATMENT

FIGURE 1. Standard films of the left wrist showed no osseous abnormality.

Standard films of the left wrist to include a scaphoid series were obtained and showed no acute osseous abnormality (Figure 1). There was no evidence of ligamentous instability and no scapholunate widening. Additionally, no evidence of any osseous necrotic process was appreciated. At this time, we elected to treat the patient conservatively in a short-arm thumb spica cast with the interphalangeal joint of the thumb free. Mr. B was referred for an MRI of the affected wrist to evaluate for a possible occult fracture or ligament disruption. Continues on page 108

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Clinical Challenge 3. DIAGNOSIS This represents an unusual case seldom reported and instructive in its uniqueness. Plain films on presentation were unremarkable and an MRI was needed to establish the diagnosis. The MRI demonstrated avascular necrosis (AVN) of the capitate with complete involvement. The patient underwent conservative management in a short-arm cast for several weeks and eventually had complete resolution of symptoms.

4. EXTENDED TREATMENT At 14 days post-presentation, MRI demonstrated changes in the patient’s capitate consistent with osteonecrosis. Images demonstrated complete involvement with uniform consistency (Figures 2 and 3). Mr. B was pain-free in his cast. At six weeks after presentation, the cast was removed and Mr. B was placed in a thumb spica brace with activity restrictions consisting of no sports and limited lifting. He reported no pain while in the cast, and was appropriately stiff when the cast was removed. Plain films of the capitate demonstrated no interval change on this visit.

in the capitate or carpal alignment (Figures 4 and 5). The scaphoid and scapholunate distance remained appropriate for the patient’s age. Mr. B was released to normal activity with a six-month return visit anticipated. Nearly 10 months post-presentation, Mr. B continued to report no symptoms. His physical exam showed a symmetric range of motion with the unaffected wrist, no tenderness, and symmetric grip strength. His plain films were interpreted as normal (Figures 6A and 6B). Two years after initial presentation, the patient underwent a physical exam to become an emergency medical technician (EMT). He was able to meet all the physical requirements for his technical college entry, and reported no symptoms. At his last encounter, Mr. B denied any further wrist pain.

5. DISCUSSION The natural history of AVN in the adult is well established in the literature, both from the standpoint of idiopathic as well as traumatic causes. Unlike the adult form, pediatric AVN is not well represented. A case presented in 2006 was, at that time, the first documented incidence of osteonecrosis of the capitate in a pediatric

FIGURE 2. A T1-weighted MRI image showing capitate involvement two weeks after presentation.

FIGURE 3. A T2-weighted MRI image also displaying capitate involvement consistent with osteonecrosis.

At three months post-presentation, a follow-up MRI was obtained. Mr. B still reported that he was symptom-free with no limitations on his activities, which he had resumed three weeks prior to this visit. His physical exam was normal in comparison to his unaffected side, with no obvious deformity, weakness, or loss of motion. The MRI showed changes consistent with early resolution of his osteonecrosis, and plain films at this visit continued to show no change

patient.1 The case described here shares some minor similarities but demonstrates singular MRI findings. Whereas both pediatric cases went on to full resolution without surgical intervention, this case study clearly represents a transition between the skeletally immature and mature hand. In the initial case, a gymnast, aged 5 years, presented with a painless loss of motion noted by his instructor.1 He had no other history of pain or trauma. His initial plain

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Clinical Challenge

FIGURE 4. A three-month follow-up MRI scan shows early resolution on T1 images.

FIGURE 5. A second MRI scan shows improvement on T2 images, with capitate showing similar signal to uninvolved wrist bones.

films showed changes in the capitate ossification center, predominantly in the proximal portion.1 An MRI taken six weeks after presentation showed diffuse involvement with a predilection for the proximal pole, as would be expected.1 That patient also underwent conservative treatment with splinting, and activity restriction continued until full resolution at his three-year follow-up.1 This appears to be the index case in the published literature. Adult idiopathic osteonecrosis or AVN of the capitate has been reported a limited number of times in the orthopedic literature and investigated by several authors.2,3 In these cases, it has been thought to share common characteristics with AVN of the scaphoid, with a similar presentation of pain, localized swelling, and decreased range of motion.2 AVN of the capitate has been shown to be unique in its nondominance preference. Anatomically, the capitate is felt

to be at risk for AVN in a fashion similar to the scaphoid, as its blood supply enters the proximal portion from a distal pedicle. This has been postulated as the etiology of osteonecrosis in the reported cases. Most authors agree that osteonecrosis of the capitate is a rare occurrence and, as stated, scarcely reported in the literature. An article published in 1984 demonstrated avascular process of bilateral capitates in an 18-year-old bus driver.3 Unlike his pediatric counterparts, this patient’s symptoms failed to remit, and he went on to surgical replacement at age 25 years.3 The authors were only able to find four published reports on AVN or osteonecrosis of the capitate. In a more recent article, Botte and colleagues found that osteonecrosis of the capitate was most commonly associated with trauma.2 The researchers indicated that nontraumatic osteonecrosis was comparatively rare and is usually associated with steroid use, gout, or Gaucher disease. They also commented that women appear to be at greater risk for osteonecrosis of the capitate, based on the literature to date. Botte’s group further noted that osteonecrosis of the capitate is more common with fractures of the neck that can result in necrosis of the capitate head. These fractures are frequently seen in association with fractures of the scaphoid, as part of a wrist injury referred to as the naviculo-capitate syndrome. The authors suggest that repetitive vibration injury may be a cause of osteonecrosis of the capitate. This may be of interest when examining patients with no trauma who have a history or occupation involving repetitive vibration.2 In the pediatric literature, vascular insufficiency in the proximal pole of the fractured scaphoid leading to necrosis is reported as extremely low in children.4 Many of the cases

FIGURES 6A and 6B. At 10 months post initial presentation, plain films are consistent with normal radiographic anatomy.

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Clinical Challenge reported were due to undiagnosed fractures that had not been adequately treated. Treatment with immobilization alone has led to spontaneous revascularization along with healing of the fracture.4 Idiopathic AVN of the lunate (Keinboch disease) or the scaphoid (Preiser disease) has been reported in children, but these are most often linked to other pre-existing conditions. Only one case of Preiser disease requiring surgery has been reported.4, 5 While this case represents only the second report of pediatric idiopathic AVN in published literature, the assumption is that other cases may have existed and gone unreported. With the pain and loss of motion combined with normal plain films, conservative treatment to avoid missing such carpal injuries as a scaphoid fracture may have treated an underlying capitate osteonecrosis. The complete resolution of symptoms and physical findings in these two cases lays the groundwork for a good prognosis in subsequent cases. With this injury as with many other pediatric injuries or insults, patient observation and time seem to bring a satisfactory resolution. In Mr. B’s case, the age of the patient and the imminence of skeletal maturity are unique and yet offer some framework for treatment guidelines in this age group. Although the patient who presented at age 18 years went on to need surgical intervention, this was not the outcome in a patient just a few months younger chronologically.

6. SUMMARY

Other than MRI, no diagnostic test is applicable in these cases. This would raise the question as to whether every child presenting with wrist pain and normal plain films needs an MRI. The cost and the logistics of obtaining MRI on every child with wrist pain would be prohibitive. However, the natural history of pediatric idiopathic AVN as presented makes the condition very amenable to conservative management and selective MRI in the judgment of the attending provider. The case of pediatric idiopathic AVN described here presents a diagnosis that may not have been available previously. The case also offers a satisfactory treatment option and reassurance for the patient’s family. In our very active young patient, a return to full, unrestricted activity and a productive future was not impaired. n Dr. Frost is an Assistant Professor in the physician assistant program at Eastern Virginia Medical School in Norfolk. References 1. Humphrey CS, Izadi KD, Esposito PW. Osteonecrosis of the capitate: a pediatric case report. Clin Orthop Relat Res. 2006;447:256-259. 2. Botte MJ, Pacelli LL, Gelberman RH. Vascularity and osteonecrosis of the wrist. Orthop Clin North Am. 2004;35:405-421, xi. 3. Bolton-Maggs BG, Helal BH, Revell PA. Bilateral avascular necrosis of the capitate. J Bone Joint Surg Br. 1984;66:557-559. Available at www.bjj. boneandjoint.org.uk/content/66-B/4/557.long. 4. Gupta A, Kay SPJ, Scheker LR. The Growing Hand: Diagnosis and Management of the Upper Extremity in Children. Elsevier Heath Services; London, United Kingdom: 1999:345-372. 5. Morrissy RT, Weinstein, SL. Eds. Lovell & Winter’s Pediatric Orthopaedics.

“Mommy is taking the nap you refuse to take.”

5th ed. Lippincott Williams & Wilkins; Philadelphia: 2001:368-369. All electronic documents accessed November 15, 2013

As with any patient presenting with findings suspicious for occult fracture, persons with similar symptoms progressing to osteonecrosis must be considered.

“I forget. If I have an adverse reaction, do I call my doctor or my lawyer?”

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CME CE

Dermatology Clinic n LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. n COMPLETE THE POSTTEST: Page 123

n ADDITIONAL CME/CE: Pages 56, 119

Turn to page 55 for additional information on this month’s CME/CE courses.

CASE #1

Open comedones and inflammatory pustules ESTHER STERN, NP-C

A man, aged 18 years, presented with complaints of severe acne on his face and upper back. He reported that he first developed mild acne at age 14 years, and it had gotten progressively worse. The patient had tried various OTC and prescription creams as well as oral doxycycline and oral minocycline for several months at a time with only mild improvement. The patient’s father had a history of severe acne that resolved in his middle-age years and resulted in permanent scarring. Examination revealed scattered open comedones and numerous inflammatory pustules and papules, as well as hyperpigmented macules and atrophic scars. What is your diagnosis? Turn to page 114

CASE #2

Linear streaks on the trunk and extremities AUDREY CHAN, MD

A man, aged 23 years, was seen as an inpatient consultation for a pruritic rash that had been present for two days. Medical history was significant for Hodgkin lymphoma, which was being treated with the ABVD chemotherapy regimen (doxorubicin, bleomycin, vinblastine, dacarbazine [DTIC-Dome]). Family history was noncontributory. A review of systems was negative for fevers but positive for chills and weight loss in the setting of chemotherapy. Social history was negative for recent consumption of shiitake mushrooms. Physical exam was notable for linear hyperpigmented streaks on the trunk and extremities. What is your diagnosis? Turn to page 115 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2013 113

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CME CE

CASE #1

Dermatology Clinic

Cystic acne

In its milder form, acne vulgaris presents with comedones and few pustules or mildly inflammatory papules. Acne vulgaris is a very common condition, with up to 85% of teenagers affected to some degree.1 Cystic acne is much less common and is characterized by larger inflammatory papules, cysts, and nodules that often resolve with permanent scarring. Practitioners should be able to recognize this variant of the disease early on and start appropriate treatment quickly to minimize permanent disfigurement. Cystic acne is generally first seen in the middle teenaged years, coinciding with rises in hormone levels. Males appear to be affected more often, but young women may see a cyclical flare of papulopustular lesions in the week prior to menstruation.2 Cystic acne is also known to affect adults aged 20 to 35 years who have no prior history of acne. Women with cystic acne should be evaluated to rule out a hyperandrogenic state.3 These patients should be asked about irregular menses, difficulty maintaining optimal

Many practitioners observe that lower doses of isotretinoin appear to be as effective as higher doses in clearing acne. weight, and hirsutism. An answer in the affirmative should prompt consideration of a referral to endocrinology to rule out polycystic ovarian syndrome or other disorders. Acne education is vital to maximizing the potential for improvement. Patients should be instructed to wash their face daily with a gentle cleanser. Scrubs or other harsh cleansing products may irritate and dry out the skin and should be avoided. Noncomedogenic moisturizers, sunscreens, and cosmetics are recommended. Isotretinoin is the most effective treatment for acne and the only acne treatment that can potentially induce disease remission. Isotretinoin inhibits sebocytes, decreases lipids, decreases inflammation, regulates keratinization, and decreases Propionibacterium acnes proliferation.4 This medication is indicated for severe nodular and cystic acne,

as well as for less severe acne that is resistant to six months of oral and topical antibiotic use, acne that is psychologically distressing, acne that relapses after cessation of oral treatments, and scarring acne. The usual dosage of isotretinoin is 0.5-1.0 mg/kg/day, in one dose or divided into two daily doses. The dose may be cautiously increased to up to 1.5 mg/kg/day in patients who do not respond to lower doses and who can tolerate the higher dose. To minimize side effects, start patients on 20 mg or 40 mg daily for the first month and then slowly increase to the desired dosage over the next month. The ideal desired cumulative dose is 120-150 mg/kg. The typical course of isotretinoin treatment is 20 weeks; however, many researchers encourage treating until clinical resolution of acne. There are insufficient data to recommend a longer-term, lower-dose isotretinoin protocol. Many practitioners observe that lower doses (i.e., 0.1 mg/kg/day) appear to be as effective as higher doses in clearing acne;5 however, it is important to be aware that patients treated with lower doses have a significantly higher rate of relapse after stopping treatment. Teratogenicity is the most concerning adverse effect of isotretinoin. The drug is contraindicated in women who are pregnant (Category X), and female patients need to be provided very clear information regarding this risk. In the United States, isotretinoin prescribers must be registered with the iPLEDGE program (www.ipledgeprogram.com), an FDA-approved a special restricted-distribution program. Female patients of childbearing potential must be using two forms of contraception for at least one month before, during, and one month after isotretinoin treatment. A negative pregnancy test is also required at least one month prior to the start of treatment, as well as monthly during treatment. Common dermatologic side effects of isotretinoin include cheilitis, mucocutaneous xerosis, dermatitis, photosensitivity, exuberant granulation tissue, and acne flare. Many of these side effects can be alleviated with the use of emollients, artificial tears, and sun protection, and occasionally by reducing the isotretinoin dosage for the first few months. Depression is a potential psychiatric adverse effect. Clinicians should screen patients at baseline for psychiatric disorders and at each follow-up visit for depressive or suicidal thoughts. While nausea is a potential GI side effect, isotretinoinâ&#x20AC;&#x2122;s association with inflammatory bowel disease is more controversial.6 Because isotretinoin therapy may cause lipid alterations, a lipid panel should be obtained monthly. Triglyceride levels >500 mg/dL should prompt a decrease in dosage along with

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appropriate therapy (conservative as well as pharmacologic, if indicated); levels >800 mg/dL require immediate cessation of therapy and evaluation for risk of pancreatitis.7 Liver enzymes should also be monitored monthly in patients taking isotretinoin. The medication should be stopped if there is a rise in liver enzymes three times greater than baseline values. Patients should be advised to avoid all alcoholic consumption to minimize the risk of hepatic toxicity. The two most concerning isotretinoin drug interactions are tetracycline (Sumycin) and vitamin A. Clinicians should emphasize the importance of the patient informing all of his or her health-care providers of the fact that he or she is taking isotretinoin. Relative contraindications for isotretinoin treatment include peanut allergy, paraben sensitivity, occupation as a pilot or taxi driver, leukopenia, and hepatic or renal disease. The patient in this case was started on isotretinoin in compliance with the iPLEDGE program guidelines. During the first two months of treatment, the dosage was titrated slowly due to mildly elevated cholesterol levels, which normalized with lifestyle improvements. After six months of treatment, and having reached the desired cumulative dose of 120 mg/kg, the patient was acne-free and showed very significant improvement of scarring. The isotretinoin was stopped, and he was maintained on topical adapalene (Differin) gel nightly. The patient was very happy with the treatment results and reported that he felt like a new person, having an acne-free face for the first time since puberty. Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J.  References 1. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009;60(5 Suppl):S1-S50. 2. Kligman AM. Postadolescent acne in women. Cutis. 1991;48:75-77. 3. da Cunha MG, Fonseca FL, Machado CD. Androgenic hormone profile of adult women with acne. Dermatology. 2013;226:167-171. 4. Ganceviciene R, Zouboulis CC. Isotretinoin: state of the art treatment for acne vulgaris. J Dtsch Dermatol Ges. 2010;8 Suppl 1:S47-S59. 5. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol. 1984;10:490-496. 6. Prevost N, English JC. Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol. 2013;26:290-293. 7. Jamshidi M, Obermeyer RJ, Govindaraj S, et al. Acute pancreatitis secondary to isotretinoin-induced hyperlipidemia. J Okla State Med Assoc. 2002;95:79-80.

CASE #2

Flagellate hyperpigmentation

Bleomycin is a glycopeptide antibiotic derived from Streptomyces verticillus. Because it inhibits cell division, bleomycin has been used as a chemotherapeutic agent in the treatment of many cancers, including Hodgkin lymphoma, testicular cancer, and squamous cell carcinoma.1 Intralesional bleomycin is used in the treatment of verruca vulgaris as an inhibitor of DNA synthesis in infected keratinocytes. When injected into cavitary spaces, including the pleura or vascular malformations, bleomycin acts as a sclerosing agent. When used in the treatment of malignancies, bleomycin causes adverse cutaneous and pulmonary reactions in 50% and 10% of treated patients, respectively.1 The cutaneous side effects of bleomycin include those common to all chemotherapeutic agents, including alopecia and stomatitis.1 Hyperpigmentation is a common cutaneous side effect of systemic bleomycin. Flagellate hyperpigmentation—seen in this patient—is a pathognomonic cutaneous side effect of bleomycin and manifests as hyperpigmented linear streaks, found most commonly on the chest and back. Flagellate pigmentation from bleomycin, also known as flagellate erythema, scratch dermatitis, and flagellate dermatitis, may occur in as many as 10% to 20% of patients treated with systemic bleomycin.2 A minority of patients are noted to have preceding flagellate erythema or urticaria-like lesions prior to the development of brown linear streaks.2 Symptomatology ranges from intense pruritus to being completely asymptomatic. Additional forms of hyperpigmentation seen with bleomycin include those localized to areas of pressure and the palmar creases.1 Other reported cutaneous side effects, relatively specific to bleomycin, include the following: painful inflammatory nodules on the fingers, verrucous plaques on the knees and elbows, and sclerodermoid changes of the fingers that can be complicated by digital gangrene due to Raynaud phenomenon.2 Bleomycin-induced flagellate erythema is most commonly seen after intravenous administration of bleomycin for chemotherapy. This reaction is usually seen after cumulative doses of 100 mg to 300 mg.2 The onset of the rash typically occurs from one day to nine weeks after bleomycin is administered, but the reported range of onset is as early as one hour and as late as six months after drug administration. Less frequently, bleomycin-induced flagellate erythema may occur after

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Dermatology Clinic

intralesional administration of the drug. One such patient developed flagellate hyperpigmentation one week after a single dose of intralesional bleomycin for a vascular malformation of the tongue.3 Another developed this reaction following intralesional injection of a cystic hygroma.4 Flagellate dermatitis also has been reported after administration of intralesional bleomycin for the treatment of plantar warts. Abess et al. reported that this reaction developed one hour after a patient received 1U of bleomycin in 14 plantar warts for a cumulative dose of 14 U.1 Other cases have been reported in the settings of intrapleural instillation for the treatment of mesothelioma.5 The enzyme hydrolase, which is present in every organ except the lung and the skin, inactivates bleomycin. This fact may explain the pulmonary toxicity and unique cutaneous side effects seen with this drug.3 The exact pathogenesis of flagellate pigmentation from bleomycin is unknown. Some hypothesize this may be postinflammatory hyperpigmentation; arguing against this theory, however, is the fact that only a minority of patients report preceding erythema. Other hypotheses include a bleomycin-induced local increase in melanogenesis or altered pigment maturation leading to enhanced distribution of pigment to horny layers.2 A leakage of drug secondary to scratching or rubbing has also been suggested.1 Last, an atypical fixed-drug-like reaction has been suggested as an etiology.1 The diagnosis of bleomycin-induced flagellate pigmentation is made clinically. The unique flagellate morphology with history of recent bleomycin exposure is diagnostic. Because the findings are nonspecific, a skin biopsy is not helpful for diagnosis. The following histopathologic findings have been reported: (1) basal layer hypermelanosis, (2) spongiosis confined to the basal cell layer in association with a perivascular lymphohistiocytic infiltrate and pigmentary incontinence, and (3) superficial and deep perivascular and periadnexal lymphocytic infiltrates, with occasional macrophages and eosinophils and a few plasma cells.1 The differential diagnosis includes other disorders with linear hyperpigmentation. Flagellate mushroom dermatitis is clinically indistinguishable from bleomycin-induced flagellate pigmentation. Often, only a history of recent consumption of raw shiitake mushrooms with no prior history of exposure to bleomycin can distinguish between the two entities. Flagellate mushroom dermatitis is seen most commonly in Japan. Although only a minority of patients with bleomycininduced flagellate dermatitis report a preceding history of erythema, in flagellate mushroom dermatitis, the majority of patients report a history of pruritic papules, vesicles, and edema prior to the development of brown streaks. Flagellate dermatitis may also be seen in patients with dermatomyositis,

so a careful history of muscle weakness and a full-body skin exam should be conducted. Cutaneous signs suggestive of dermatomyositis include heliotrope rash, shawl sign, V-sign, periungual telangiectases with alternating dilatation and dropout of nailfold capillaries, and Gottron papules. Linear postinflammatory hyperpigmentation from other dermatoses should be considered, including trauma and contact allergens that can result in linear streaks (poison ivy and phytophotodermatitis). However, these lesions tend to appear on the exposed extremities; bleomycin-induced flagellate pigmentation has a predilection for the trunk. There is no specific treatment for bleomycin-induced flagellate pigmentation. Hyperpigmentation usually resolves three to four months after discontinuation of therapy, but some patients see resolution even with continued administration of bleomycin.2 Rarely, hyperpigmentation can persist beyond one year.6 Most therapies are aimed at symptomatic relief. Because these lesions tend to be truncal, a class I topical corticosteroid such as clobetasol 0.05% ointment b.i.d. for two to three weeks is most commonly used. Use of ultrapotent topical steroids on the face, groin, and axillae should be avoided. For severe discomfort, a short prednisone taper may be employed. Oral antihistamines may also provide relief. Unfortunately, the patient described in this case was lost to follow-up. n Dr. Chan is a third-year dermatology resident at Baylor College of Medicine in Houston. References 1. Abess A, Keel DM, Graham BS. Flagellate hyperpigmentation following intralesional bleomycin treatment of verruca plantaris. Arch Dermatol. 2003;139:337-339. Available at archderm.jamanetwork.com/article. aspx?articleid=479222 2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:2011. 3. Ibrahimi OA, Anderson RR. Images in clinical medicine. Bleomycininduced flagellate hyperpigmentation. N Engl J Med. 2010;363:e36. 4. Manoj J, Kaliyadan F, Dharmaratnam AD. Palmar and flagellate hyperpigmentation following low dose intralesional injection of bleomycin for cystic hygroma. Dermatol Online J. 2008;14:19. 5. Fernandez-Obregon AC, Hogan KP, Bibro MK. Flagellate pigmentation from intrapleural bleomycin. A light microscopy and electron microscopy study. J Am Acad Dermatol. 1985;13:464-468. 6. Resende C, Araújo C, Gomes J, Brito C. Bleomycin-induced flagellate hyperpigmentation. BMJ Case Rep. 2013 Jun 5;2013. All electronic documents accessed November 15, 2013.

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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.

Garcinia cambogia Garcinia cambogia is yet another entrant in the growing list of natural supplements being marketed as the answer to obesity. G. cambogia is most well-known for its use as a spice. This product, which is classified as a fruit, is naturally found throughout southeastern Asia, India, and western Africa.1 One of nearly 300 species of Garcinia, G. cambogia is the one most studied for its weight-loss potential.1 G. cambogia grows as a small tree and produces a rusty-red round fruit.2 It is the rind of this fruit that is used for both culinary and therapeutic purposes.2

Background Obesity is a tremendous health problem, not just in the United States but globally as well.An estimated 1 billion adults worldwide are overweight, and nearly one-third of those are considered clinically obese.3 In the United States alone, the overall cost of obesity was estimated by the CDC to be nearly $150 billion per year.4 G. cambogia became popular as a weight-loss aid when it was noted to enhance satiety in its native regions.5 A secondary effect of the fruit is its potent laxative action.6 The active ingredient of G. cambogia is hydroxycitric acid (HCA).5

Science The mechanism of fat metabolism is complex, and the role of G. cambogia in this process is debatable. Metabolically, HCA appears to be the source of early satiety. This acid enters the energy-production process of the Kreb’s cycle and ultimately

increases hepatic glycogen synthesis and inhibits formation of low-density lipoproteins.5 This is thought to signal to our brains that we have had enough to eat. Some suggest that HCA interacts with the production of the adipose-controlling hormone leptin, but these claims have yet to be substantiated by clinical trials. In a meta-analysis literature review, researchers identified only 23 trials that met review criteria.7 Fewer than half of those ultimately met the proper standards for well-done randomized, placebo-controlled trials. After the final data analysis, use of G. cambogia was associated with a very slight (0.88 kg) weight loss over control groups, but also with twice the number of adverse GI effects. Korean researchers studied the effects of G. cambogia, placebo, and another weight-loss supplement in 86 overweight adults in a 10-week randomized trial.8 At the end of the study, no statistically significant weight loss was found in any of the three groups. In another small trial, researchers studied 24 overweight adults over two weeks of daily intake of G. cambogia HCA extract.5 In addition to actual weight loss being monitored, 24-hour

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ALTERNATIVE MEDS UPDATE energy intake was tracked. By the end of the trial, energy intake was reduced by 15% to 30% in the G. cambogia group over placebo, with a very modest trend in weight loss. Finally, a study in India focused on 60 obese individuals who were randomized to HCA plus two other supplements, or placebo.9 At the end of eight weeks, both HCA groups had a 5% to 6% reduction in weight and BMI. Food intake, total cholesterol, LDL cholesterol, and triglycerides all decreased in the HCA groups, and HDL levels increased.

Safety Unfortunately, evidence-based literature demonstrates the potential for adverse events in G. cambogia/HCA. In addition to significant GI upset, increasing reports of hepatic injury are surfacing. For example, researchers found that daily feeding with HCA supplement did result in decreased fat accumulation and glucose resistance in obese mice, but at the expense of significant hepatic fibrotic changes and inflammation.1 Several cases of acute liver failure and another resulting in death have been associated with a popular weight-loss product composed primarily of HCA.10,11 As a result, the FDA publicly warned health-care providers about the possible association of this product with lethal liver damage, and the product was removed from the marketplace.12

clear that more human clinical trials need to be conducted before health-care providers can give informed support for this product. n References 1. Kim YJ, Choi MS, Park YB, et al. Garcinia Cambogia attenuates diet-induced adiposity but exacerbates hepatic collagen accumulation and inflammation. World J Gastroenterol. 2013;19:4689-4701. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3732841/. 2. Márquez F, Babio N, Bulló M, Salas-Salvadó J. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia

Research shows that G. cambogia is not a confirmed weight-loss aid.

The use of G. cambogia was associated with a very slight weight loss, but also with twice the number of adverse GI effects.

Interactions cost, how supplied

extracts in humans. Crit Rev Food Sci Nutr. 2012;52:585-594. 3. Shrivastava, D. Formulation of sustained release tablet of anti-obesity drug Garcinia cambogia. World Journal of Pharmacy and Pharmaceutical Sciences. 2012;1: 731-743. 4. Centers for Disease Control and Prevention. Adult obesity facts. Available at www.cdc.gov/obesity/data/adult.html. 5. Westerterp-Plantenga MS, Kovacs EM.The effect of (-)-hydroxycitrate on energy intake and satiety in overweight humans. Int J Obes Relat Metab Disord. 2002;26:870-872. 6. Skidmore-Roth, L. Mosby’s Handbook of Herbs & Natural Supplements. 3rd ed. Elsevier Mosby; St. Louis: 2006:23-35 7. Onakpoya I, Hung SK, Perry R, et al.The use of Garcinia extract (hydroxycitric acid) as a weight loss supplement: A systematic review and meta-analysis of randomized clinical trials. J Obes. 2011;2011:509038. Available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3010674. 8. Kim JE, Jeon SM, Park KH, et al. Does Glycine max leaves or Garcinia Cambogia promote weight-loss or lower plasma cholesterol in overweight individuals: a randomized control trial. Nutr J. 2011;10:94. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3189865. 9. Preuss HG, Bagchi D, Bagchi M, et al. Effects of a natural extract

Drug or herbal interactions with G. cambogia are speculative; however, caution should be used when combining this agent with any product that is metabolized primarily through the liver. A month’s supply of dried powder-filled capsules costs about $30, depending on the source.

Summary

of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss. Diabetes Obes Metab. 2004;6:171-180. 10. Stevens T, Qadri A, Zein NN.Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med. 2005;142:477-478. 11. McDonnell WM, Bhattacharya R, Halldorson JB. Fulminant hepatic failure after use of the herbal weight-loss supplement 12. Ezine. Hydroxycitric acid, bad science and liver failure. Available at ezinearticles.com/?Hydroxycitric-Acid,-Bad -Science-and-Liver-Failure&id=2342676. All electronic documents accessed November 15, 2013.

Exilis. Ann Intern Med. 2009;151:673-674.

The identification of a simple, safe, affordable weight-loss product would be a welcome in our society. However, the threat of potentially lifethreatening liver disease is a stong deterrent to G. cambogia use. Regardless of the current data, it is 118 THE CLINICAL ADVISOR • DECEMBER 2013 • www.ClinicalAdvisor.com

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CME CE

Dermatologic Look-Alikes n LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. n COMPLETE THE POSTTEST: Page 123

n ADDITIONAL CME/CE: Pages 56, 113

Turn to page 55 for additional information on this month’s CME/CE courses.

Localized vesicles on the trunk KERRI ROBBINS, MD

CASE #1

CASE #2

A young woman presented with a lesion on her left abdomen that had been present since birth. She requested an appointment with a dermatologist because she was bothered by the appearance of the lesion and troubled by the occasional drainage of clear fluid. The lesion had remained stable in size for years, and there was no associated pain or pruritus. No prior treatment had been attempted. History was significant for varicella as a child. Review of systems was otherwise negative. On physical exam, clear and hemorrhagic vesicles were appreciated on the left mid-abdomen.

A woman, aged 62 years, complained of a painful rash. The eruption began as pain and hyperesthesia on her left chest, flank, and back three days prior to presentation. One day earlier, she had noticed a red patch on her left chest that later developed vesicles. OTC hydrocortisone provided no relief. History was significant for primary varicella as a child. Physical examination revealed grouped vesicles on an erythematous base on the left chest. Erythematous edematous plaques were also developing on the left flank and left back.

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CASE #1

Dermatologic Look-Alikes

Microcystic lymphatic malformation

Anomalies of the lymphatic system include lymphede ma and lymphatic malfor mations. Lymphedema is a result of aplasia, hypoplasia, or obstruction of the lym phatic network. On the other hand, lymphatic malforma tions are caused by hyperpla sia of the lymphatic pathways. Lymphatic malformations have been known by many different names, including lymphangioma, cavernous lymphangioma, lymphagioma circumscriptum, and cystic hygroma. More recently, lymphatic malformations have been classified and named based on the size of their mal formed channels: microcystic, macrocystic, or combined (microcystic/macrocystic). Macrocystic lymphatic malformations have previously been known as cystic hygromas and cavernous lymph angiomas in the literature. They are most commonly seen on the neck, axilla, and lateral chest wall and are character ized by large lymphatic channels and cysts. Many cases are diagnosed prenatally by ultrasound and may be associated

The lesions may occur anywhere on the skin but are commonly seen in the oral mucosa, especially the tongue or cheek. with karyotype abnormalities, malformation syndromes, or teratogenic agents. Clinically, a large and somewhat translucent soft mass that may be enhanced by transillumi nation is seen under normal-appearing skin. Intralesional hemorrhage occurs in approximately 35% of lymphatic malformations and may cause the cyst to become tense, tender, swollen, and purple or yellow in color.1 Infection can also complicate as many as 71% of lesions, because the malformed lymphatics are less able to clear foreign mate rial and contribute to antibody production.1 Rarely, vital structures may become obstructed due to the swelling that may be associated with bleeding, infection, or viral illness. Microcystic lymphatic malformations have been most commonly known as “lymphangioma circumscriptum” in previous literature. These malformations represent

microscopic aggregations of ill-defined small lymphatic channels. Lesions commonly appear at birth but may arise at any age. The lesions may occur anywhere on the skin but are commonly seen in the oral mucosa, especially the tongue or cheek. Microcystic lymphatic malformations usu ally present during infancy as cutaneous plaques or nodules with crops of clear or hemorrhagic vesicles scattered on the surface. The vesicles are often compared to the appearance of frog spawn and may vary in size and number over time. Occasionally, intermittent lymph drainage, inflammation, and secondary infection may occur. Hemorrhage may also occur in these superficial lesions, presenting as intermittent swelling or bruising. Most lymphatic malformations can be diagnosed by history and physical examination alone. To confirm the diagnosis and define the extent and type of malformation, magnetic resonance imaging (MRI) may be obtained. Ultrasonography is not as informative as an MRI but may be useful, as it does not require sedation. The differential diagnosis for macrocystic lymphatic malformations include lipoblastoma, teratoma, broncho genic cyst, branchial cyst, thyroglossal duct cyst, infantile myofibromatosis of intramuscular location. In adults, B-cell lymphoma of the parotid area also must be considered. The differential diagnosis for a microcystic lymphatic malfor mation includes verruca vulgaris, molluscum contagio sum, herpes simplex, herpes zoster, and epidermal nevus. Lymphatic malformations are usually present at birth or develop shortly thereafter and do not resolve with time; hence, a history that is focused on initial presentation and duration should help to clinch the diagnosis. Macrocystic lymphatic malformations demonstrate large, irregularly shaped cystic spaces lined by a single layer of endothelial cells in the dermis and in subcutaneous tissue. Smaller, thinner channels may be seen interconnecting the larger channels. The stroma may be loose or fibrotic and scattered aggregates of lymphocytes are often appreci ated. Microcystic lymphatic malformations predominantly involve the superficial dermis; however, extension into the dermis and subcutaneous tissue may be seen. Numerous irregular, thin-walled vascular channels that are lined by a single layer of barely visible endothelial cells and varying numbers of smooth muscle cells are seen cutting through collagen bundles. The vascular channels may have sparse proteinaceous material or a few red blood cells, or be empty. Lymphatic malformations are benign and require no inter vention if they are small and/or asymptomatic. Occasionally, bleeding may occur within the lesion, and those patients

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are best treated with rest. If needed, pain medication or prophylactic antibiotics to prevent infection may be given. For lesions that are symptomatic, cause significant pain or deformity, or threaten vital structures, sclerotherapy (usually performed by an interventional radiologist) is commonly the first-line management. Sclerotherapy causes an inflammatory reaction with subsequent scarring and shrinking of the cyst walls. Sclerotherapy will reduce the size of the lymphatic malformation but will not completely remove it. Sclerosing agents that are used include doxycycline, sodium tetradecyl sulfate (Sotradecol), ethanol, OK-432 (Picibanil) (killed group Streptococcus pyogenes), and bleomycin. The most common complication of sclerotherpay is skin ulceration. Lesions may also recur and oftentimes patients need repeat sclerotherapy over the course of their lifetime. Surgical management may also be considered; however, sclerotherapy has superior efficacy and a lower complication rate than does resection.2 Resection is generally considered a viable option for small, localized, symptomatic lymphatic malformations. Vaporization with a CO2 laser may be successful if deeper components are not present.3 Side effects are infrequent and minor, including dyspigmentation and mild scarring. Pulsed-dye laser and intense-pulsed-light systems also have been reported as effective. Electrodessication may allow symptomatic improvement of superficial lymphatic malformations.4 Radiotherapy has been successful in a few select refractory cases. Since the patient in this case was cosmetically bothered by her lymphatic malformation, she was referred to interventional radiology for further evaluation and treatment with sclerotherapy.

CASE #2

Herpes zoster

Varicella zoster virus (VZV) is the etiologic agent of varicella (chickenpox) and herpes zoster (shingles). Before the development of the varicella vaccine, varicella occurred in 90% of U.S. children prior to age 10 years. Varicella is an eruption characterized by disseminated pruritic vesicles. After a person recovers from varicella, the virus remains dormant and can reactivate years later, causing herpes zoster. An estimated

1 million cases of herpes zoster occur each year. Approximately 20% of healthy adults and 50% of immunocompromised individuals will develop the infection. About half of all cases occur in adults aged 60 years and older; however, younger persons who had primary varicella within the first year of life and those who are immunosuppressed are also at risk. Herpes zoster typically develops only once in a lifetime; severity and incidence increase with age. After an episode of primary varicella, the virus invades the sensory dorsal root ganglion cells and remains dormant there until reactivation at a later date. Although the exact factors involved in reactivation are unknown, the virus is thought to begin replicating either spontaneously or after an episode of stress, fever, radiation therapy, trauma, or immunosuppression. While airborne transmission is the usual route of varicella, it can also be spread through direct contact with vesicular fluid. In contrast, herpes zoster can only be transmitted through direct contact with vesicular fluid. Patients who come in contact with the vesicular fluid of herpes zoster will only develop varicella if they have not been previously exposed to the virus. It is important to note that a person with varicella or zoster cannot transmit zoster to another patient, since it represents reactivation of the VZV in a specific host. Herpes zoster classically occurs unilaterally within a given dermatome. The thoracic dermatome is most commonly involved, followed by the cranial, lumbar, and sacral dermatomes. Patients usually have a one-day to several-day prodrome of intense pain that may be associated with hyperesthesia, tingling, tenderness, or pruritus. The eruption initially presents as erythematous papules and plaques within a given dermatome. Soon thereafter, grouped vesicles develop on this erythematous base. New lesions appear for several days and may become hemorrhagic, necrotic, or bullous. There is often some overflow into the dermatomes above and below the affected area. However, if a patient has visceral involvement and/or develops more than 20 vesicles outside the area of the primary or adjacent dermatomes, he or she is defined as having disseminated zoster. Rarely, a patient may have the intense pain without the eruption; this is termed zoster sine herpete. Postherpetic neuralgia is the most common sequelae following herpes zoster, with 10% to 15% of all patients developing this complication.5 Other complications include secondary bacterial infections, scarring, ophthalmic zoster, Ramsay Hunt syndrome, motor nerve neuropathy, vasculopathy, pneumonitis, and hepatitis. Complications tend to occur more commonly in those who are older or immunosuppressed. The differential diagnosis of herpes zoster includes herpes simplex virus (HSV), microcystic lymphangiomas, localized

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contact dermatitis, and such bacterial skin infections as bullous impetigo and cellulitis. A thorough history and physical examination is usually sufficient to make the diagnosis of herpes zoster. If further testing is needed, a Tzanck smear, direct fluorescent antibody (DFA), and/or lesional biopsy will aid in the diagnosis. Viral cultures have a low yield, confirming the diagnosis in only 60% to 64% of cases.6 The Tzanck smear and DFA have rapid turnaround times, which can be invaluable when making the decision to treat. Only a DFA or immunohistochemical staining will allow distinction between HSV and VZV infections. Varicella, herpes zoster, and herpes simplex are virtually indistinguishable with routine hematoxylin and eosin (H&E) staining. Intraepidermal vesiculation or ulceration, along with epidermal necrosis and ballooning degeneration, are commonly seen. Herpetic cytopathic changes include pale keratinocytes with steel-gray nuclei, margination of chromatin at the edge of the nucleus, nuclear molding, nuclear dust of neutrophils, multinucleated giant cells, and pink intranuclear inclusions. The FDA approved the live attenuated VZV vaccine (Oka strain; Varivax) in March 1995. The vaccine is highly effective, with a seroconversion rate in vaccinated children of 96%. If a vaccinated child does subsequently become infected, not only is the primary infection less severe, but there is also a decreased risk of developing zoster.7 Zostavax, the vaccine to prevent herpes zoster, is recommended for adults aged 60 years and older. However, in 2011 the FDA expanded the age indication to include adults aged 50 years through age 59 years. The vaccine was found to reduce the overall incidence of shingles by 51% and the incidence of postherpetic neuralgia (PHN) by 67%.8 FDA-approved treatments for herpes zoster in immunocompetent patients include acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex). Treatment within 72 hours after onset of the first vesicle is most advantageous; however, studies have shown that therapy initiated within seven days also appears to be beneficial.9 Recent studies have shown that the initiation of gabapentin (Horizant, Neurontin) along with valacyclovir may be beneficial in reducing the incidence of postherpetic neuralgia.10 For immunocompromised patients and those with disseminated disease, intravenous acyclovir is the preferred treatment. The woman in this case was treated with valacyclovir and gabapentin, resulting in resolution of the rash and no incidence of PHN. n Dr. Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston.

References 1. Padwa BL, Hayward PG, Ferraro NF, Mulliken JB. Cervicofacial lymphatic malformation: clinical course, surgical intervention, and pathogenesis of skeletal hypertrophy. Plast Reconstr Surg. 1995;95:951-960. 2. Smith MC, Zimmerman MB, Burke DK, et al. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope. 2009;119:107-115. 3. Savas JA, Ledon J, Franca K, et al. Carbon dioxide laser for the treatment of microcystic lymphatic malformations (lymphangioma circumscriptum): a systematic review. Dermatol Surg. 2013;39:1147-1157. 4. Emer J, Gropper J, Gallitano S, Levitt J. A case of lymphangioma circumscriptum successfully treated with electrodessication following failure of pulsed dye laser. Dermatol Online J. 2013;19:2. Available at escholarship.org/ uc/item/63v8s62s. 5. Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract. 1975;25:571575. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2157719/. 6. Solomon AR, Rasmussen JE, Weiss JS. A comparison of the Tzanck smear and viral isolation in varicella and herpes zoster. Arch Dermatol. 1986;122:282-285. 7. Hayward A, Villanueba E, Cosyns M, Levin M. Varicella-zoster virus (VZV)-specific cytotoxicity after immunization of nonimmune adults with Oka strain attenuated VZV vaccine. J Infect Dis. 1992;166:260-264. 8. Centers for Disease Control and Prevention. Herpes zoster vaccination information for health care professionals. Available at www.cdc.gov/vaccines/vpd-vac/shingles/hcp-vaccination.htm. 9. Decroix J, Partsch H, Gonzalez R, et al. Factors influencing pain outcome in herpes zoster: an observational study with valaciclovir. J Eur Acad Dermatol Venereol. 2000;14:23-33. 10. Lapolla W, Digiorgio C, Haitz K, et al. Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study. Arch Dermatol. © The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

CME CE

2011;147:901-907. Available at archderm.jamanetwork.com/article. aspx?articleid=1105538. All electronic documents accessed November 15, 2013.

“We’ve been together so long we can finish each other’s divorce threats.”

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POSTTEST Expiration date: December 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

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 56

page 113

page 119

Minimizing radiation risk from diagnostic radiology

Case #1: Cystic acne

Case #1: Microcystic lymphatic malformation

1. Which of the following is a predictor of significant intracranial injury? a. Intractable emesis b. Age >65 years c. Scalp hematoma d. All of the above 2. In the PECARN study, a CT of the head was recommended in all cases in which there was (a) a. History of a bike accident without a helmet b. Severe, nonradiating headache c. Abnormal neurologic examination d. Loss of consciousness, for any duration 3. Compared with using a CT scan to determine the possibility of a pulmonary embolism, a disadvantage of a VQ scan is that a. A screening chest x-ray is needed. b. IV contrast must be used. c. It has a lower sensitivity. d. There are high levels of radiation exposure. 4. Abdominal ultrasound should be considered initially in younger patients in whom there is suspicion for a. Biliary disease b. Acute appendicitis c. Diverticulitis d. Ischemic bowel TO TAKE THE POSTTEST please go to CliniAd.com/1gbvxWW

1. What dermatologic side effect is associated with isotretinoin? a. Photosensitivity b. Cheilitis c. Acne flare d. All of the above 2. Which antibiotic causes a drug interaction with isotretinoin? a. Cefazolin (Ancef, Kefzol) b. Tetracycline (Sumycin) c. Azithromycin (Zithromax, Zmax) d. Ciprofloxacin (Cipro, Proquin)

1. Where are microcystic lymphatic malformations most commonly found? a. Digits b. Oral mucosa c. Axilla d. Lateral chest 2. What is first-line management for microcystic lymphatic malformations? a. Sclerotherapy b. Surgical excision c. CO2 laser vaporization d. Electrodessication

Case #2: Flagellate hyperpigmentation

Case #2: Herpes zoster

3. Where is flagellate hyperpigmentation most commonly seen? a. Trunk b. Extemities c. Scalp d. Groin

3. What dermatome is most frequently involved in herpes zoster? a. Cranial b. Lumbar c. Thoracic d. Sacral

4. Consumption of which of the following can result in flagellate dermatitis? a. Shellfish b. Dairy products c. Raw shiitake mushrooms d. Undercooked poultry

4. Valacyclovir (Valtrex) along with what medication may be beneficial in reducing the incidence of postherpetic neuralgia? a. Venlafaxine (Effexor) b. Gabapentin (Horizant, Neurontin) c. Bupropion d. Tramadol

TO TAKE THE POSTTEST please go to CliniAd.com/182fmGb

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Evidence-Based Medicine This department uses the best available scientific findings to offer practical guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

ANTIBIOTIC PROPHYLAXIS MIGHT REDUCE SYMPTOMATIC UTI AFTER REMOVAL OF URINARY CATHETERS IN SOME POSTSURGICAL PATIENTS, BUT EVIDENCE IS INSUFFICIENT TO SUPPORT ROUTINE USE Level 2: Mid-level evidence Urinary tract infections (UTIs) are among the most common hospital-acquired infections, and a large proportion of them are associated with urinary catheters. The Infectious Diseases Society of America recommends against prophylaxis at the time of catheter removal due to concern about selecting for antimicrobial resistance (Clin Infect Dis. 2010;50:625-663). A systematic review of six randomized trials and one prospective cohort study compared the efficacy of antibiotic prophylaxis with placebo or no treatment for prevention of symptomatic UTI following shortterm urinary catheterization (duration ≤14 days) in 1,520 predominantly postsurgical patients. Antibiotics used included ciprofloxacin (Cipro, Proquin), ranging from a single dose to three days of therapy (in three trials and cohort study); trimethoprim-sulfamethoxazole (Bactrim, Septra, Sulfatrim), ranging from a single dose to 10 days of therapy (in two trials); and nitrofurantoin (Furadantin, Macrobid, Macrodantin) (two doses in one trial). Median duration of catheterization ranged from 1.9 to 11 days in prophylaxis groups and from 1.8 to 33 days in control groups. Follow-up ranged from four days to six weeks. In analysis of all studies, antibiotic prophylaxis was associated with reduced risk of symptomatic UTIs (risk ratio 0.45, 95% CI 0.280.72), with a number needed to treat (NNT) of 14 to 34, assuming a 10.5% rate of UTIs in controls. Only two of the seven trials included

It is not clear that treating everyone to prevent a UTI is superior to treating the much smaller number of patients who actually get a UTI.

medical patients, and the total number of medical patients included in the meta-analysis was only 76 (5%). Subanalyses of the five studies of only surgical patients found similar relative risks as the entire analysis, but there was no subanalysis that included only medical patients. Although this meta-analysis demonstrated a significant decrease in symptomatic UTI, there are a number of concerns that limit the generalizability of the findings. There was significant heterogeneity of the patient populations (some trials restricted to genitourinary surgery patients and others excluding them), duration of catheter use, duration of follow-up, and selection of antibiotic. At present, recommendations to reduce catheter-associated UTIs focus on appropriate catheter use, insertion technique, and early removal. Such measures were not clearly implemented in all trials, which dated back to 1984. Finally, it is not clear that treating everyone to prevent a UTI is a superior strategy to treating the much smaller number of patients who actually get a UTI. Additional studies are needed to identify which specific populations might benefit from routine prophylaxis.

INTERMITTENT PNEUMATIC COMPRESSION APPEARS TO REDUCE RISK OF DVT AFTER ACUTE STROKE Level 2: Mid-level evidence Patients who are hospitalized and immobile following an acute stroke are at increased risk The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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Evidence-Based Medicine for deep vein thrombosis (DVT), and most guidelines recommend antithrombotic drugs for DVT prophylaxis in these patients. Mechanical prophylaxis with intermittent pneumatic compression (IPC) is commonly used for surgical patients, but its efficacy in patients with stroke (and in medical patients in general) has not been well established. The CLOTS 3 trial evaluated IPC for prevention of DVT in 2,876 patients with acute stroke. Patients (median age 76 years) who had had an acute stroke within three days and were unable to walk to the toilet without help were randomized to IPC for ≥30 days vs. no IPC, and were followed for six months. IPC was applied continuously, except during washing, physical therapy, and compression duplex ultrasound. Treatment was discontinued early if the patient became independently mobile, was discharged from hospital, declined to continue IPC, or had adverse events. Patients in each group could receive heparin for prophylaxis or treatment at the discretion of treating clinicians. In each group, 24% were receiving warfarin (Coumadin, Jantoven) or heparin at recruitment or had received thrombolysis (alteplase [Activase]) for treatment of acute stroke.The primary outcome was any proximal DVT (symptomatic or asymptomatic detected on ultrasound) within 30 days. Median duration of IPC use was nine days (only 31% used the device every day). The primary outcome occurred in 8.5% with IPC vs. 12.1% without IPC (p <0.05, NNT 28). Symptomatic proximal or calf DVTs occurred in 4.6% vs. 6.3% (p=0.045, NNT 59). The beneficial effects of IPC on DVT rates were similar in subgroup analyses of patients who did or did not receive heparin, warfarin, or alteplase. Rates of prophylactic and therapeutic heparin use after randomization were similar between the IPC and no-IPC groups. IPC was also associated with a reduced rate of any DVT at six months (16.7% vs. 25.1%, p=0.001, NNT 12), and with nonsignificant reductions in mortality at 30 days (10.8% vs. 13.1%, p = 0.057) and at six months (22.3% vs. 25.1%, p=0.059). Skin breakdown was more common in the IPC group. There was no significant difference in the rate of falls.

IN PATIENTS WITH HIGH-RISK SMOLDERING MYELOMA, EARLY TREATMENT MAY DELAY DISEASE PROGRESSION AND INCREASE SURVIVAL Level 2: Mid-level evidence Standard care for patients with smoldering (asympto matic) myeloma is observation for emergence of myelomarelated organ impairment with monitoring of serum and urine paraprotein levels. The risk of disease progression is

generally low (about 10% annually over the first five years) (N Engl J Med. 2002;346:564-571), and guidelines recommend chemotherapy only in cases of symptomatic myeloma-related organ impairment (Br J Haematol. 2011;154:32-75). However, in a sizable subpopulation of asymptomatic patients with greater bone marrow infiltration, the risk of progression is increased. A recent unblinded randomized trial evaluated the efficacy of early treatment in 125 patients with high-risk smoldering myeloma. Patients aged 38 years to 91 years with high-risk smoldering myeloma (43% with diagnosis within previous six months) were randomized to early treatment vs. observation. Early treatment consisted of induction with lenalidomide (Revlimid) 25 mg/day on days 1-21 plus dexamethasone (Decadron, Dexamethasone Intensol, Dexpak) 20 mg/day on days 1-4 and 12-15 every four weeks for nine cycles, followed by maintenance therapy with lenalidomide 10 mg/day on days 1-21 every four weeks for two years. High-risk disease was defined as either plasma-cell bone marrow infiltration ≥10% plus a monoclonal component (IgG level ≥3 g/dL, IgA level ≥2 g/dL, or urinary Bence Jones protein level >1 g/day) or one of these criteria plus ≥95% phenotypically aberrant plasma cells in the bone marrow plasma cell compartment with ≥25% decrease in one to two uninvolved immunoglobulins. After median follow-up of 40 months, early treatment was associated with longer time to progression than observation (hazard ratio for progression 0.18, p <0.001). The median time to progression was not reached in the early treatment group (i.e., less than half the group had progression during follow-up), vs. 21 months in the observation group. Early treatment was also associated with significantly higher threeyear survival (94% vs. 80%, p=0.03, NNT 8). In the early treatment group, at least partial response was observed in 79% during the induction phase and in 90% during maintenance.

COLCHICINE HASTENS RESOLUTION AND REDUCES RECURRENCE AFTER FIRST ATTACK OF ACUTE PERICARDITIS Level 1: Likely reliable evidence The first attack of acute pericarditis often has a viral cause, while recurrent disease is theorized to be immune-mediated. Colchicine (Colcrys) has been shown to speed recovery and reduce the risk of further recurrence in patients with recurrent pericarditis (Ann Intern Med. 2011;155:409-414), but its efficacy for the first attack of acute pericarditis has not been previously established. The ICAP trial compared colchicine vs. placebo in 240 patients with a first episode of acute pericarditis (N Engl J Med. 2013;369:1522-1528).

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IN TWIN PREGNANCY WITH CEPHALIC PRESENTATION OF FIRST TWIN, PLANNED VAGINAL DELIVERY DOES NOT INCREASE NEONATAL RISKS COMPARED WITH PLANNED CESAREAN DELIVERY Level 1: Likely reliable evidence Twin pregnancies are associated with greater perinatal risks than singleton pregnancies, and due in part to caution over these risks, rates of elective cesarean births for twins have increased worldwide in recent years. Some observational data have suggested that vaginal delivery may increase adverse outcomes compared to elective cesarean, but there has been no strong evidence to recommend a policy of planned cesarean delivery in pregnancies without specific indications. A large randomized trial compared the delivery strategies of planned vaginal delivery and planned cesarean section in 2,804 twin pregnancies in which the first twin was presenting cephalically (N Engl J Med. 2013;369:1295-1305). Women with twin pregnancy (gestational age 32 weeks to 38 weeks and six days) were randomized to planned vaginal delivery (with cesarean section only if indicated) vs. planned cesarean section. Inclusion criteria were first twin in cephalic presentation and expected birth weight of both twins 1,500-4,000 g (3.3-8.8 lbs), confirmed by

Patients (mean age 52 years) with their first episode of acute pericarditis were randomized to colchicine 0.5 mg (twice daily if >70 kg [154.3 lbs] or once daily if ≤70 kg) vs. placebo for three months. All patients also had conventional treatment with aspirin or ibuprofen for three to four weeks, or prednisone for patients with contraindications for nonsteroidal anti-inflammatory drugs. The primary outcome was incessant or recurrent pericarditis during follow-up. Incessant disease was defined as persistent symptoms or no symptom-free period for more than six weeks. Recurrent disease was defined as a second episode of pericarditis following a symptom-free period of more than six weeks. Mean follow-up was 22 months. The incidence of incessant or recurrent pericarditis was 16.7% with colchicine vs. 37.5% with placebo (p <0.001, NNT 5), and remission rates at 1 week were 85% with colchicine vs. 58.3% with placebo (p <0.001, NNT 4). Colchicine was also associated with reduced persistence of symptoms at 72 hours (19.2% vs. 40%, p=0.001, NNT 5), and reduced risk of pericarditis-related hospitalization during follow-up (5% vs. 14.2%, p <0.001, NNT 4). There were no significant differences in rates of adverse events, and no serious adverse events occurred in either group. Twin pregnancies show greater perinatal risks that must be managed.

ultrasound fewer than seven days before randomization. In cases of noncephalic presentation of the second twin in the planned-vaginal-delivery group, the delivery method was at the discretion of the obstetrician, and could include total breech extraction, external cephalic version with cephalic vaginal delivery, or cesarean section. Exclusion criteria were monoamniotic twins, fetal reduction after 13 weeks gestational age, and contraindication to labor or vaginal delivery. Mothers and neonates were followed to 28 days after delivery. The primary outcome was a composite of fetal or neonatal death and serious neonatal morbidity. Cesarean deliveries were performed in 90.7% of the plannedcesarean group. In the planned vaginal delivery group, 39% had cesarean delivery for both twins and 4.2% had cesarean for the second twin only. The rates of the composite primary outcome were 1.9% with planned vaginal delivery vs. 2.2% with planned cesarean (not significant). Fetal or neonatal death occurred in 0.6% with planned vaginal delivery and 0.9% with cesarean, and serious neonatal morbidity occurred in 1.3% of each group. There were no significant differences in rates of maternal death or serious morbidity between groups. This trial suggests one way in which the current high rates of cesarean section may safely be reduced. n

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COMMENTARY Debra Clements Coats, RN, BSN, MSN, FNP-BC, is employed with Matrix Medical Network and with an infectious-disease practice in Greensburg, Pa.

Should radiologists give test results? Nurse practitioners (NPs) and physician assistants (PAs) frequently order radiologic imaging studies for their patients. Both the patients and the ordering practitioners are anxious to get those results, but there are often delays in receiving radiology test results in the primary-care setting. Patient satisfaction is a top priority in health care, and patients want “instant interpretation” of their radiologic studies. But who should be delivering these results to the patient: the radiologist or the ordering clinician?

I cannot imagine a radiologist telling a patient that he or she has a mass in the lung.

An article published early this year in the Journal of the American College of Radiology (2013;10:122-127, available at www.jacr.org/ article/S1546-1440(12)00498-X/fulltext; accessed November 15, 2013) discussed the findings of an online survey in which primarycare physicians were asked if they wanted radiologists to contact patients directly with radiology results. The providers were also asked to identify the most significant problem with radiology reporting. The majority of the 100 respondents were satisfied with radiology reporting and recommendations given within those reports in general, found Andrew J. Gunn, MD, and fellow investigators. However, 95% of respondents felt that the ordering physicians should deliver the results, and no respondents felt that the radiologist should deliver results directly to the patient. I do not dispute the knowledge base of radiologists. Their expertise in the interpretation of radiologic imaging is vital to appropriate treatment. However, the ordering physician, an NP, or a PA should be the one sharing the imaging findings with the patient. It is important for the clinician to have a plan of care in place before delivering any radiologic results. Patients are going to have so many questions for the health-care professional delivering the test results, and I do not believe radiologists should be put in the position of having to field such questions. Having

a background in oncology nursing, I cannot imagine a radiologist telling a patient that he or she has a mass in the lung. The patient is going to want to discuss a plan of care as soon as he or she hears this news, and the radiologist will not have that information. This is unfair to the patient as well as to the radiologist. I believe the medical professional ordering the imaging should be the one to deliver abnormal results, as he or she is the one who knows why the test was ordered. When the patient asks, “What are my options and what do I do next?” the practitioner delivering the results needs to have some answers. Yet I do also believe that it is perfectly acceptable for a radiologist to inform a patient of normal test findings. This would expedite the process of getting the results to the patient and decrease the patient’s time in anxiety-ridden limbo. Some might argue that if allowing radiologists to deliver normal results becomes the norm, then patients will automatically assume that if they don’t get an immediate answer from the radiologist, the results are bad. However, this reporting process is already in place: When doctors themselves call a patient, they usually are delivering abnormal results. In the coordination of care, having a plan of care in place at the time of delivery of abnormal radiologic test results is ultimately more important than providing the patient with “speedy” results. n

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General Surgery Physician Assistant Central California Central California Faculty Medical Group (CCFMG), affiliated with the University of California San Francisco Fresno Medical Education Program has an excellent opportunity for a licensed Physician Assistant. The selected applicant will be involved in all levels of patient care within the Surgery Department at Community Regional Medical Center in Fresno for days and weekends/some nights. Excellent salary and benefit package. Please E-mail or FAX CV to: Diane O’Connor, Recruiter, CCFMG E-Mail: Diane.Oconnor@ccfmg.org FAX#: (559) 443-2691 EOE www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2013 129

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