November 2013 Clinical Advisor

THE CLINICAL ADVISOR • NOVEMBER 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

■■Hormones and CV risk ■■Sleep apnea guideline ■■BP screening in children

ADVISOR FORUM

■■Smoking and low libido ■■Hepatits C: When to refer ■■Classifying dysplastic nevi

| N OV E M B E R 2 013 | www.ClinicalAdvisor.com

GOUT IN PATIENTS WITH

KIDNEY DISEASE As kidney function decreases, incidence of gout (shown) increases.

LEGAL ADVISOR

Untreated bacterial infection in a patient with no spleen

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n CE Feature

COW’S MILK PROTEIN ALLERGY PAGE 76

VOLUME 16, NUMBER 11

n Dermatologic Look-Alikes

YOUNG BOYS WITH PEELING SKIN PAGE 111

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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.

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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 11, 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.

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CONTENTS NOVEMBER 2013

NEWS AND COMMENT 26 Newsline ■■Studies look at hormones and health risks ■■OSA guideline calls for weight loss, CPAP ■■Repeat bone testing may not predict fractures ■■Inhaled steroids and pneumonia ■■Treating unhealthful behaviors ■■Vitamin B may protect against stroke ■■Colonoscopy remains best for prevention ■■USPSTF still won’t push youth BP screening ■■Few thyroid findings call for biopsy ■■Men most likely to be admitted for UTI

76 CME/CE Identifying and addressing infant allergy to cow’s milk protein Cow’s milk protein allergy is relatively common during the first year of life.

Unfortunately, the condition is easily missed or mislabeled.

DEPARTMENTS How estrogen therapy affects health risks 26

93 Legal Advisor Emergency clinicians improperly attended to a bacterial infection in a patient with no spleen.

95 Clinical Challenge An adolescent presented with persistent upper-extremity pain, redness, and axillary swelling upon lifting weights.

40 Drug Update ■■Long-term, once-daily COPD treatment 119 Commentary Can running barefoot reduce injury? 58

FEATURES 46 Gout management in patients with CKD The most recent guidelines from the American College of Rheumatology include drug and nondrug therapies for hyperuricemia.

CA1113_TOC.indd 8

Follow us on Twitter @ClinicalAdvisor

99 Stat Consult Find out the most recent information on diagnosing and treating heatstroke.

Continues on page 18

58 A better understanding of barefoot running Research on the relationship between footwear and injury rates is limited. A switch to a minimalist shoe or barefoot running should be made gradually.

MAKING CONTACT

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

A skin rash can indicate food allergy 76

Like us on Facebook facebook.com/TheClinicalAdvisor

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Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

10/30/13 1:36 PM

1

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.

002060-130903_I0062_A3_Sita_Ad_FR2.indd 1

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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

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

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

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

DIFFERENCE FROM SITAGLIPTIN

– 0.37*

(95% CI: –0.50, –0.25); P<0.05

Sitagliptin 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%; sitagliptin 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 sitagliptin + 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.

002060-130903_I0062_A3_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 sitagliptin‡: 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 sitagliptin‡: 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. ‡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 10/10/13 4:09 PM

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

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

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

DIFFERENCE FROM SITAGLIPTIN

– 0.37*

(95% CI: –0.50, –0.25); P<0.05

Sitagliptin 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%; sitagliptin 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 sitagliptin + 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.

002060-130903_I0062_A3_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 sitagliptin‡: 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 sitagliptin‡: 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. ‡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 10/10/13 4:09 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

002060-130903_I0062_A3_Sita_Ad_FR2.indd 4-5

October 2013

002060-130903

>> 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.

K02CAN13149

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

10/10/13 4:09 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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October 2013

002060-130903

>> 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.

K02CAN13149

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 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)

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Placebo n=646 Creatinine (mg/dL)

0.84

0.82

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 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)

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Placebo n=646 Creatinine (mg/dL)

0.84

0.82

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

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 103 CME/CE Dermatology Clinic n Extremely pruritic red lesions that would urticate on stroking developed on the chest of a woman in her late 40s.

n Addition of vasopressin plus

n A man with HIV and end-stage renal

disease presented with a peeling rash that had a “flaky paint” appearance on his trunk and extremities.

“Flaky paint” ulceration in a man with HIV 103

108 Alternative Meds Update Products containing green coffee extract have become popular for their potential to aid weight loss.

115 CME/CE Posttest

ADVISOR FORUM

111 CME/CE Dermatologic Look-Alikes Two young boys—one aged 4 years and the other aged 5 years—present with desquamating skin.

116 Evidence-Based Medicine n Addition of co-trimoxazole to cephalexin does not increase cure rate of uncomplicated cellulitis n Apixaban is as effective as conventional therapy for treatment of acute venous thromboembolism and reduces bleeding risk

steroids to epinephrine increases survival to discharge with favorable neurologic outcomes after in-hospital cardiac arrest n Gentle wiping of face, nose, and mouth appears as effective as suction for clearance of secretions at birth of term neonates n For pressure ulcers, air-fluidized mattresses, protein supplements, radiant heat dressings, or electrical stimulation may improve healing

Anticoagulant proven useful against VTE 116

86 Consultations ■■Frozen shoulder susceptibility ■■Vaginal dryness and decreased libido caused by smoking ■■Nephrotoxic medications for patients on dialysis ■■And more 88 Clinical Pearls ■■Make pediatric exams all fun and games ■■Jump away from stomach pain

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Stages of pregnancy Pregnancy is measured in trimesters from the first day of a woman’s last menstrual period and normally lasts approximately 40 weeks from conception to the birth of the baby. This time is roughly divided into three periods: first trimester, second trimester, and third trimester. Learn more about the stages of pregnancy in this slideshow.

Prostate biopsy causes anxiety even when negative Potential psychological harm associated with biopsy even in absence of cancer diagnosis.

Parents want e-mail consults for pediatric illnesses About half of parents feel that the co-pay for an e-mail consultation should be $0.

Flu vaccine lowers risk for cardiac events Getting a flu shot was associated with lower risk for cardiac events, with the effect more pronounced in those with more active coronary disease.

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

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Robyn Carlisle, MSN, CNM, WHNP Trusting your instincts in medicine Medical knowledge and clinical skill are imperative, but most medical providers will tell you that there are times when instinct trumps fact.

Leigh Montejo, MSN, FNP-BC Insurance exchanges encourage patient autonomy Too often, patients rely on the provider to “fix” them, signifying an unwillingness to be participants in their own care.

Jim Anderson, MPAS, PA-C, ATC I, Politician?

As I consider running for the American Academy of Physician Assistants Board of Directors, it’s a good time to review the benefits of grassroots politics.

Yellow plaques with vision loss A visually impaired patient presents with subtle yellow plaques in the inguinal folds.

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Robyn Carlisle, MSN, CNM, WHNP Managing family members’ expectations In many instances, it is not enough to meet the patient’s needs: Clinicians must also deal with family members and their expectations.

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Newsline

Weight loss and CPAP advised for sleep apnea page 28

N O V E M B E R 2 0 13

Inhaled steroids can invite more pneumonia page 31

Men more often hospitalized for UTI treatment page 39

© SCIENCE SOURCE / DU CANE MEDICAL IMAGING

Studies look at hormones and health risks

Estrogen therapy raised risk for pulmonary embolism (orange).

events and all-cause mortality, but that compared with conventionaldose oral CEE, oral estradiol may be assoicatied with a lower risk for stroke, and transdermal estradiol may be associated with a lower risk for coronary heart disease.

As the researchers emphasized in the journal Menopause, additional research is needed to confirm these hypotheses.

In a smaller study focusing on 384 postmenopausal women aged 30 to 79 years old, Nicholas L. Smith, PhD, and colleagues uncovered a greater risk for venous thrombosis among women who used CEE compared with women who used estradiol. As the authors noted in JAMA Internal Medicine, CEE users also were found to have an increased but statistically nonsignificant risk for myocardial infarction, and no increased risk for ischemic stroke.

Percentage of adults who use prescription sleep aids About 4% of U.S. adults aged 20 years and older used prescription sleep aids in the past month.

8

7.0 6.0

6

Percent

SEVERAL recent research efforts have yielded more information as to how estrogen therapy affects a woman’s risks for various cardiovascular events and other medical conditions.

Extended follow-up data from the two Women’s Health Initiative (WHI) trials on menopausal hormone therapy prompted investigators to conclude that the findings do not support use of this treatment for the prevention of cardiovascular disease or other chronic disease ( JAMA. 2013; 310[13]:1353-1368). Among postmenopausal women with an intact uterus, use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) compared with placebo heightened the risks for coronary heart disease, stroke, and pulmonary embolism, as well as for invasive breast cancer, dementia (in women aged 65 years and older), gallbladder

disease, and urinary incontinence.

This regimen did, however, reduce the risks for hip fractures, diabetes, and vasomotor symptoms. Most of those risks and benefits dissipated when the intervention ended.

In the same study, women with prior hysterectomy who received CEE without MPA demonstrated more balanced risks and benefits. Compared with placebo users, these women still incurred increased risks for stroke and venous thrombosis but had a significantly lower risk for breast cancer, along with reduced risks for hip fractures and total fractures. A decrease in breast cancer emerged postintervention as well.

Separately, Chrisandra L. Shufelt, MD, MS, and colleagues used WHI data to determine that various doses and regimens of hormone therapy were associated with similar rates of cardiovascular

4.9

5.7

60-69

70-79

4.1

4 1.8

2 Source: CDC/NCHS, National Health and Nutrition Examination Survey

5.5

0

All

20-39

40-49

50-59

Age in years

80 and over

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

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Newsline WEIGHT LOSS as needed and therapy involving continuous positive airway pressure (CPAP) or mandibular advancement devices are the best treatments for obstructive sleep apnea (OSA) in adults, according to a new clinical practice guideline from the American College of Physicians (ACP).

In its clinical recommendations (Ann Intern Med. 2013;159:471483), the ACP advises that all overweight and obese individuals with a diagnosis of OSA be encouraged to lose weight.

Although CPAP should be used as initial therapy, mandibular advancement devices can be used as an alternative treatment to CPAP by patients who prefer such devices or who suffer adverse effects from CPAP therapy.

The guideline authors stated that they had insufficient evidence to determine the efficacy or comparative efficacy of several other treatments for OSA, including positional therapy vs.

CPAP; oropharyngeal exercise; palatal implants vs. sham implants in persons with mild to moderate OSA; surgical interventions compared with control treatment, or with CPAP, or with mandibular advancement devices; and atrial overdrive pacing (a potential treatment option for persons who already have dual-chamber pacemakers, which have incidentally been shown to improve symptoms of breathing disorders).

In a separate report, this one in JAMA Otolaryngology–Head & Neck Surgery, Andrea Nath, MD, and fellow researchers described

© SCIENCE SOURCE / MAURO FERMARIELLO

OSA guideline calls for weight loss, CPAP

Weight loss is advised in all obese people with OSA.

a high rate of residual OSA after adenotonsillectomy among children younger than age 3 years.

Predictors included severity of preoperative OSA as determined by polysomnogram results. The authors concluded that postoperative polysomnograms might be indicated in these patients.

BONE mineral density (BMD) testing as a means of predicting hip fractures or other major fractures added only limited value in older persons when the measurement was taken within four years after the previous one.

The population-based cohort study yielding this f inding involved 310 men and 492 women (mean age: 74.8 years) from the Framingham Osteoporosis study.

The participants had had two measures of femoral neck BMD, taken four years apart. None of the participants were being treated for osteoporosis.

Vitamin D did not improve BMD at the hip, spine, or forearm.

Throughout a median follow-up of 9.6 years, the average change in BMD was –0.6% per year. A total of 113 (14.1%) participants experienced major osteoporotic fractures of the hip, forearm, spine, and shoulder.

However, the change in BMD provided little additional information beyond baseline BMD for the clinical management of osteoporosis. The second measurement reclassified a small proportion of persons as being at risk for osteoporotic fracture, but the reclassification may be too small to justify the common clinical

practice of repeating a BMD test every two years ( JAMA. 2013; 310[12]:1256-1262).

Separately, a large meta-analysis indicated that the widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate. Ian R. Reid, MD, and colleagues reported in The Lancet that among more than 4,000 healthy adults, vitamin D supplementation did not improve total hip, spine, or forearm BMD, or BMD in the body as a whole.

© SCIENCE SOURCE / WILL & DENI MCINTYRE

Repeat bone testing may not predict fractures

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

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Newsline Inhaled Treating unhealthful behaviors steroids and pneumonia

Intervene directly to help adopt more healthful lifestyles.

needs of the entire population more effectively.

According to the advisory, fostering healthy lifestyle change may resemble a two-tiered, steppedcare model. In the first service tier, clinicians provide low-intensity “5As” intervention (Assess the risk behavior, Advise change, Agree on an action plan, Assist with treatment, and Arrange followup). In the second service tier, the interdisciplinary team collaborates to draw on community- and technology-based resources that can provide intensive behavioral intervention to patients who are at moderate and high levels of cardiovascular risk.

The statement includes several suggestions for approaches clinicians can take to help a person adopt more healthful behaviors, such as avoiding the use of commanding language when speaking; encouraging the patient to adopt specific, attainable goals; and scheduling regular follow-up to assess the patient’s progress.

Vitamin B may protect against stroke VITAMIN B supplementation for homocysteine reduction significantly decreased stroke events in a large meta-analysis described in Neurology (2013;81[15]:12981307): Investigators observed a 7% reduction in overall stroke events resulting from lowered homocysteine levels following supplementation with vitamin B. No such risk reduction was seen in subgroups divided according to primary or secondary prevention measures, ischemic vs.

hemorrhagic stroke, or occurrence of fatal stroke, however.

Vitamin B supplementation did have beneficial effects on stroke reduction in subgroups that had at least three years of follow-up time, no background of cereal folate (vitamin B9) fortification, and no chronic kidney disease. The intervention also showed stroke-reduction benefits for persons with systolic BP >130 mm Hg and lower antiplatelet drug use.

© THINKSTOCK

ACCOR DI NG t o recent research, inhaled corticosteroids increase the risk of recurrent pneumonia among high-risk pneumonia survivors (Clin Infect Dis. 2013;57[8]:1138-1144).

In the case-control study, clinical and five-year follow-up data were collected on persons aged 65 years and older (mean age: 79 years) who had had pneumonia. Overall, 123 of 870 (14%) current users of inhaled corticosteroids experienced recurrent pneumonia during the follow-up period, compared with 395 of 4,603 never-users (9%).

Compared with never-use of inhaled corticosteroids, use of these agents was associated with a 90% relative increase in risk for recurrent pneumonia among seniors who had survived an initial episode but were still at high risk for developing another bout.

However, no association existed between past use of inhaled corticosteroids and pneumonia, with 9% of past users and 9% of neverusers experiencing pneumonia recurrence.

In a statement accompanying the findings, Dean T. Eurich, PhD, who led the study, noted that given the emerging evidence on inhaled corticosteroids, “Health professionals have to use their clinical judgment to try and determine which patients should remain on the drugs, especially for patients with pneumonia.”

CLINICIANS should focus as much on behavior changes as on biomarkers when working to improve patient health, according to a science advisory from the American Health Association (AHA) that includes ideas for accomplishing this goal.

In “Better Population Health Through Behavior Change in Adults: A Call to Action,” published by Circulation, Bonnie Spring, PhD, and other members of various AHA committees who authored the policy statement urge providers to help patients achieve sustained improvements in tobacco use, obesity, poor-quality diet, and physical inactivity. Two main steps are recommended: First, clinicians should intervene directly and as members of an interprofessional health-care team to help individuals adopt more healthful lifestyles. Second, clinicians should advocate for health-care system and policy improvements to address the behavior-change

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2013 31

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Newsline SCREENING colonoscopy and screening sigmoidoscopy were associated with reduced mortality from colorectal cancer, but only colonoscopy was associated with reduced mortality from proximal colon cancer in a recent study.

Among 88,902 persons participating in the Nurses’ Health Study and the Health Professionals Follow-up Study, 85% had an endoscopic colon exam over 22 years of follow-up. A total of 1,815 cases of colorectal cancer developed, and 474 disease-related deaths occurred.

Both colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy also was associated with a modest reduction in the incidence of proximal colon cancer. Reduced

mortality from proximal colon cancer was observed after screening colonoscopy, but not after sigmoidoscopy.

Reiko Nishihara, PhD, of the Dana-Farber Cancer Institute in Boston, and fellow investigators also reported in The New England Journal of Medicine that persons who had no findings on colonoscopy had a much lower risk for colorectal cancer for as long as 15 years, which supports the standard recommendation that persons should undergo a colonoscopy every 10 years beginning at age 50 years.

Primary-care clinicians are key to the prevention of colorectal cancer incidence and death in older adults, by increasing screening rates among such patients.

Data from Medicare beneficiaries and control patients aged 67 to

© SCIENCE SOURCE / AJ PHOTOS

Colonoscopy remains best for prevention

Colonoscopy reduced mortality from proximal colon cancer.

85 years revealed that compared with persons who had zero or one primary-care visits in the 4-to27-month period before receiving a diagnosis of colorectal cancer, persons with five to 10 visits had lower incidence of and mortality from the disease (Ann Intern Med. 2013;159[7]:437-446).

TEN YEARS after reaching a similar conclusion, the United States Preventive Services Task Force (USPSTF) has again found insufficient evidence to recommend for or against routine screening for primary hypertension in asymptomatic children and adolescents to prevent subsequent cardiovascular disease in childhood or adulthood.

In seeking to update the childrelated portion of the 2003 recommendation on screening for high blood pressure, the USPSTF found inadequate evidence to change its stance from the earlier

Elevated BMI is a risk factor for high BP in children and adolescents.

document, when the group found insufficient evidence to assess the balance of benefits and harms of blood pressure screening for asymptomatic youths.

As noted in the new recommendation statement, authored by Virginia A. Moyer, MD, MPH, on behalf of the USPSTF and available in both Annals of Internal Medicine (annals.org/article. aspx?articleid=1747317, accessed October 15, 2013) and Pediatrics, the strongest risk factor for primary hypertension in children and adolescents is elevated body mass index. Other risk factors listed by

the USPSTF are low birth weight, male sex, ethnicity, and a family history of hypertension.

According to the USPSTF, blood pressure screening with sphygmomanometry may identify children and adolescents with hypertension with reasonable sensitivity, but false-positive results may occur with normalization of subsequent blood pressure measurements. Stage 1 hypertension in children is treated with lifestyle and pharmacologic measures, although medications are not recommended as first-line therapy.

© THINKSTOCK

USPSTF still won’t push youth BP screening

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

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Newsline THE RESULTS of a recent retrospective case-control study suggest that only three nodule characteristics found on thyroid ultrasound imaging are associated with risk for thyroid cancer.

A total of 11,618 thyroid ultrasound examinations performed in 8,806 persons yielded 105 diagnoses of thyroid cancer. Thyroid nodules were common among persons who received a thyroid cancer diagnosis (96.9%), and also in patients who did not (56.4%).

The on ly nodu le-related ultrasound findings associated with thyroid cancer risk were

microcalcifications, size >2 cm, and solid rather than cyst-like composition. Rebecca SmithBindman, MD, and fellow investigators wrote in JAMA Internal Medicine that if one of those three characteristics were to be used as an indication for biopsy, most cases of thyroid cancer would be detected (sensitivity 88%), with a high false-positive rate (44%) and a low positive likelihood ratio (2.0), and 56 biopsies would be performed for each cancer diagnosis. If two of the characteristics were required for biopsy, the sensitivity rate would be lower (52%),

© SCIENCE SOURCE / MEDICAL BODY SCANS

Few thyroid findings call for biopsy

CT shows an abnormal left lobe of the thyroid (red).

but so would the false-positive rate (7%); the positive likelihood ratio would be higher (7.1), and only 16 biopsies would be performed per cancer diagnosis.

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Newsline

Illustration shows bacteria (blue) in the urinary tract.

Sammon and colleagues analyzed national data on individuals presenting to emergency departments in the United States between 2006 and 2009 seeking UTI treatment. In one of those years alone—2007—more than 8.6 million outpatients visits

were made for UTI (23% made to emergency departments), with 84% of those visits being made by women.

Of the 10.8 million patients presenting for UTI treatment throughout the study period, 1.8 million (16.7%) were admitted to the hospital for further management. Admitted patients were older, had a higher proportion of pyelonephritis, were male, and had Medicare. After multivariable analysis, the independent predictors of hospital admission included pyelonephritis, male gender, and advancing age. n

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CLINICIANS typically see more women than men with a primary diagnosis of urinary tract infection (UTI), but men are more often hospitalized for the condition.

“UTIs are especially common in women, with half of women reporting having had at least one by age 32 [years],” affirmed Jesse D. Sammon, DO, in a statement in World Journal of Urology.

However, “We found that those patients who were hospitalized for treatment of urinary tract infections were most often older men, as well as [persons] with serious kidney conditions.”

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important risk and safety information: Published clinical trial results support the use in children three years of age and older. Do not use on large areas of damaged skin, puncture wounds, animal bites or serious wounds. Do not spray in eyes. Over spraying may cause frostbite. Freezing may alter skin pigmentation.

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© SCIENCE SOURCE / DAVID MACK

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CA1113_Newsline.indd 39

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DrugUpdate Long-term, once-daily COPD treatment Product: Breo Ellipta Company:

GlaxoSmithKline Pharmacologic class: Corticosteroid + longacting b2-agonist Active ingredients: Fluticasone furoate 100 µg, vilanterol 25 µg; per inhalation; dry powder for oral inhalation.

Indication: Long-term maintenance treatment of airflow obstruction in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

To reduce exacerbations of COPD in patients with a history of exacerbations.

Limitations of use: Breo Ellipta is not indicated for relief of acute bronchospasm or for the treatment of asthma.

Pharmacology: Fluticasone furoate is a synthetic trifluorinated corticosteroid with antiinflammatory activity.

Vilanterol, a long-acting b2-agonist, relaxes bronchial smooth muscle and inhibits the release of

mediators of immediate hypersensitivity from cells, especially from mast cells.

Clinical trials: The safety and efficacy of Breo Ellipta were evaluated in 7,700 subjects with COPD in four confirmatory trials of six and 12 months’ duration, three 12-week active comparator trials,

and dose-ranging trials of shorter duration.

Trials 1 and 2 were 24-week, randomized, double-blind, placebocontrolled trials that evaluated the efficacy of Breo Ellipta on lung function in patients with COPD. In both trials, Breo Ellipta 100 µg/25 µg demonstrated a larger increase in the weighted mean forced expiratory volume in 1 second (FEV1) (0–4 hours) relative to placebo (Trial 1: 214 mL, 95% CI [161,

Breo Ellipta is approved for maintenance treatment of airflow obstruction in COPD.

266]; Trial 2: 173 mL, 95% CI [123, 224]) and fluticasone furoate 100 µg (Trial 1: 168 mL, 95% CI [116, 220]; Trial 2: 120 mL, 95% CI [70, 170]) at Day 168.

At Day 169, in both trials, Breo Ellipta 100 µg/25 µg demonstrated significant increases in trough FEV1 compared with placebo (Trial 1: 144 mL, 95% CI [91, 197]; Trial 2: 115 mL, 95% CI [60, 169]).

The comparison of Breo Ellipta 100 µg/25 µg with vilanterol did not achieve statistical significance.

For Trials 3 and 4 results or more clinical trial data, see full labeling.

Adults: One inhalation once daily. Rinse mouth after use.

Children: Not established.

Contraindications: Severe hypersensitivity to milk proteins.

Warnings/Precautions: Increased risk of asthmarelated deaths. Do not initiate in rapidly or acutely deteriorating COPD. Not for relief of acute bronchospasm. Not for use with other longacting b2-agonists. Do not exceed recommended dose. Prescribe a shortacting, inhaled b2-agonist Continued pg. 44

© SCIENCE SOURCE / SCOTT CAMAZINE

New drug information from the publishers of MPR

For more products, visit www.eMPR.com

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

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DrugUpdate Breo Ellipta from pg. 40

adrenal axis suppression, intraocular pressure, glaucoma, or cataracts.

Discontinue if paradoxical bronchospasm occurs; use alternative therapy.

Cardiovascular disease (especially coronary insufficiency, arrhythmias, hypertension). Convulsive disorders. Thyrotoxicosis.

Hyperresponsiveness to sympathomimetics.

Diabetes. Ketoacidosis.

Hypokalemia. Hyper­ glycemia. Moderate or severe hepatic impairment; monitor. Assess bone mineral density if risk factors

exist (e.g., osteoporosis, postmenopausal). Labor and delivery. Pregnancy (Category C). Nursing mothers.

Interactions: Caution with concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole). Caution with concomitant monoamine oxidase inhibitors, tricyclic antidepressants,

or drugs known to prolong the QT interval or within two weeks of discontinuing such agents (increased cardiac effects), potassium-depleting diuretics. Antagonized by b-blockers.

Adverse reactions: Nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis; risk of asthma-related death.

How supplied: Dry powder inhaler—30 doses n For more information, call 888.825.5249 or visit www.myBreo.com.

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

for acute symptoms; monitor for increased need. Monitor for signs/ symptoms of pneumonia. Immunosuppressed.

Tuberculosis. Systemic infections. Ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin or antiviral ­prophylactic therapies. Monitor for adrenal insufficiency when transferring from systemic steroids. Re-evaluate periodically. Monitor for hypercorticism and hypothalamic-pituitary-

“I don’t mind giving up the appearance of privacy to live with the illusion of safety.”

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44 THE CLINICAL ADVISOR • NOVEMBER 2013 • www.ClinicalAdvisor.com

CA1113_DrugUpdate_v2.indd 44

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FEATURE: MARY ROGERS SOREY, ACNP-BC

Gout management in patients with CKD The most recent guidelines from the American College of Rheumatology include pharmacologic and nonpharmacologic therapies for hyperuricemia.

G

out, a painful form of inflammatory arthritis, occurs in the setting of hyperuricemic monosodium urate crystals deposited in joints and tissues.1 Incidence of gout increases as kidney function decreases. Almost 40% of patients with gout have chronic kidney disease (CKD).2 The kidneys excrete uric acid, predisposing persons with CKD to hyperuricemia.

Unfortunately, these patients have contraindications to a number of agents used in the management of gout.3,4 In addition, thiazide and loop diuretics, medications that elevate serum uric acid levels, are often the first-line treatments for CKD.5 According to guidelines set forth by the American College of Rheumataology (ACR), CKD is an indication for urate-lowering therapy (ULT) in patients with a history of gout attacks or hyperuricemia.5 Each year 3.9 million patient visits are made for gout, and the majority of cases are managed by a primary-care provider (PCP).2 This article is designed to help guide PCPs in the management of gout in persons with CKD while reflecting the 2012 ACR recommendations.

Discussion

Tophi are solid deposits of monosodium urate crystals that form in the joints.

The ACR acknowledges that diet and lifestyle modifications alone are not likely to lower serum uric acid to therapeutic levels or serve as gout prophylaxis.5 The primary goals of diet and lifestyle changes are to promote overall health and better management of comorbidities. For all patients, the ACR task force recommends

46 THE CLINICAL ADVISOR â&#x20AC;˘ NOVEMBER 2013 â&#x20AC;˘ www.ClinicalAdvisor.com

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GOUT MANAGEMENT

Case study Mr. K, aged 45 years, presented with complaints of four acute gout episodes over the previous six months. Although he was not experiencing an active flare at the time of his visit, he had heard television ads encouraging people to discuss their gout with a practitioner. Mr. K’s gout had been well controlled with allopurinol (Aloprim, Lopurin, Zyloprim), but he stopped taking the medication. Mr. K followed medical nutrition therapy for diabetes, but drank one or two diet sodas daily. He also reported drinking a few beers on the weekend. Mr. K had no regular exercise regimen.

Medical history was significant for aspiration-proven gout, stage 3 CKD, type 2 diabetes, hypertension, obesity, and hyperlipidemia. Medications included losartan (Cozaar), hydrochlorothiazide, insulin glargine (Lantus), glimepiride (Amaryl), and atorvastatin (Lipitor). Significant physical exam findings included obesity (BMI 32), chronic tophi on the right olecranon and right hand, and elevated BP (137/84 mm Hg).

Pertinent labs showed elevated serum creatinine (2.0 mg/ dL), elevated estimated glomerular filtration rate (eGFR) (31 mL/min/1.73 m2), elevated serum uric acid (10.3 mg/dL), and elevated hemoglobin A1c (7.1%).

Mr. K’s treatment plan started with lifestyle modifications to limit his alcohol intake (especially beer), avoid sodas, increase exercise, and follow his diabetes diet more closely. The patient was also referred to a diabetes educator. Since hydrochlorothiazide is often an iatrogenic cause of gout attacks, this medication was stopped. Although the patient’s BP was >130/80 mm Hg and may necessitate a loop diuretic in the future, a decision was made to hold off on this step for now. Based on the Kidney Disease Outcomes Quality Initiative guidelines for BP control, a calcium channel blocker would be a reasonable substitution (Am J Kidney Dis. 2007;49[2 Suppl 2]:S12-S154). Another option would be to increase the losartan dosage, but monotherapy is rarely sufficient for BP control in an individual with CKD. Mr. K’s allopurinol was reinitiated (100 mg daily), coupled with overlapping colchicine (Colcrys) therapy (0.6 mg three times per week). The patient was also given a prescription for oral prednisone (50 mg tablet for three days with a 10-day taper) to be used for the next acute gout flare. Mr. K was advised to monitor his blood glucose closely and was asked to return in two weeks for follow-up blood tests and further titration of allopurinol, if needed.

weight loss if obese, overall healthful diet, exercise, smoking cessation, and good hydration.

While recognizing that an improved diet is insufficient monotherapy for most, the panel did recommend specific dietary guidelines. All gout patients are advised to limit intake of alcohol, particularly beer.5 Regardless of gout activity, alcohol overuse should be avoided in all patients. (The ACR defines alcohol overuse as more than one serving per day for women and more than two servings per day for men.)

Avoidance of food and sodas sweetened with high-fructose corn syrup is also recommended.

Both thiazide and loop diuretics promote hyperuricemia.3 The ACR suggests eliminating offending agents if deemed nonessential.5 However, both types of diuretics are often first-line choices for BP management in the CKD patient.6 Given the health-related quality-of-life concerns of many gout patients, substitution of a non-urate-elevating

antihypertensive should be considered whenever possible.5 Sufficient BP control is rarely achieved with monotherapy in the CKD patient.7 A diuretic may be required in the future to control BP and reduce extracellular fluid.

Table 1 describes the classification of CKD based on estimated glomerular filtration rate (eGFR). CKD stage 2 through stage 5 with hyperuricemia and a history of acute gout activity is, by itself, an indication to initiate ULT.5 The target serum uric acid should be <6 mg/dL. To achieve symptomatic relief, target serum levels may need to be 5 mg/dL. When initiating ULT, acute gout prophylaxis should be started simultaneously.8 The ACR addressed the misconception that ULT may not be initiated during active flares.5 As long as appropriate anti-inflammatory management is administered (e.g., oral corticosteroid taper), ULT can be started during acute flares.8 The xanthine oxidase inhibitors (XOIs) allopurinol and febuxostat (Uloric) are

For more news, opinion, and clinical features on gout and other rheumatic diseases, visit our Rheumatology Information Center at

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recommended as first-line ULT agents for patients with CKD. While cost was not taken into consideration in the ACR recommendations, restricting the use of febuxostat to those patients with an intolerance or a contraindication to allopurinol due to cost issues has been suggested.9 Probenecid (Benemid, Probalan) is a uricosuric agent recommended as an alternative ULT agent if XOIs are not tolerated or are ineffective. Probenecid is not recommended in patients with a creatinine clearance <50 mL/min.

For any patient, the initial dose of allopurinol should be <100 mg/day and <50 mg/day in patients with CKD stage 4 or stage 5.5 Starting at a low dose is a strategy designed to decrease gout flares associated with initiation of ULT and to lessen the risk of allopurinol hypersensitivity and other adverse reactions.8 Allopurinol should be increased every two to five weeks based on serum uric acid levels and clinical response. The maintenance dose can be >300 mg/ day, even in persons with CKD, as long as patients receive education and providers monitor for adverse events and hypersensitivity. Providers should monitor for pruritus, rash, elevated hepatic transaminases, and eosinophilia. There is an algorithm for dosing allopurinol based on creatinine clearance, but it was not recommended by the ACR because it is not evidence-based.5,10 Patient education is essential for successful treatment of gout in individuals with CKD. Once palpable tophi and symptoms of acute and chronic gout have dissipated, pharmacologic and nonpharmacologic ULT should be maintained indefinitely.5 PCPs should inform each patient that ULT has to be taken daily, especially when the person is symptom-free, to prevent recurrence. Allopurinol should be thought of as “the cure.”

Because lower serum uric acid levels are associated with less frequent acute flares, ULT is considered the mainstay in gout management. However, the initiation of ULT is also associated with increased acute gout attacks.8 Thus, prophylactic therapy should be started at the same time as or just prior to ULT. For patients with gout, the ACR recommends low-dose colchicine or low-dose nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line prophylactic agents.6 Low-dose oral prednisone and prednisolone are considered second-line agents. In patients with CKD, however, NSAIDs can cause acute worsening of eGFR and are contraindicated in all stages of CKD.11 Colchicine is excreted renally and can accumulate to toxic levels in renal impairment.12,13 Colchicine is not contraindicated, but dose adjustment and close monitoring are suggested.

Signs of toxicity include leukopenia, elevation of aspartate aminotransferase, and neuropathy.

POLL POSITION

Despite greater efficacy compared with allopurinol, does cost affect how you prescribe febuxostat?

4%

n Yes, I only prescribe it to patients with allopurinol intolerance or contraindication n No

n=109

96%

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

TABLE 1. GFR categories in CKD GFR category

GFR (mL/min/1.73 m2)

Terms

G1

>90

Normal or high

G2

60-89

Mildly decreased

G3a

45-59

Mildly to moderately decreased

G3b

30-44

Moderately to severely decreased

G4

15-29

Severely decreased

G5

<15

Kidney failure

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.

KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150.

The pain of an acute gout flare can be excruciating.

Pharmacologic therapy should be started promptly—preferably within 24 hours for the most effective relief.8 Oral corticosteroids provide relief of pain and inflammation and are a good choice for the patient with CKD. The ACR recommends prednisone 0.5 mg/kg for two to five days at full dose, then tapered over seven to 10 days and stopped.

Corticosteroids are not contraindicated in patients with diabetes, but blood glucose levels should be monitored.

Adjustments to glycemic agents may be needed.

Intra-articular corticosteroids are also appropriate for acute gout management.6 The size and number of joints involved, as well as practice setting, can limit this option. Since injections require an office visit, intra-articular injections are less convenient than oral medications, which can be initiated by patients at home when symptoms arise. If using intraarticular corticosteroids, the provider must confirm that the joint is not infected.

Continues on page 54

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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.

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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

10/7/13 4:45 PM

NEW in chronic weight management

Make weight loss matter Introducing 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

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.

BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH. BELV1022

© 2013 Eisai Inc.

All rights reserved.

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Printed in USA.

10/2013

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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: • 30 kg/m2 or greater (obese), or • 27 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

02-11099C_R02_BELVI_ASize_2single_pg_sprd.indd 3

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. Adverse 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)

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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

02-11099C_R02_BELVI_ASize_2single_pg_sprd.indd 4

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. BELV1022A © 2013 Eisai Inc. All rights reserved. Printed in USA. 10/2013

10/7/13 4:45 PM

GOUT MANAGEMENT

Conclusion

11. National Kidney Foundation. K/DOQI clinical practice guidelines for

In late 2012, the ACR published new guidelines for gout management. Part 1 of the guidelines is dedicated to the nonpharmacologic and pharmacologic management of hyperuricemia, and Part 2 addresses management of acute attacks and prophylaxis.5,8 In addition, the 2012 ACR guidelines emphasize recognizing comorbidities and discuss diet and lifestyle modifications, the elimination of offending agents, and therapy education. These guidelines also offer pharmacologic recommendations for the CKD patient with gout. n

chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266.

12. Ben-Chetrit E, Scherrmann JM, Zylber-Katz E, Levy M. Colchicine disposition in patients with familial Mediterranean fever with renal impairment. J Rheumatol. 1994;21:710-713.

13. Wallace SL, Singer JZ, Duncan GJ, et al. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout.

J Rheumatol. 1991;18:264-269.

14. Juraschek SP, Kovell LC, Miller ER 3rd, Gelber AC. Association of kidney disease with prevalent gout in the United States in 1988-1994 and 2007-2010. Semin Arthritis Rheum. 2013;42:551-561.

Ms. Sorey is a nurse practitioner in the nephrology division at Duke University Medical Center in Durham, N.C.

All electronic documents accessed October 15, 2013.

References 1. Choi HK, Mount DB, Reginato AM, et al. Pathogenesis of gout. Ann Intern Med. 2005;143:499-516.

2. Krishnan E, Lienesch D, Kwoh CK. Gout in ambulatory care settings in the United States. J Rheumatol. 2008;35:498-501.

3. Keenan RT, O’Brien WR, Lee KH, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011;124:155-163.

4. Fuldeore MJ, Riedel AA, Zarotsky V, et al. Chronic kidney disease in gout in a managed care setting. BMC Nephrol. 2011;12:36. Available at www.biomedcentral.com/1471-2369/12/36.

5. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic

“Are you happy with your current ball?”

nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-1446.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3683400/. practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 Suppl 2):S12-S154.

7. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1-S290.

8. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64:1447-1461. Available at www.ncbi.nlm.nih.gov/pmc /articles/PMC3662546/.

9. Stevenson M, Pandor A. Febuxostat for the management of hyperuricaemia in patients with gout: a NICE single technology appraisal.

Pharmacoeconomics. 2011;29:133-140.

10. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity.

Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984;76:47-56.

“Hi, Steve Smith here. Just calling to say hello and touch base. Well, bye.

Hi. Steve Smith here. Just calling to say hello and touch base. Well, bye. Hi…”

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

6. Kidney Disease Outcomes Quality Initiative (K/DOQI). KDOQI clinical

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FEATURE: BRADLEY J. WARR, PhD, MPAS, PA-C; REBECCA E. FELLIN, PhD; AND JOSEPH F. SEAY, PhD

A better understanding of barefoot running Research on the relationship between footwear and injury rates is limited. A switch to a minimalist shoe or barefoot running should be done gradually.

W

ith the increasing popularity of minimalist footwear and barefoot running, it is imperative that clinicians understand running mechanics and the potential implications of these footwear options.

Approximately 19 million Americans run at least 100 days per year.1 Although running is excellent cardiovascular exercise, a published systematic review reported that the incidence of lower-extremity injuries among runners ranged from 19% to 79%.2 In recent years, there has been a trend of runners switching from traditional running shoes to barefoot running or to minimalist shoes. This switch is likely driven by the possibility of increased performance3-5 and more important, the possibility of reducing injury.6-8 Up to 22% of runners have tried running barefoot, and 30% have reported using minimalist shoes.9

© THINKSTOCK

Understanding foot-strike patterns

Studies suggest that runners with lower impact-loading have reduced injury risk.

Rather than being a function of what is worn (or not worn) on the foot, the potential benefits of adopting a barefoot or alternative running style (e.g. Chi running, pose running, minimalist footwear)10 may have more to do with what part of the foot impacts the ground first. Running is often seen as a rapid series of footfalls generating high forces and impacts several hundred times per mile.

Impact-loading includes the vertical impact peak (indicated in Figure 1). Within this curve, claims of decreased injury have focused on a reduction of impact-loading, which consists of decreasing the loads and rate of loading shortly after foot strike. Impact-loading includes the vertical impact

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Vertical impact peak

RFS FFS MFS

Force (BW)

2

1

0

0

25

50

75

100

% Stance

FIGURE 1. Comparison of vertical ground reaction force traces for ­different foot-strike types (rearfoot [RFS], midfoot [MFS], and forefoot [FFS]) in shod runners during the stance phase of running. Note the difference in foot-strike types at the beginning of stance, where increased loading has been linked to injury. The peak force, which has not been linked to injury risk, is similar across foot-strike types.

a MFS or FFS pattern associated with an alternative running style will ultimately decrease impact loading.14,15 There are minimal data to describe the distributions of foot-strike patterns among recreational runners, as all of the data are from half-marathon or full-marathon races. Among marathoners, 75% to 89% ran with an RFS pattern, 3% to 24% ran with an MFS pattern, and only 1% to 2% ran with an FFS pattern.16,17 Certainly, a potential bias exists in the distribution numbers based on the study participants’ ability to train for and compete in a half-marathon or full marathon: Despite the increasing popularity of recreational road racing, only 2.2 million runners (including those running multiple races and international runners) completed half-marathons and/or full marathons in the United States during 2011.18,19 Since only a small percentage of American runners (<12%) run half- or full marathons, these reported distributions may not translate to all recreational runners.

Injury implications of foot-strike patterns

peak—which occurs shortly after foot strike before the center of mass is over the foot—and the rate of loading from foot strike to that peak. Research suggests that runners with lower impact-loading have reduced injury risk.6,7,11,12 The way the foot strikes the ground can be categorized into three distinct foot-strike patterns: (1) a rearfoot strike (RFS) pattern is a foot strike in which the heel, or rear third of the sole, is the first part of the foot to come in contact with the ground; (2) a midfoot strike (MFS) pattern is a foot strike in which the middle third of the sole makes contact with the ground first; and (3) a forefoot strike (FFS) pattern is a foot strike in which the third of the sole makes contact with the ground first.13 Different foot-strike patterns affect the profile of the force curve generated when the foot hits the ground, and this in turn affects the transmission of energy through the musculoskeletal system. As observed in Figure 1, the typical RFS is characterized by a pronounced vertical impact peak of the vertical ground reaction force, whereas the MFS and FFS patterns do not have a pronounced vertical impact peak.

The vertical impact peak, which occurs within the first 50 milliseconds of stance, results from the abrupt collision of the heel with the running surface. This collision causes part of the body’s mass to decelerate rapidly (i.e., the leg), while the rest of the body decelerates more gradually. Therefore, runners who land heel-first during a running stride (RFS) generate higher peak impact forces that are transmitted more rapidly throughout the musculoskeletal system compared with FFS runners.8,14,15 Because of this reduced impact-loading in MFS/FFS runners, it is hypothesized that runners who adopt

RFS with higher impact-loading appears to carry a higher risk of injury compared with RFS with lower impacts. Researchers have reported that RFS runners with retrospective tibial stress fractures had higher impact loads than did uninjured RFS runners.11 Additionally, a two-year prospective study found that RFS runners who sustained an injury of any type had higher impact-loading than did uninjured RFS runners.12 These studies suggest that even within RFS (and without changing foot-strike pattern), decreased impact-loading may reduce injury risk. As impact-loading is reduced in MFS and FFS runners, it has been theorized that running injuries can be mediated by changing one’s foot-strike pattern from RFS to MFS or FFS. To date, this conclusion has not been strongly supported by a large prospective study.

In contrast to RFS runners, experienced barefoot runners maintain an FFS pattern with a plantar-flexed ankle.15 Landing on the forefoot with a plantar-flexed ankle results in attenuation of peak impact forces when compared with running shod and utilizing an RFS pattern.15 A 2010 study found reduced impact-loading in barefoot runners compared with shod runners.14 Again, this reduction in peak impact force is not necessarily a function of running without shoes; it is more likely associated with which portion of the foot strikes the ground first. Although the authors of the 2010 study suggested that reduction in forces associated with an FFS pattern may reduce injury in runners, they acknowledged that there had only been anecdotal reports of injury reduction in barefoot runners.14 Only recently, a small retrospective analysis of 52 collegiate cross-country runners indicated that

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runners who utilized an RFS pattern experienced twice as many stress injuries as did those who utilized an FFS pattern.8 Altering foot-strike patterns

There is currently no justification for changing the foot-strike pattern in an asymptomatic runner. However, emerging evidence shows that changes to foot-strike patterns may be a useful tool for mitigating the effects of injuries related to running. In a case series of 10 individuals who suffered from chronic exertional compartment syndrome, all were able to change their running style from an RFS to an FFS pattern over a six-week period of supervised instruction.6 The changed running style resulted in decreased intracompartmental pressures as measured by an orthopedic surgeon using an intracompartmental pressure monitor. The subjects continued to run and train with a reduction in pain one year after the intervention began.6 In another case series, three runners underwent eight supervised sessions of gait-retraining over a two-week period to adopt a non-RFS pattern, which reduced their patellofemoral pain. The new patterns were maintained for at least three months with a reduction in pain.7 Researchers have utilized real-time audio and/or visual feedback to decrease impact-loading in runners.20 Some individuals changed from an RFS pattern to an FFS pattern, and others decreased loads while maintaining an RFS pattern.

Before recommending altering foot-strike patterns to mitigate injury, more research in larger cohorts of runners is necessary.

Other than the previously discussed studies, there is a paucity of literature supporting injury reduction in barefoot or alternative running styles. Other reports associating resolution of injury with alterations in foot-strike pattern have been anecdotal. Review articles have described the need for larger prospective studies to support more definitively the hypothesis that non-RFS runners are experiencing fewer injuries.21 No known large-scale studies systematically support either hypothesis. Larger-scale prospective studies are ultimately needed to determine the strength of relationship between foot-strike patterns and injury. Challengingly, these studies will need to control for running mileage, injury history, and other factors that may confound the results.

RFS runner changes from a traditional shoe to a minimalist shoe (or no shoe), landing on the heel will ultimately be too painful to maintain due to the lack of cushioning. One theory holds that in order to avoid heel pain and keep running, runners will naturally transition to MFS or FFS. A positive side effect of this pain and alteration of foot-strike pattern is the reduction in impact-loading with an MFS or FFS running style. Researchers have reported that lowerextremity kinematics while wearing minimalist shoes, such as Vibram FiveFingers, were similar to running barefoot in terms of peak impact forces, with a tendency to land on the forefoot with the ankle in plantarflexion.15 However, a nonpeer-reviewed study examining runners who had recently transitioned to minimalist shoes found that some runners maintained RFS patterns.22 Additionally, clinicians and researchers anecdotally report that this presumed alteration in foot-strike pattern does not always occur with a change in footwear. Therefore, transitioning to minimalist footwear or barefoot running may increase injury risk if runners increase their loads by maintaining an RFS pattern despite the reduced or eliminated heel-cushioning.

Transitioning from traditional footwear

Regardless of the science that supports or refutes the potential benefits, some patients will insist on running barefoot or with minimalist footwear. The clinician should inquire about the intentions and goals of such a patient to help him or her make a sound decision and avoid injury. When transitioning from a traditional running shoe, patients should be advised to proceed TABLE 1. Tips for transitioning from traditional running shoes Be patientâ&#x20AC;&#x201D;plan to make the transition over at least six to eight weeks.

Focus on landing softly on the forefoot, not on the heel.

Try running in place to get the feel for forefoot landings.

Take smaller strides with a faster step rate.

Run no more than 10% of your typical distance for the first two to three weeks.

Gradually increase mileage by 10% to 20% every couple of weeks.

Avoid running two days in a row for the first four weeks.

Minimalist footwear and barefoot running

Strengthen the leg and foot muscles.

Prior to the 1970s, endurance runners wore narrow, thinsoled shoes that would now be considered track flats. Since then, traditional running shoes have evolved to include a wide and thickly cushioned sole likely to reduce pain of repeated heel strikes in RFS. Barefoot running and minimalist shoes offer less heel-cushioning. It is postulated that when an

Stretch the calf, foot, and hamstrings after running.

Consistent soreness after several weeks indicates a need to rest and reduce mileage.

Stop running if you experience pain.

Adapted from Army Medicine. Minimalist running shoes. Available at www.armymedicine .army.mil/mrs/index.cfm, accessed October 15, 2013.

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gradually and to stop running if they experience pain (Table 1). The feet and lower extremities need time to adapt to the changes in loading patterns.23 Runners are advised to start by walking in the alternate shoe type and then cautiously add short periods of running. Some shoe companies have developed protocols for a safe transition from traditional footwear to the minimalist- or barefoot-style shoe.24,25 The common theme among the different protocols is a gradual progression in wear time for the newer type of shoe. Some protocols recommend that the transition occur over a six-to-eight-week period.24,26 However, these protocols have not been scientifically studied to examine injury risk during the transition. Patients should be warned that it may take longer for some to transition away from traditional footwear. Patients should also be alerted to the potential hazards of running barefoot in extremely hot and cold environments or on exceptionally rigorous surfaces that may increase risk of injury.

Even when the implications of such a transition are well understood, modifying one’s foot-strike pattern or making substantial changes in footwear is not without risk. There have been case reports of metatarsal stress fractures in experienced runners attempting to transition to barefoot-simulating footwear.27 However, stress fractures are a common injury in runners with traditional footwear, so it is difficult to determine if the new shoe caused the injury. Patients transitioning to barefoot running or minimalist shoes may experience foot and calf pain, muscle strains, blisters, cuts and abrasions, or plantar fasciitis.28 Even after a 10-week transition, runners using minimalist shoes had a significantly higher occurrence of bone-marrow edema identified by MRI when compared with a control group using a traditional running shoe.29

foot-strike pattern or to minimalist or barefoot running.

Individuals who insist on using minimalist footwear or on transitioning to barefoot running should be advised to make a gradual transition and to cease running in the event of pain. n Dr. Warr, Dr. Fellin, and Dr. Seay are clinical researchers with the U.S. Army Research Institute of Environmental Medicine, Military Performance Division, in Natick, MA. The opinions or assertions expressed in this article are the private views of the authors and are not the official views of the U.S. Army or the Department of Defense.

The authors would like to acknowledge Dr. Allison Altman for her contribution of data used in Figure 1. Research was supported in part by an appointment (Dr. Fellin) to the Postgraduate Research Participation Program funded by the U.S. Army Research Institute of Environmental Medicine and administered by the Oak Ridge Institute for Science and Engineering.

References 1. NY Daily News. Running more popular than ever in US; survey finds Americans running in record numbers. Available at www.nydailynews. com/life-style/health/running-popular-survey-finds-americans-runningrecord-numbers-article-1.1117641.

2. van Gent RN, Siem D, van Middelkoop M, et al. Incidence and determinants of lower extremity running injuries in long distance runners: a systematic review. Br J Sports Med. 2007;41:469-480. Available at bjsm.bmj. com/content/41/8/469.long.

3. Perl DP, Daoud AI, Lieberman DE. Effects of footwear and strike type on running economy. Med Sci Sports Exerc. 2012;44:1335-1343.

4. Hanson NJ, Berg K, Deka P, et al. Oxygen cost of running barefoot vs. running shod. Int J Sports Med. 2011;32:401-406.

5. Robbins SE, Hanna AM. Running-related injury prevention through barefoot adaptations. Med Sci Sports Exerc. 1987;19:148-156.

Conclusion

6. Diebal AR, Gregory R, Alitz C, Gerber JP. Forefoot running improves

Some recreational runners have begun switching from traditional running shoes for a multitude of reasons, including injury prevention, rehabilitation, improved performance, and even to alter their foot-strike pattern. Because clinical research is limited, it is difficult to predict how or if minimalist shoes or alterations in biomechanics may influence the musculoskeletal health of these runners. Limited studies show that FFS and MFS reduce peak impact forces that are transmitted through the skeletal system and may have different and possibly reduced injury profiles. Recent research indicates that runners with lower impact-loading have lower injury rates. However, no long-term research exists regarding altering foot-strike pattern (or footwear) and injury rates.

More research is needed before clinicians can routinely recommend that injured runners transition to an alternate

pain and disability associated with chronic exertional compartment syndrome. Am J Sports Med. 2012;40:1060-1067.

7. Cheung RT, Davis IS. Landing pattern modification to improve patellofemoral pain in runners: a case series. J Orthop Sports Phys Ther.

2011;41:914-919.

8. Daoud AI, Geissler GJ, Wang F, et al. Foot strike and injury rates in endurance runners: a retrospective study. Med Sci Sports Exerc.

2012;44:1325-1334.

9. Rothschild CE. Primitive running: a survey analysis of runners’ interest, participation, and implementation. J Strength Cond Res. 2012;26:2021-2026.

10. Goss DL, Gross MT. A review of mechanics and injury trends among various running styles. US Army Med Dep J. 2012;Jul-Sep:62-71.

11. Milner CE, Ferber R, Pollard CD, et al. Biomechanical factors associated with tibial stress fracture in female runners. Med Sci Sports Exerc.

2006;38:323-328.

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12. Davis I, Bowser B, Mullineaux DR. Do impacts cause running injuries? A prospective investigation. Presented at the American Society of Biomechanics 34th Annual Meeting; Providence, R.I.; August 2010.

Available at www.asbweb.org/conferences/2010/abstracts/472.pdf.

13. Cavanagh PR, Lafortune MA. Ground reaction forces in distance running. J Biomech. 1980;13:397-406.

14. Lieberman DE, Venkadesan M, Werbel WA, et al. Foot strike patterns and collision forces in habitually barefoot versus shod runners. Nature.

2010;463:531-535.

15. Squadrone R, Gallozzi C. Biomechanical and physiological comparison of barefoot and two shod conditions in experienced barefoot runners. J Sports Med Phys Fitness. 2009;49:6-13.

16. Hasegawa H, Yamauchi T, Kraemer WJ. Foot strike patterns of runners at the 15-km point during an elite-level half marathon. J Strength Cond Res. 2007;21:888-893.

17. Larson P, Higgins E, Kaminski J, et al. Foot strike patterns of recre-

“It’s designed to generate electricity by moving with fluctuations in the Dow.”

ational and sub-elite runners in a long-distance road race. J Sports Sci. 2011;29:1665-1673.

18. Running USA. Annual marathon report 2012. Available at www.runningusa.org/annual-reports.

19. Running USA. Annual half-marathon report 2012. Available at www.runningusa.org/annual-reports.

20. Crowell HP, Davis IS. Gait retraining to reduce lower extremity loading in runners. Clin Biomech (Bristol, Avon). 2011;26:78-83. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3014399/.

21. Jenkins DW, Cauthon DJ. Barefoot running claims and controversies: a review of the literature. J Am Podiatr Med Assoc. 2011;101:231-246.

22. The American Council on Exercise. Like barefoot, only better?

Available at www.acefitness.org/certifiednewsarticle/1641/.

23. Altman AR, Davis IS. Barefoot running: biomechanics and implications for running injuries. Curr Sports Med Rep. 2012;11:244-250.

“Am I to understand that my proposal is greeted with some skepticism?” © The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

24. Merrell. Merrell barefoot training plan. Available at www.merrell. com/~Uploaded/Assets/MERR/Files/Merrell_BarefootTrainingPlan.pdf.

25. Vibram FiveFingers. Barefoot running FAQs. Available at www.vibramfivefingers.com/faq/barefoot_running_faq.htm.

26. Army Medicine. Minimalist running shoes. Available at www.armymedicine.army.mil/mrs/index.cfm.

27. Giuliani J, Masini B, Alitz C, Owens BD. Barefoot-simulating footwear associated with metatarsal stress injury in 2 runners. Orthopedics.

2011;34:e320-e323.

28. Altman AR, Davis IS. Running-related injuries during the transition from shod to barefoot. Presented at the American College of Sports Medicine Annual Meeting; San Francisco, Calif.; May 31, 2012.

29. Ridge ST, Johnson AW, Mitchell UH, et al. Foot bone marrow edema after a 10-wk transition to minimalist running shoes. Med Sci Sports Exerc.

2013;45:1363-1368.

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“Call Jane.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2013 73

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CME CE

PROGRAM OUTLINE NOVEMBER 2013

0.5 CREDITS

Page 76 FEATURE Identifying and addressing infant allergy to cow’s milk protein Jae Kim, MD, PhD Jae Kim, MD, PhD, has no relationships to disclose relating to the content of this article.

■■ LEARNING OBJECTIVES: • Identify presence of cow’s milk protein allergy (CMPA) in infants.

• Counsel parents of infants with CMPA on appropriate nutrition options.

0.5 CREDITS

Page 103 DERMATOLOGY CLINIC Red coalescing lesions on the chest Dustin Larsen and Julia R. Nunley, MD Dustin Larsen and Julia R. Nunley, MD, have no relationships to disclose relating to the content of this article.

Peeling rash 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 111 DERMATOLOGIC LOOK-ALIKES Young boys with desquamating skin Christopher Chu and Adam Rees, MD Christopher Chu and Adam Rees, MD, have no relationships to disclose relating to the content of this article.

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

Page 85, 115 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 November 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

n EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Identify presence of cow’s milk protein allergy (CMPA) in infants.

• Counsel parents of infants with CMPA on appropriate nutrition options. n COMPLETE THE POSTTEST: Page 85 n ADDITIONAL CME/CE CREDIT: Pages 103, 111

FEATURED COURSE

Turn to page 75 for additional information on this month’s CME/CE courses.

This activity is supported by an educational grant from Mead Johnson Nutrition and jointly sponsored by Medical Education Resources (MER), Nurse Practitioner Associates for Continuing Education (NPACE), and Haymarket Medical Education (HME).

Faculty Jae Kim, MD, PhD Assistant Clinical Professor of Pediatrics University of California, San Diego San Diego, CA Release Date: November 2013 Expiration Date: November 2014 Estimated time to complete the educational activity: 30 minutes Target Audience: This activity has been designed to meet the educational needs of Primary Care Physicians, Pediatricians, Physician Assistants, Nurse Practitioners, and Dieticians.

Physician Credit: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of MER and HME. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: MER designates this educational activity for a maximum of 0.5 AMA PRA Category 1 creditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Dietician Credit: Medical Education Resources (Provider Number ME110) is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered Dieticians (RDs) and Dietetic Technicians (DTRs) will receive 0.5 continuing professional education unit (CPEU) for completion of this program/material.

Nursing Credit: 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 (ANCC).

Credit Designation: NPACE designates this educational activity for a maximum of 0.5 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

Disclosure Policy—MER MER ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure that all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high quality CME activities that promote improvements or quality in health care and not the business interest of a commercial interest.

Disclosure Policy—NPACE NPACE is committed to ensuring all educational activities are balanced and free from bias. All faculty participating in our programs disclose any relationships they may have with commercial interest whose products or services are related to the content of the activity. NPACE’s status as an accredited

provider of continuing nursing education does not imply endorsement by NPACE or ANCC of any commercial products discussed in conjunction with this program. NPACE maintains content integrity and prevents bias in the presence of commercial support through: 1) disclosure by activity planners, authors and content reviewers of relevant relationships with any commercial interest, or lack thereof; 2) disclosure of commercial support; 3) removal individuals with conflict of interest from the activity; 4) revising the role of the individual with the conflict so that the relationship is no longer relevant to the activity; 5) not awarding contact hours for a portion or all of the activity; 6) undertaking review of the activity by a content reviewer to evaluate for bias, balance, evidence-based content or other indicators of integrity; 7) monitoring the activity to evaluate for bias; and/or 8) reviewing participant feedback.

Faculty Disclosures Jae Kim, MD, PhD, has no financial relationships to disclose.

Staff/Planners’ Disclosures Joe Kopcha, Marina Galanakis, Krista Sierra, Susan Basilico, and Marjorie Hale of HME have no financial relationships to disclose.

MER Content Manager has no financial relationships to disclose. Marjorie Crabtree, MSN, DNP; Karen Windle, RNC, MS, MHNP-BC; and R. Mimi Secor, MS, Med, FNP-BC, FAANP, of NPACE have no financial relationships to disclose.

Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period November 2013 through November 2014, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online. Physicians may register at www.myCME.com (November 2013); and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER, NPACE, HME, or Mead Johnson Nutrition. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER, NPACE, HME, and/or Mead Johnson Nutrition. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

Jointly sponsored by

Commercial support for this activity was provided through an educational grant from

®

Nurse Practitioner Associates

for Continuing Education

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JAE KIM, MD, PhD

SAFETY FIRST IN INFANT FEEDING

Identifying and addressing infant allergy to cow’s milk protein Cow’s milk protein allergy is relatively common during the first year of life.

Unfortunately, the condition is easily missed or mislabeled.

T

he prevalence of food allergy has been as high as 19% to 35% by parental reporting in epidemiologic studies, but only 2% to 8% by objective diagnosis by food challenge.1 In the United States, food allergies occur in 6% to 8% of younger persons and 2% of adults. Food allergies are an important component of the “allergic march,” since they often precede, and may potentially promote, the development of other allergic diseases, including allergic rhinitis and asthma.1,2 Cow’s milk protein allergy (CMPA) is a common food allergy with an estimated prevalence of 2% to 3% in the first year of life.3 CMPA can occur in both breastfed and formulafed infants, as well as when cow’s milk is introduced into

the diet.4 Due to differences in diagnostic criteria and symptoms that often mimic other allergic diseases, CMPA is easily missed or mislabeled in the primary-care setting.4,5 Furthermore, despite the high prevalence of suspected food allergy (including CMPA) by parental reports, relatively few parents or caregivers seek medical care for their children’s food problems.1 Thus, there is a need for parents, caregivers, and clinicians to recognize CMPA as a condition with diverse clinical symptoms and a significant cause of infant distress and to increase their awareness of the factors that contribute to the development of CMPA as well as the importance of an accurate diagnosis.

Case study

© ISTOCKPHOTO

Mark B. is an 8-week-old infant whose parents believe may have some type of gastrointestinal (GI) disorder. Mark’s mother breastfed him from birth to age 6 weeks. Since he was born, Mark has experienced intermittent spitting-up and diarrhea; he cries and seems to be in pain after almost every feeding. His previous pediatrician observed that Mark was gaining weight and suggested that the boy was being breastfed too frequently. Mark’s mother started allotting more time between feedings, and his symptoms nearly disappeared. She recently returned to work and began feeding her son traditional ready-to-feed formula. Over the past week, the boy’s GI symptoms have returned, and he has now developed mild eczema on the backs of his elbows and knees.

Frequent skin rashes, such as eczema, can be a symptom of food allergy.

Immunopathogenesis and multifactorial pathophysiology of CMPA

CMPA develops as an immunologic reaction to one or more milk proteins, which distinguishes the condition from lactose intolerance and other adverse reactions to cow’s milk protein www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2013 77

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COW’S MILK PROTEIN ALLERGY

(CMP).4 CMPA may be mediated by immunoglobulin (Ig) E or by non-IgE factors.1,4,5 IgE-mediated reactions involve relatively simple immunologic mechanisms, eliciting symptoms from several minutes to several hours after contact with the allergen and termed “immediate hypersensitivity” reactions.6 In CMPA, the first stage of an IgE-mediated reaction involves sensitization, in which an aberrant secretion of antibodies against CMP bind to the surfaces of mast cells and basophils.6 Subsequent exposure to milk proteins triggers activation of the mast-cell-bound IgE and a rapid release of inflammatory mediators (e.g., histamine, platelet-activating factor, and others) to produce the allergic reaction.6 A substantial proportion of children with suspected CMPA do not have high levels of cow’s-milk-specific IgE anti­ bodies, resulting in negative results on skin-prick and serum-antibody tests; thus, these children have a non-IgEmediated reaction.6 In these individuals, the CMPA reaction is characterized by a delayed onset of symptoms from one hour to many days after ingestion of CMP.6 These delayed hypersensitivity reactions are thought to be mediated by T helper 1 (Th1) cells, interactions between T lymphocytes, or mast cell and neuronal-mediated changes in intestinal motility.6 There is considerable evidence to suggest a direct relationship between non-IgE-mediated reactions and age, since a high proportion of non-IgE-mediated reactions resolve in children but there is a high prevalence of these reactions in adults.6 The immune system also regulates the balance between oral tolerance and hypersensitivity to CMP through the complex actions of other mediators produced by T lymphocytes.6 Suppression of reactive antigen-specific T-cells and production of T regulatory cells that inhibit the inflammatory response appears to occur in both IgE- and non-IgE-mediated reactions.6 In addition, T-cell dysfunction plays a major role in the lack of tolerance to CMP, while the development of T-cells in childhood is associated with increased tolerance.6 Role of genetics and socioenvironmental factors in the development of CMPA

As with other allergic diseases, both genetics and environmental factors play a role in the development of CMPA.3 The critical time for these factors to come into play with CMPA is in early infancy or even during pregnancy. 3 According to the American Academy of Pediatrics (AAP), children with a first-degree relative with atopic disease are at high risk for developing allergic disease.7 This risk is increased by 20% to 40% with one atopic parent or 25% to 35% with an atopic sibling to as much as 40% to 60% if both

parents have documented allergic disease.4 Although genetic factors account for an estimated 50% to 70% of allergy and asthma, most children who become atopic in their early years are from families with no history of allergy.7 Whether breast milk can protect against the development of food allergy and other atopic diseases has been examined in a number of studies.8,9 Breastfeeding can protect infants of mothers without atopic disease against allergies, but there is little evidence to support maternal dietary restrictions during pregnancy or lactation as a means of preventing the development of food allergy in infants.8 On the other hand, mothers with atopic disease tend to have higher levels of cytokines and chemokines associated with allergy in their breast milk and a lower level of a specific cytokine that promotes tolerance to foods, which may increase the risk that the infants of these mothers develop food allergies during lactation.7,9,10 Sensitization to food allergens occurs primarily in the first year of life, and CMPA is often the first allergy to appear in sensitized infants.7 A number of prenatal and perinatal factors may contribute to an increased risk of development of CMPA.3 In a Swedish population-based study, infants of mothers aged 30 to 34 years at delivery were 58% more likely to develop CMPA than were babies born to mothers younger than age 25 years, and cesarean section increased the risk by 18% compared with vaginal delivery.3 In contrast, a greater number of previous deliveries, multiple pregnancies, and smoking were associated with about a 30% lower risk.3 Other factors that may increase the risk for food allergy include prematurity and low birth weight, although study results are inconsistent.3 Socioeconomic factors also seem to contribute to the development of food allergy. In the Infant Feeding Practices Study II (IFPS II) of 2005-2007, a survey of 2,441 U.S. mothers of healthy singletons younger than age 1 year, several demographic, maternal, and family history characteristics were associated with probable food allergy in the infants, including higher maternal education; living in rural or urban areas; black race; male gender; and a family history of food allergy, type 1 diabetes, or obesity.1 Challenges in diagnosing CMPA

The foundation of CMPA diagnosis is a comprehensive history—including a family history of atopic disease—a careful physical examination, and allergy testing.4,11,12 Unfortunately, no single symptom is indicative of CMPA, a factor that contributes to the difficulties distinguishing CMPA from nonallergic food problems and other allergic conditions.1,4

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The most frequently reported symptoms of CMPA (Table 1) are manifested in the GI tract (50% to 60%), skin (50% to 60%), and respiratory tract (20% to 30%), and usually target more than one organ or system.2,4,12 Symptoms often occur within the first few weeks after introduction of CMP and may be mild, moderate, or severe based on subjective parental descriptions.4,12 Infants also may exhibit persistent distress or colic for several hours a day at least three days a week to suggest an allergic reaction.4 The timing and pattern of symptoms can aid in a differential diagnosis.4 A child with IgE-mediated CMPA typically presents with urticaria, vomiting, cough and wheeze, and less commonly, hypotension, within one to two minutes of ingesting cow’s milk.5 Non-IgE-mediated reactions to cow’s milk may present with predominantly GI symptoms—repetitive vomiting with or without diarrhea, abdominal pain, and bloody stools—that develop several hours after ingesting cow’s milk.5 Atopic dermatitis is sometimes associated with food-specific IgE-reaction, and a worsening of eczema is often considered an expression of CMPA.5 Skin-prick tests for determination of specific IgE can be performed, but these tests indicate sensitization to the substrate and are not necessarily proof of an allergic reaction.12 Patch tests may be helpful in the diagnosis of non-IgEmediated reactions.12 The double-blind, placebo-controlled food challenge is the gold standard for the diagnosis of CMPA.11,12 Because such testing is expensive and timeconsuming, however, open food challenge is often used in clinical practice.12 CMPA should be differentiated from other diagnoses, including allergic reactions to other foods (e.g., eggs, soy,

and wheat) or environmental substances, infection, anatomic abnormalities, metabolic abnormalities, celiac disease, pancreatic insufficiency (e.g., as in cystic fibrosis), malabsorption syndromes, and malignancy.5 Comorbid allergic reactions to soy, wheat, peanuts, eggs, fish, and other foods may occur with CMPA, depending on regional dietary practices.5 Symptoms of CMPA also can exist concomitantly with gastroesophageal reflux disease.5 Colic should be considered during the differential diagnosis, although about 10% of formula-fed infants with CMPA have colic episodes as a symptom.5 In addition, atopic dermatitis may exist with CMPA in some infants, particularly in younger infants with more severe atopic dermatitis.5 Parents, caregivers, and clinicians have different perceptions of food allergy and difficulty in recognizing the symptoms.1 In the IFPS II, the mothers of 502 of the 2,441 infants (20%) reported food problems, but fewer than half the infants (200 infants, or 40%) were taken to a clinician for diagnosis and even fewer (123 infants, or 25%) were tested for food allergy. Of the infants seen by a clinician, 6% were considered to have a probable food allergy, and 15% had such other food-related problems as allergy to eggs, peanuts, or wheat. Cow’s milk, including cow’s milk infant formula, was the most common cause of food-associated problems in 95% of the infants diagnosed with probable food allergy.1 Irritability and GI symptoms were common in these infants; they also were more likely to have respiratory congestion.1 Mothers were more likely to report rash or eczema, hives, swollen eyes or lips, and other skin-related symptoms in the infants diagnosed with food allergy.1 Continues on page 80

TABLE 1. Clinical manifestations suggesting CMPA Organ system

Severe manifestations

Moderate-to-mild manifestations

GI

Failure to thrive Iron deficiency anemia Enteropathy

Regurgitation and vomiting Diarrhea Constipation Colitis Colic/abdominal pain

Skin

Exfoliation/severe atopic dermatitis

Atopic dermatitis Angioedema Urticaria Swollen lips

Respiratory tract

Laryngeal edema

Rhinitis Conjunctivitis Wheezing

General

Anaphylaxis

Irritability

Adapted from De Greef E, Hauser B, Devreker T, et al. Diagnosis and management of cow’s milk protein allergy in infants. World J Pediatr. 2012;8:19-24.

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CME CE

COW’S MILK PROTEIN ALLERGY

CMPA is often overdiagnosed among children with food allergy symptoms. A study of 381 infants exhibiting a possible adverse reaction to cow’s milk found that 243 of them (64%) were mislabeled with CMPA.5 Almost 30% of infants with mislabeled reaction presented within the first month of life, and nearly half presented in the first two months, compared with only 9% and 20% of infants with IgE-confirmed CMPA, respectively (Figure 1). The symptoms in most infants with mislabeled CMPA involved a single organ, primarily GI or skin; in contrast, IgE-confirmed CMPA affected several organ systems, signif icantly more skin and respirator y symptoms, and significantly fewer nonspecific symptoms.5 Health-care providers attributed the symptoms to cow’s milk in more than half the infants with mislabeled CMPA. Clinician-diagnosed atopic dermatitis was associated with mislabeled CMPA in 15.3% of infants, compared with only 4.7% of infants with IgE-mediated CMPA.5 Management strategies for infants and children with CMPA

Breast milk provides the ideal nutritional, immunologic, and physiologic nourishment for all newborns while promoting maturation of the infant’s immune system.7 However, breastfeeding exclusively for the first four to six months of life reduces

the risk for CMPA and minimizes the most severe allergic manifestations during early childhood.4,7,12 In addition, CMPA can develop in breastfed infants, and different management strategies that take into account the severity of symptoms are required for these breastfed and formula-fed infants.4 Only about 0.5% of infants exclusively breastfed exhibit a clinical reaction to CMPA, usually with mild to moderate GI or dermatologic symptoms.4,12 For those infants, breastfeeding should continue but with cow’s milk eliminated from the mother’s diet.12 In addition, CMP should be strictly avoided in any supplementary feeding given to the infant.12 This maternal elimination diet should be continued for a minimum of two to four weeks.12 The advice of a nutritionist may be recommended to help the mother maintain a nutritionally balanced diet, particularly adequate calcium intake.12 If the child’s symptoms resolve after two to four weeks, cow’s milk should be reintroduced into the maternal diet; recurrence of symptoms requires elimination of CMP for the duration of breastfeeding.12 For the small proportion of formula-fed infants with a true IgE-mediated CMPA and mild-to-moderate symptoms, the preferred source of nutrition is a hypoallergenic formula with extensively hydrolyzed proteins (eHF), which are less likely to stimulate antibody production (Figure 2).12,13 Even

35 Mislabeled CMPA (n=243) 30

IgE-mediated CMPA (n=138)

Percentage of patients

25

20

15

10 5 0

0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 >8

Month Months Months Months Months Months Months Months Months

Age at onset of symptoms

FIGURE 1. Age at onset of confirmed IgE-mediated and mislabeled CMPA in a cohort of 381 infants5 80 THE CLINICAL ADVISOR • NOVEMBER 2013 • www.ClinicalAdvisor.com

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FIGURE 2. Decision tree for diagnosis and treatment of formula-fed infants with clinical manifestations of CMPA

partially hydrolyzed cow’s milk formula can be beneficial.

This formula has been shown to reduce flares of allergic dermatitis in atopic infants with no negative effect on growth rate and to provide an allergy-preventive effect until age 10 years in children with diagnosed allergic disease.14 During a diagnostic elimination diet, all other foods should be withheld to avoid possible manifestations due to other food allergens, and the cow’s-milk-free diet should be maintained for at least six months.12 Clinical symptoms should resolve with the use of eHF if CMPA is present; CMP then can be reintroduced progressively, with the infant monitored closely for recurring symptoms.12 In rare cases, symptoms of CMPA may persist on eHF, and a chemically made amino acid-based formula, which is not derived from cow’s milk or other native protein, may be effective.12 Symptoms that fail to improve with eHF or amino acid formula may be indicative of another diagnosis and warrant referral to a pediatric allergy specialist.

For infants who are not exclusively breastfed for four to six months or who are formula-fed and at high risk for atopic disease, eHF may provide additional benefit. An AAP 2008 position paper states that eHF may delay or prevent the

development of atopic dermatitis in early childhood and may be more effective than partially hydrolyzed formulas.8 The AAP statement is based on clinical evidence, including a study of 2,252 newborns randomly assigned at birth to three different hydrolyzed formulas or cow’s milk formula as a substitute for, or a supplement to, breastfeeding.15 Compared with the use of cow’s milk formula, the relative risk for developing atopic dermatitis in the first six years of life was no different with extensively hydrolyzed whey formula, but was lower with partially hydrolyzed whey formula and extensively hydrolyzed casein formula.15 Treatment of CMPA using an eHF is also a cost-effective option to amino acid-based formula, according to a 12-month study of matched groups of infants with a mean age of about 3 months.16 Approximately 40% of the infants had a combination of GI symptoms and eczema; another 39% had only GI symptoms and 13% presented with eczema only.16 In both groups, the mean time to resolution of symptoms was 1.2 months, although the infants receiving eHF had significantly fewer doctor visits over the 12 months (13.1 vs. 17.5, P<0.001), and the cost of managing the eHF-treated infants was lower.16 Continues on page 82

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CME CE

COW’S MILK PROTEIN ALLERGY

Factors contributing to nutritional imbalances in infants and children with CMPA

Given the frequency of reporting of food-related problems during the first year of life, as well as the frequency of mislabeled CMPA among infants with similar symptoms of food allergy, it is important to educate parents, caregivers, and clinicians as to how to differentiate between allergic and non-allergic food-related problems.4,5 Many mothers report food-related problems in their infants, yet relatively few seek medical attention for these problems.1 Furthermore, only a small proportion of those infants who visit are tested for food allergy.1 As a result, mothers may make uninformed decisions based on limited knowledge of food allergy symptoms and restrict nutritionally important foods.1 Equally important, clinicians often overdiagnose CMPA based on symptoms alone, which may lead to unnecessarily restrictive diets that limit the calories and nutrients necessary for growth.1,5 In addition to the adverse nutritional consequences, unfounded strict food-allergen practices negatively affect the quality of life of children and their caregivers.1 Two recent Brazilian studies underscored the high prevalence of nutritional deficits among infants placed on inappropriate substitute formulas for suspected or confirmed CMPA.17,18 In the first, 513 of 9,478 children up to age 24 months (5.4%) were referred by a pediatrician to a pediatric gastroenterologist primarily for GI symptoms; the specialist confirmed the diagnosis in 211 (2.2%).18 Nearly half of these 211 infants had been switched inappropriately to a different formula (i.e., soy, goat’s milk, or lactose-free cow’s milk) by the pediatrician, and only 16% were using an eHF or amino acid-based formula.18 Analysis of z-score deviations suggested that malnutrition or failure to thrive occurred in a substantial proportion of these infants, with weight-for-age deficits in 15.1%, weight-for-height deficits in 11.3%, and height-for-age deficits in 23.9%.18 The second trial was a smaller study of 214 children younger than age 3 years who also primarily had GI symptoms; some also had cutaneous and/or respiratory manifestations.17 At study entry, 67.8% of the children were of normal weight

by BMI, 12.9% were considered thin or severely thin, and 20.3% were at risk for overweight or obesity.17 The majority (65.1%) were using soy-based formulas, and 24.5% were on hydrolyzed protein or amino acid-based formulas.17 There was a significant difference in the proportion of children on these formulas who had thin or severely thin BMI compared with the 10% of children on cow’s-milk-based formulas (8.7% vs. 41.7%, P<0.001).17

The findings of both studies support exclusive breastfeeding for the first four to six months of life and indicate that GI manifestations of CMPA, whether confirmed or suspected, lead to nutritional impairment.4,17,18 Highly effective replacement diets are needed to control symptoms and promote nutritional recovery in order to avoid malnutrition.17,18 Although double-blind placebo-controlled food challenges are not universally used in the management of children with CMPA, excluding CMP can convince parents to stop an unnecessary elimination diet in their children with suspected CMPA as well as allow for reintroduction of CMP in some children who exhibit partial tolerance to the protein.19,20 One study found that 70% of infants became tolerant to CMP at age 1 year, and even patients who could tolerate relatively small amounts of CMP reported a significant improvement in quality of life.20 Prognosis for CMPA and other childhood allergies

The prognosis for infants with CMPA is relatively good; the allergy persists in only a small percentage of children who develop it.4,21 Most children (85%) outgrow CMPA by age 3 years, with the allergy spontaneously disappearing in 50% by age 1 year and 70% by age 2 years.7,21 The likelihood that a child will become tolerant to CMP depends on his or her age and the level of specific IgE at the time of diagnosis.4,21 A 2007 study reported that 19% of children with CMPA developed tolerance by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by age 16 years.7 Children with the highest levels of cow’s-milk-specific IgE are least likely to outgrown their CMPA, while children who have negative reactions to the radioallergosorbent test or skin-prick test tend become tolerant sooner than those with positive test results.4,7 Atopic dermatitis, another common allergy that often develops in infancy, is frequently associated with food allergy, and 40% to 50% of children younger than age 1 year with CMPA may also be diagnosed with atopic dermatitis.21 Conversely, about one-third of children with atopic dermatitis also have CMPA, and the development of tolerance to CMP appears to be slower than in children with CMPA alone, resolving in 50% by age 7 years.21 As in children with CMPA alone, cow’s-milk-specific IgE levels at diagnosis are a prognostic factor for the time to develop tolerance to CMP in children with concurrent atopic dermatitis.21 In one study, CMPA resolved in only 19% of children with atopic dermatitis and higher cow’s-milk IgE levels by age 5 years.21 In general, children with concurrent atopic dermatitis or respiratory allergy are least likely to outgrow their early

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CMPA.7 Children with CMPA who develop other atopic conditions need specialized long-term care with follow-up of cow’s-milk-specific IgE levels to predict the appropriate timing for reintroduction of cow’s milk into the diet.21 Special attention is also needed to avoid accidental exposure to cow’s milk and the possible development of other atopic conditions over time.2 Current research to prevent sensitization to foods

Many clinicians believe that the mainstay of therapy for any food allergy is complete avoidance of the culprit food, such as milk or soy.11 Elimination of milk, an important source of fat and protein for young children, from the diet raises concerns about gaps in nutrition.11 Furthermore, CMP is present in many common foods (e.g., puddings, lunch meats, salad dressings), as well as in some milk, cream, and butter substitutes labeled “non-dairy.”11 The practice of food avoidance assumes that preventing or delaying the early onset of food allergy may avoid the “allergic march”— the progression from food allergy to allergic rhinitis or asthma at a later age.7 More recent research, however, supports just the opposite approach to preventing food allergy—exposure to food allergens in early life—while still recognizing the central role of food allergy in the development of other atopic diseases, including eczema.7 In contrast to food avoidance, exposure to food allergens in early life may improve tolerance of the infant immune system to the allergens and prevent sensitization.7 Desensitization protocols expose a child with food allergy through specific oral tolerance induction (SOTI) to the allergen.7 Several studies have demonstrated tolerance achieved in children with CMPA by initiating SOTI with minute quantities of cow’s milk that are increased over time, with the children able to tolerate up to 250 mL of cow’s milk after three to 12 months on the protocol.7 In a study of 118 children, 75% became tolerant after one year and were able to follow an unrestricted diet; another 16% were considered partially tolerant and were able to consume 5 mL to 150 mL of cow’s milk with no allergic reaction.20 Adverse effects were mild, and parent satisfaction was high.20 Another approach to protect against food allergies is the use of such probiotics as lactobacilli.22 Although the pathogenesis and development of oral tolerance in CMPA is not fully understood, differences in the composition of intestinal bacterial of infants with CMPA and healthy infants suggest that this altered composition creates an imbalance in the immune response to food allergens, resulting in both local and systemic reactions.22 Supplementation of formula with

Lactobacillus has been effective in reducing the incidence and severity of atopic dermatitis in newborns and infants younger than age 2 years, and in decreasing GI symptoms.7,22 In infants with CMPA, supplementation of eHF with Lactobacillus accelerated the development of tolerance to cow’s milk after food challenge.22 These are promising findings, but more research is needed to provide a better understanding of the role of probiotics for the prevention and treatment of CMPA and other atopic diseases.6 Summary

CMPA is the most common cause of food allergy, affecting about 3% of all infants in the first year of life, and can develop in both breastfed and formula-fed infants. Parents and caregivers often attribute GI, dermatologic, or respiratory symptoms to a food allergy, fail to consult with a clinician, and restrict nutritionally important foods from their children’s diets. Even when parents seek medical advice, clinicians may overdiagnose food allergy and recommend unnecessary elimination diets that can pose risks to the child’s health and quality of life.

Breastfeeding exclusively for the first four to six months of life is recommended as the best protection against development of CMPA in the infant. When CMPA is correctly diagnosed, management involves elimination of CMP from the maternal diet of breastfed infants and the use of eHF or partially hydrolyzed infant formula as the sole or supplementary source of nutrition. Differentiation of food allergy from other food-related problems is important to prevent or decrease the incidence of food allergies in young infants and to minimize risks to the child’s growth and development. n References 1. Luccioli S, Ross M, Labiner-Wolfe J, Fein SB. Maternally reported food allergies and other food-related health problems in infants: characteristics and associated factors. Pediatrics. 2008;122:S105. Available at pediatrics. aappublications.org/content/122/Supplement_2/S105.long.

2. Santos A, Dias A, Pinheiro JA. Predictive factors for the persistence of cow’s milk allergy. Pediatr Allergy Immunol. 2010;21:1127-1134.

3. Metsälä J, Lundqvist A, Kaila M, et al. Maternal and perinatal characteristics and the risk of cow’s milk allergy in infants up to 2 years of age: a casecontrol study nested in the Finnish population. Am J Epidemiol.

2010;171:1310-1316. Available at aje.oxfordjournals.org/content/171/12/1310.long.

4. Vandenplas Y, Koletzko S, Isolauri E, et al. Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch Dis Child.

2007;92:902-908. Available at adc.bmj.com/content/92/10/902.long.

5. Elizur A, Cohen M, Goldberg MR, et al. Mislabelled cow’s milk allergy in infants: a prospective cohort study. Arch Dis Child. 2013;98:408-412.

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CME CE

COW’S MILK PROTEIN ALLERGY

6. Vitaliti G, Cimino C, Coco A, et al. The immunopathogenesis of cow’s

15. von Berg A, Filipiak-Pittroff B, Krämer U, et al. Preventive effect of

milk protein allergy (CMPA). Ital J Pediatr. 2012;38:35. Available at www.

hydrolyzed infant formulas persists until age 6 years: long-term results

ijponline.net/content/38/1/35.

from the German Infant Nutritional Intervention Study (GINI). J Allergy

7. Joneja JM. Infant food allergy: Where are we now? JPEN J Parenter Enteral

Clin Immunol. 2008;121:1442-1447.

Nutr. 2012;36:49S-55S.

16. Taylor RR, Sladkevicius E, Panca M, et al. Cost-effectiveness of using an

8. Greer FR, Sicherer SH, Burks AW, et al. Effects of early nutritional inter-

extensively hydrolysed formula compared to an amino acid formula as

ventions on the development of atopic disease in infants and children: the

first-line treatment for cow milk allergy in the UK. Pediatr Allergy Immunol.

role of maternal dietary restriction, breastfeeding, timing of introduction

2012;23:240-249.

of complementary foods, and hydrolyzed formulas. Pediatrics.

17. Aguilar AL, Maranhão CM, Spinelli LC, et al. Clinical and follow up

2008;121:183-191. Available at pediatrics.aappublications.org

assessment of children in a program directed at the use of formulas for

/content/121/1/183.long.

cow’s milk protein allergy. Rev Paul Pediatr 2013;31:152-158.

9. Kuitunen M, Kukkonen AK, Savilahti E. Impact of maternal allergy and

18. Vieira MC, Morais MB, Spolidoro JVN, et al. A survey on clinical

use of probiotics during pregnancy on breast milk cytokines and food anti-

presentation and nutritional status of infants with suspected cow’s milk

bodies and development of allergy in children until 5 years. Int Arch Allergy

allergy. BMC Pediatrics. 2010;10:25. Available at www.biomedcentral.com/

Immunol. 2012;159:162-170.

1471-2431/10/25.

10. Coscia A, Orrù S, Di Nicola P, et al. Cow’s milk proteins in human milk.

19. Dambacher WM, de Kort EHM, Blom WM, et al. Double-blind placebo-

J Biol Regul Homeost Agents. 2012;26(3 Suppl):39-42.

controlled food challenges in children with alleged cow’s milk allergy: preven-

11. Kattan JD, Cocco RR, Järvinen KM. Milk and soy allergy. Pediatr Clin

tion of unnecessary elimination diets and determination of eliciting doses.

North Am. 2011;58:407-426. Available at www.ncbi.nlm.nih.gov/pmc/arti-

Nutrition J. 2013;12:22. Available at www.nutritionj.com/content/12/1/22.

cles/PMC3070118/.

20. Longo G, Berti I, Barbi E, et al. Diagnosed child, treated child: food

12. von Berg A, Filipiak-Pittroff B, Kramer U, et al. Allergies in high-risk

challenge as the first step toward tolerance induction in cow’s milk protein

school children after early intervention with cow’s milk protein hydroly-

allergy. Eur Ann Allergy Clin Immunol. 2012;44:54-60.

sates: 10-year results from the German Infant Nutritional Intervention

21. Suh J, Lee H, Lee JH, et al. Natural course of cow’s milk allergy in chil-

(GINI) study. J Allergy Clin Immunol. 2013;131:1565-1573.

dren with atopic dermatitis. J Korean Med Sci. 2011;26:1152-1158. Available

13. O’Connor NR. Infant formula. Am Fam Physician. 2009;79:565-570.

at www.ncbi.nlm.nih.gov/pmc/articles/PMC3172651/.

Available at www.aafp.org/afp/2009/0401/p565.html.

22. Canani RB, De Costanzo M. Gut microbiota as potential therapeutic

14. Jin YY, Cao RM, Chen J, et al. Partially hydrolyzed cow’s milk formula

target for the treatment of cow’s milk allergy. Nutrients. 2013;5:651-662.

has a therapeutic effect on the infants with mild to moderate atopic der-

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3705311/.

matitis: a randomized, double-blind study. Pediatr Allergy Immunol.

2011;22:688-694.

All electronic documents accessed October 15, 2013.

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CME CE

POSTTEST Expiration date: November 2014

Credit Designation: MER is accredited by the ACCME to provide continuing medical education for physicians. MER designates this educational activity for a maximum of 0.5 AMA PRA Category l Credit™.

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 0.5 contact hours of credit.

Dietician Credit: Medical Education Resources (Provider Number ME110) is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered Dieticians (RDs) and Dietetic Technicians (DTRs) will receive 0.5 continuing professional education unit (CPEU) for completion of this program/material.

Participants should only claim credit commensurate with the extent of their participation in the activity.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Posttest must be completed and submitted online. Please go to CliniAd.com/1dJWId5.

CREDITS: 0.5

| Safety first in infant feeding: identifying and addressing infant allergy to cow’s milk protein

1. In cow’s milk protein allergy (CMPA), the first stage of an IgE-mediated reaction involves: a. Sensitization b. Activation of the mast-cell-bound IgE c. Rapid release of inflammatory mediators d. None of the above 2. According to the American Academy of Pediatrics, which of the following factors is linked with an increased risk that a child will develop atopic disease? a. Being formula-fed from birth b. Having a first-degree relative with atopic disease c. Having a mother with asthma or eczema d. Premature birth 3. Which of the following statements about CMPA is true? a. The most frequently reported symptoms are almost always confined to the gastrointestinal tract. b. It tends to be undiagnosed among children with food allergy symptoms. c. Most children will outgrow the condition by age 3 years. d. Skin-prick tests are used to confirm the diagnosis.

4. For the small proportion of formula-fed infants with a true IgE-mediated CMPA and mild-to-moderate symptoms, the preferred source of nutrition is: a. Any hypoallergenic formula b. A hypoallergenic formula with extensively hydrolyzed proteins c. Soy-based formula d. None of the above 5. Approximately 40% to 50% of children younger than age 1 year with CMPA may also be diagnosed with: a. Respiratory allergy b. Pollen allergy c. Atopic dermatitis d. Other food allergies

TO TAKE THE POSTTEST please go to CliniAd.com/1dJWId5

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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 NOVEMBER 2013

Consultations Frozen shoulder susceptibility . . . . . . 86 Vaginal dryness and decreased libido caused by smoking. . . . . . . . . 86 Nephrotoxic medications for patients on dialysis. . . . . . . . . . . . . . 87 When to refer cases of hepatitis C for specialist treatment . . . . . . . . . . 87 Standard classification of dysplastic nevi. . . . . . . . . . . . . . . . . 88

Clinical Pearls Make pediatric exams all fun and games. . . . . . . . . . . . . . . . . . . . 88 Jump away from stomach pain . . . . . . 88

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 FROZEN SHOULDER SUSCEPTIBILITY Why are individuals with diabetes especially prone to developing frozen shoulder?—KELLY EELLS, APNP, Sheboygan, Wis. Frozen shoulder, or adhesive capsulitis, has a prevalence in the general population of about 2%. In patients with diabetes, the prevalence is estimated at anywhere from 10% to 29%. The increase is felt to be largely due to the changes that occur in the presence of elevated blood glucose levels. Glucose and collagen interact in what is known as “cross-linking,” which produces a glycosylated end product that is rigid and irreversible. This same process is also thought to be involved in the development of microantiopathy associated with diabetes.

—Sherril Sego, FNP-C, DNP (181-1)

VAGINAL DRYNESS AND DECREASED LIBIDO CAUSED BY SMOKING A number of my female patients are indigent and smoke.

What can be used to treat vaginal dryness and decreased libido in these women?—MARYLOU POTTS, ARNP, Ocala, Fla. For women with vaginal dryness, topical lubricants can afford relief.

There are numerous low-cost OTC lubricants to choose from, but a

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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woman who uses condoms or a diaphragm should be steered towards water-based lubricants only, as oil-based products may break down latex and thus decrease the efficacy of her birth control or STDprevention method. If the patient is not using one of these latexbarrier methods, olive oil or 100% pure coconut oil can be used for lubrication. For peri- or postmenopausal women who are experiencing vaginal dryness from vaginal atrophy, topical low-dose estrogen in the form of a ring, a cream, or a pill can also be used. Smoking is not a contraindication for such products.

For virtually all women, I consider the complaint of a decreased libido a symptom rather than a disease. A thorough history and examination needs to be obtained to assess for the underlying cause of decreased libido. Such causes include dyspareunia (caused by vaginal dryness, vaginal infection, uterine fibroids), depression, certain medications (e.g., selective serotonin reuptake inhibitors, antipsychotics, antiepileptics) relationship issues, substance abuse, stress, fatigue, body issues, and lack of privacy. In addition to treating any underlying issue that is causing or contributing to a woman’s decreased libido, I recommend that providers discuss how sexual desire varies from woman to woman. Libido can also vary tremendously within one woman’s life span, depending on external circumstances. All of this is quite normal. Listening to the patient’s story and normalizing her experience (if no pathology is found) will likely be more therapeutic than experimenting with one of the many unproven pharmaceutical agents now available.—Mary Newberry, CNM, MSN (181-2)

NEPHROTOXIC MEDICATIONS FOR PATIENTS ON DIALYSIS Can drugs that are contraindicated in patients with severe renal impairment be used in individuals with end-stage renal disease (ESRD) who are actively receiving hemodialysis?

Will these medications be dialyzed out before negatively

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.

affecting the renal system?—BLAIR BUEHLER, DNP/ FNP-S, Memphis, Tenn.

Patients on dialysis because of ESRD already present with an irreversibly impaired renal system. Since dosing adjustments to protect kidney function are routinely made based on a patient’s renal function, attempting to dose nephrotoxic medications affords negligible benefits to someone already at this stage of kidney failure.

If a patient on dialysis presents with a condition for which he or she could benefit from a nephrotoxic medication, the drug may be given if the benefit outweighs the risk. This scenario would apply in most situations, unless the patient has residual renal function (i.e., making >100 cc of urine per day). Patients receiving medications that fall in this category should be followed for drug levels when appropriate.

Hemodialysis patients typically receive treatment three times a week.

Medications, most of which are eliminated by the kidney, often have longer half-lives and should be dosed and timed accordingly. When in doubt, consult with a nephrologist or a clinical pharmacist.

Some substances are completely contraindicated, including gadolinium (used in MRI exams) and metformin (Fortamet, Glucophage, Glumetza, Riomet).—Debra Coplon, DNP, Memphis Internal Medicine and Pediatrics, Memphis, Tenn. (181-3)

WHEN TO REFER CASES OF HEPATITIS C FOR SPECIALIST TREATMENT I work with an incarcerated population in which 40% of my patients have hepatitis C. Given limited resources, which patients would benefit most from specialist referral?—SALLY DAVIS, PA-C, Chico, Calif.

The standard of care for many patients with hepatitis C consists of combination therapy with an oral protease inhibitor (boceprevir [Victrelis] or telaprevir [Incivek]), along with pegylated interferon

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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© CIENCE SOURCE / THOMAS DEERINCK, NCMIR

Advisor Forum

The hepatitis C virus (orange) can lead to liver degeneration and scarring.

and ribavirin (Copegus, Rebetol, Ribasphere, Virazole). Patients undergoing treatment may experience profound fatigue, depression, and a slew of side effects (e.g., blood dyscrasias, infections, muscle and joint pain, hair loss, thyroid dysfunction, psychiatric changes).

The treatment is expensive and long-term (24-48 weeks, longer in the immunosuppressed). There are four genotypes of hepatitis C. Patients with genotype 1 can expect a 40% to 45% response rate after 48 weeks of treatment. Patients with genotypes 2 or 3 can expect a 70% to 80% response rate after only 24 weeks of treatment. Studies suggest that a drop in hepatitis C viral load within 12 weeks of treatment is correlated with treatment success.

High success rates are also seen in patients with an elevated CD4 count prior to treatment and those in otherwise good health. For patients with hepatitis C who are not candidates for treatment or who have a lower chance of treatment response, it remains important to protect and support the liver as well as to keep the immune system healthy.—Claire Babcock O’Connell, MPH, PA-C (181-4)

STANDARD CLASSIFICATION OF DYSPLASTIC NEVI Different dermatopathologists report dysplastic nevi with different descriptors. Some simply write “dysplasia,” whereas others add “mild,” “moderate,” or “severe” to the description. Follow-up recommendations for the different levels of dysplasias vary depending on which expert you ask. What are the standards?—KATHLEEN HAYCRAFT, DNP, FNP/PNP-BC, DCNP, Hannibal, Mo. The first thing to know is that your biopsy report is only as good as the pathologist who is reading it. Skin biopsies are particularly difficult to read and require expert analysis, so I am happy to hear

that you are sending pigmented biopsies to a dermatopathologist instead of a general pathologist.

Dysplastic (or atypical) moles have clinical and histologic appearances that are different from typical common nevi. Simply writing “dysplastic” or “atypical” without including a recommendation to excise completely or a level of atypia (i.e., mild, moderate, or severe) is unacceptable. The NIH consensus statement on the diagnosis and early treatment of melanomas clearly states that pathology reports for atypical nevi should include information about the degree of melanocyte atypia (available at consensus.nih.gov/1992/1992Melanoma088html.htm, accessed October 15, 2013).

A severely dysplastic nevus should be excised with a 2-mm margin of healthy skin because of frequent overlap with melanoma in situ.

A lesion that is mildly atypical with no clinically apparent residual nevus does not need re-excision. Monitor the area for a year and instruct the patient to return if there is any repigmentation or change in appearance. If the lesion was moderately dysplastic and not completely excised, a conservative re-excision should be discussed with the patient. The decision to re-excise should be made based on the original index of concern, size, location, and the patient’s history of sun exposure, personal and family history of skin cancer, and ability and interest in conservative re-excision vs. clinical follow-up.

All patients with one atypical mole should have a full skin examination and be counseled on skin self-examinations. These patients should also avoid tanning beds, excessive sunlight exposure, and use sunscreen or sunprotective clothing. The use of serial photography to monitor the skin will also be helpful in the long term-care of patients with dysplastic nevi.— Abby A. Jacobson, MS, PA-C, Delaware Valley Dermatology Group, Wilmington, Del. (181-5)

CLINICAL PEARLS MAKE PEDIATRIC EXAMS ALL FUN AND GAMES Use finger puppets to turn a pediatric neurologic exam into a series of games. By holding the child’s head still with one hand, you can use the puppet on your other index finger to check cardinal fields of gaze. Additionally, having the child touch his or her nose and then your finger puppet is a good way to initiate the finger-nose test for dysmetria of reach.—BETH HEUER, CPNP-PC, Pittsburgh, Pa. (181-6) JUMP AWAY FROM STOMACH PAIN If a patient with abdominal pain can do jumping jacks, you can rule out peritonitis and appendicitis (in a child).—RUTH MORGAN, PA-C, Elkins, WVa. (181-7) n

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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.

Yellow plaques with vision loss An ophthalmologist refers a 52-year-old patient with a history of hypertension to the dermatology clinic due to vision loss. The ophthalmologist noted angiod streaks of the patient’s retina. A total body skin examination revealed subtle yellow plaques in the inguinal folds.

WHAT IS YOUR DIAGNOSIS?

• Pseudoxanthoma elasticum • Cutis laxa • Marfan syndrome • Ehlers-Danlos syndrome

● See the full case at CliniAd.com/19Nu4mU

Itchy rash on the eyelid A woman, aged 74 years, complains of a very itchy rash on her eyelids. Her medical problems include hypertension and glaucoma. Current medications include lisinopril and prescription eye drops.

WHAT IS YOUR DIAGNOSIS?

• Periorbital dermatitis • Eyelid dermatitis • Cellulitis • Impetigo ● See the full case at CliniAd.com/H206Cr

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.

Enlarged and swollen lips

Back plaque after a heart attack

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LEGAL ADVISOR CASE

Unidentified sepsis leads to death

BY ANN W. LATNER, JD

Ms. V disliked working the night shift in the busy emergency department (ED) of a regional medical center, but the policy was that shifts had to be varied. The nurse practitioner found the nights to be either very slow and boring or unbelievably busy. As soon as she walked in at 8:00 pm on that April evening to start her 14-hour shift, Ms. V knew it was going to be one of the busy nights.

Ms. V saw five patients in the first hour before she was assigned to Mrs. J’s case. Mrs. J was a 39-year-old mother of two who had been in the middle of a family vacation when she became ill. The family was on a car trip from another state when Mrs. J began feeling increasingly nauseated and started experiencing chills. She took acetaminophen, thinking it was a fever, but she did not improve. After another hour in the car, the family decided it was time to find a hospital.

The triage nurse in the ED noted that Mrs. J’s BP was 111/68 mm Hg, her heart rate was 163 beats per minute, her temperature was 102°F, and she reported her pain as being a 9

© SCIENCE SOURCE / JOHN COLE

Emergency clinicians improperly attended to a bacterial infection in a patient with no spleen.

A 39-year-old woman presents to the emergency department with nausea, stomach cramps, alternating chills and fever, and an elevated heart rate.

out of 10. Mrs. J’s medical history included thyroid disease, Hodgkin disease, and migraine headaches. Her surgical history included an appendectomy, a lumpectomy, and exploratory spleen removal.

Ms. V was assigned to the case and went in to see the patient for the first time at 9:00 pm.

She reviewed the triage nurse’s report and then spoke to the patient.

“Your heart rate is quite high,” said Ms. V. “Yes,” replied Mrs. J, “It usually runs high when I’m sick. Do you think I will be here long?

We are on our vacation, and I hate to spend any part of it in the hospital. My children will be very disappointed.”

Ms. V chatted with the patient about her two young children—a boy and a girl—until the emergency physician, Dr. P, arrived. He ordered routine lab work, including blood and 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 urine samples, blood cultures, a chest x-ray, and an ECG. The blood work was initially negative for bacteria, but Mrs. J’s WBC count was 14,000 cells/µL. Dr. P, concerned that the patient might have meningitis, conducted a lumbar puncture, which revealed clear spinal fluid. The physician ruled out bacterial meningitis.

Over the next several hours, Ms. V attended to the patient, who was given ibuprofen to reduce her fever, ondansetron (Zofran, Zuplenz) for nausea, and meperidine (Demerol) and lorazepam (Ativan) for pain. At 1:30 am, Dr. P noted a differential diagnosis of viral infection, bacterial infection, upper respiratory infection, urinary tract infection, and viral meningitis, and ordered that the patient be discharged.

An hour later, Ms. V noticed that Mrs. J’s heart rate was up to 155 and BP was 115/75. She mentioned the elevated heart rate to the patient’s husband and Dr. P but did not note it on the chart. Dr. P ordered metoprolol (Lopressor, Toprol) to lower the heart rate. By 3:00 am, Mrs. J’s heart rate was down to 133 and her BP was 87/52, and Dr. P finalized her discharge from the hospital. Mrs. J and her husband were instructed to return to the ED if symptoms worsened or didn’t improve. Ms. V wished her patient well, and advised her to enjoy the rest of her vacation.

By 9:00 am the next day, Ms. V was looking forward to going home and getting some sleep. Her thoughts of sleep evaporated, however, when an ambulance pulled up bearing Mrs. J, who was in obvious distress. As the physician began intubating her, Ms. V quickly got a history from the patient’s husband. According to Mr. J, when they returned to the hotel, Mrs. J was tired and groggy and fell asleep. But a few hours later she woke up not feeling well and suffering from stomach cramps and chills. Her husband thought she had a fever and gave her ibuprofen, which had worked earlier. He fell asleep, and was awakened later by his wife moaning in pain. He noticed that her bottom lip was discolored and he called 911.

Later, despite the best efforts of emergency personnel, Mrs. J coded and was pronounced dead. The cause of death was later determined to be septic shock due to acute bilateral adrenal hemorrhage.

Ms. V was informed that she and Dr. P were being sued for medical malpractice.

At trial, the plaintiffs alleged that Dr. P did not meet the standard of care because although he ordered metoprolol to lower Mrs. J’s heart rate prior to discharge, he did not address the cause of the tachycardia, which was indicative of sepsis.

The plaintiffs argued that Ms. V was negligent for failing to document the elevated heart rate on discharge, for failing to voice concerns or advocate for the patient, and for failing

to point out to Dr. P that the plaintiff had had her spleen removed, thus putting her at higher risk for sepsis. During testimony, Dr. P admitted that he failed to determine that Mrs. J did not have a spleen, and that an untreated bacterial infection in a patient with no spleen could be catastrophic.

On cross examination, he testified that had he known about the splenectomy, he would have admitted Mrs. J and immediately administered antibiotics. After several days of testimony by experts on both sides, the jury deliberated for three hours and returned a verdict for the plaintiffs in the amount of $1.2 million. The jury found Dr. P 60% at fault and Ms. V 40% at fault.

Legal background

To convict a clinician of medical malpractice, a jury must find a breach of standard of care, and that the breach was the cause of the harm. In this case, the defense’s argument was that the patient’s death was not caused by the clinicians’ breach of duty, but rather that the patient’s chances of survival were so poor by the time she came in that she likely would have died regardless. Because the defendants were arguing that their breach was not the cause of death, they both admitted the breach in duty, which was not advocating for the patient or reading the patient’s chart well enough to know that she did not have a spleen. When their lack-of-causation argument failed to move the jury, their defense fell apart.

Protecting yourself

Ms. V did not act as an advocate for her patient. Taking notes, especially in a case where there are abnormal vital readings at the time of discharge, is essential. But even more essential than chart notating is making sure that all practitioners involved are aware of anything that might impact the patient’s care. In this case, Ms. V should have pointed out to the physician that Mrs. J had no spleen and thus was at risk for sepsis. Had this been brought to the forefront, the patient’s abnormal heart rate and fever would have been understood in context, and might have led to the proper diagnosis.

Being an advocate means being familiar with everything in the patient’s chart, and being willing to voice concerns when necessary. Ms. V did not point out to the physician that the patient had had a splenectomy. Dr. P did not read the chart thoroughly enough to see that information himself.

And because of those oversights, Mrs. V did not receive the antibiotics that might have saved her life. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Clinical Challenge Difficulty lifting the right arm drives a young man to seek help MARGARET QUINN, DNP, CPNP

An adolescent presented with persistent upper-extremity pain, redness, and axillary swelling upon lifting weights.

Mr. H, aged 17 years, was brought in to see his primarycare provider after experiencing pain when he manipulated his right arm. He presented and was examined by the pediatric nurse practitioner (NP), who confirmed right axilla pain that increased when Mr. H was weightlifting and raising his arm over his head. The pain started two weeks ago, after the patient returned to his weightlifting routine at the gym. (The teenager had stopped weight-training for a brief period of time.) Mr. H reported that the pain was dull and constant, but that it did not cause him to limit his daily activities.

CASE

1. HISTORY Mr. H’s history was unremarkable for any significant childhood illnesses. His immunizations were up-to-date. The young man was a smoker and attended vocational school. He denied illicitdrug use and excessive alcohol consumption, but admitted to having used anabolic steroids in the past. His family history was unremarkable.

© PHOTO CREDIT

2. EXAMINATION

Thoracic phlebography shows deep vein thrombosis of the subclavian vein.

Mr. H was a pleasant teenager who, on examination, immediately complained of significant tenderness in the right axilla. The tenderness was noted on palpation at the mid-axillary junction, without lymph node tenderness or swelling to the pectoralis major or latissimus dorsi muscles. Full range of motion was noted in the arms and shoulders bilaterally, and bilateral strength was also equal.

After initial presentation, Mr. H was encouraged to return to the gym. A modified weightlifting routine was recommended, and Mr. H was instructed to apply ice to the affected area after training. In addition, the NP ordered a nonsteroidal anti-inflammatory medication for residual pain.

Two days later, Mr. H returned to the clinic noting that the pain was not subsiding. At this www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2013 95

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Clinical Challenge point, Dr. R—the on-call physician—evaluated Mr. H. Dr. R diagnosed myositis and prescribed 60 mg of prednisone once daily for five days and 800 mg ibuprofen every eight hours. Ten days later, the patient presented with redness and swelling of the right arm. An ultrasound was ordered at that time, and the teen was admitted to the regional pediatric center with a diagnosis of deep vein thrombosis (DVT) of the right subclavian vein.

3. DIFFERENTIAL DIAGNOSIS Initially, there were several diagnoses to consider, including tendinitis, myositis, superior vena cava syndrome, upper-extremity DVT, antiphospholipid syndrome, and clotting disorder.

4. LABORATORY DATA AND DIAGNOSIS The initial ultrasound revealed several clots to the right subclavian vein. Mr. H’s platelet count was low at 90,000/µl and partial thromboplastin time (PTT) was elevated at 45 seconds. At the two-month follow- up with the hematologist, the patient’s platelet count increased to 187,000/µl and antifactor Xa (anti-Xa) was within normal limits at 0.96 IU/mL. Additional labs ordered two months later were remarkable for lupus anticoagulant panel with a prolonged prothrombin time of 16 seconds, and a prolonged PTT of 46 seconds. The PTT did not correct with 1:1 mixing.

A dilute Russell Viper Venom Time (dRVVT) screen was prolonged and the dRVVT ratio was high. The hexagonal phospholipid neutral study was positive at 25 seconds, and the platelet neutralization study was also high. Anticardiolipin immunoglobulin (Ig) G antibodies were elevated. IgM and IgA levels were negative. A heparin anti-Xa level was therapeutic at 0.91 IU/mL. A magnetic resonance angiogram and a magnetic resonance venogram of the right upper extremity revealed fixed focal narrowing of the right subclavian vein distal to the head of the clavicle, with the arms raised and at the patient’s side, congruent with the diagnosis of thoracic outlet syndrome. There were no arterial abnormalities, and no additional thrombus was noted.

5. TREATMENT The patient was kept on 90 mg enoxaparin (Lovenox), which was administered subcutaneously once a day through the diagnostic phase. Mr. H was also referred to a vascular surgeon. After a two-month interval, the patient returned

to the hematology clinic. Mr. H had been noncompliant with his enoxaparin treatments and did not follow up with the vascular surgeon. At that time, a repeat ultrasound was ordered, and a persistent partial thrombosis of the subclavian, axillary, and basilica veins was noted.

6. DISCUSSION Venous thromboembolic disease is the most common manifestation of antiphospholipid antibody syndrome (APS). APS is characterized by arterial and venous thrombosis, with the presence of antiphospholipid antibodies or positive lupus anticoagulant.1 The deep veins of the extremities are most often affected, followed by axillary, retinal, hepatic, and cerebral sinus vessels.2 It is common for antiphospholipid antibodies to be seen in conjunction with other autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. This patient’s condition was complicated by the concurrent diagnosis of thoracic outlet syndrome (TOS). TOS is a cause of neck and shoulder pain with varying etiologies, primarily neurological from nerve or vascular compression with related edema and cyanosis of the limb.3 Most cases of TOS are treated with physical or occupational therapy, with palliative and supportive treatments.3 It is unlikely that TOS was the cause of these thrombolytic events in this patient, but rather was confounded by the APS. The diagnostic testing performed to confirm APS includes immune and coagulation studies—specifically lupus anticoagulant (LA), IgG or IgM cardiolipin antibodies, or IgG or IgM anti-beta-2 glucoproteins. 2 Most patients with laboratory findings of LA do not have SLE. The dRVVT is a test to detect LA, and is prolonged if LA antibodies are identified in the serum.4 Serial testing is encouraged after 12 weeks to confirm the diagnosis of APS. Treatment can be individualized based upon symptomatology and gender, as APS results in high pregnancy-morbidity and fetal mortality. Asymptomatic patients with positive laboratory tests may not require any specific treatment.

Patients with thrombolytic events or obstetric complications are treated with anticoagulant therapy. Because recurrence of venous or arterial thrombosis can be as high as 70%, long term anticoagulant therapy is indicated.1,2 Oral anticoagulants are the best available and most effective treatments for the prevention of recurrent venous or arterial thrombosis. Longterm anticoagulant therapy is recommended to prolong the international normalized ratio to 2.0-3.0.5 Continues on page 98

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Clinical Challenge Low-molecular-weight heparin in combination with lowdose aspirin is recommended to avoid pregnancy loss in women with APS. Steroids or intravenous immunoglobulin are also known to be effective in those who have an increase in bleeding or who require surgery.2

7. SUMMARY As individual diagnoses, APS and TOS can be managed with minimal long-term sequelae for the patient with appropriate pharmacologic and therapeutic maintenance interventions.

Multiorgan failure secondary to widespread thrombotic disease known as catastrophic APS (CAPS) is a risk for any patient with APS due to the effects on the microvasculature system, and is a rare and serious complication.6 Patients diagnosed with CAPS require intensive treatment with corticosteroids, immunosuppression, intravenous IgG, and/ or plasma exchange.2 Due to his lack of compliance with the medication regimen and specialty follow-up, Mr. H has been made aware of these risks. In addition, he was counseled to follow up appropriately going forward. n

“Sold, to the gentleman with the paddle.”

Dr. Quinn is a clinical assistant professor at Rutgers College of Nursing in New Brunswick, N.J. References 1. Acikel S, Akdemir R, Dogan M, et al. Antiphospholipid syndrome: coexistence of left ventricular apical thrombosis and deep vein thrombosis causing pulmonary thromboembolism in a patient with systemic lupus erythematosus. Echocardiography. 2010;27:198-201.

Lab Med. 2011;135:1092-1096. Available at www.archivesofpathology.org/ doi/full/10.5858/2010-0325-RSR.1.

3. Laulan J, Fouquet B, Rodaix C, et al. Thoracic outlet syndrome: definition, aetiological factors, diagnosis, management and occupational impact.

J Occup Rehabil. 2011;21:366-373. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3526474/.

4. Sood R, ed. Textbook of Medical Laboratory Technology. London, England: Jaypee Brothers Medical Publishers; 2006:296-307.

5. Horner KE, Phillips BB, Newkirk E, et al. Evaluation of anticoagulation in patients with antiphospholipid syndrome. Am J Health Syst Pharm.

2008;65:964-967.

6. Katikireddi VS, Kandiah DA. Progression of antiphospholipid antibody syndrome to catastrophic antiphospholipid antibody syndrome acutely with cessation of antithrombotic therapy. Intern Med J. 2012;42:585-591.

All electronic documents accessed October 15, 2013.

“Read it in the hollow, affectless voice of a man with nothing left to lose, Daddy.”

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

2. Sangle NA, Smock KJ. Antiphospholipid antibody syndrome. Arch Pathol

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Stat Consult

A quick review of common conditions, using the best global evidence

Description

• Hyperthermia (core [rectal] body temperature >40°C [104°F]) associated with ——Central nervous system dysfunction ——Signs of multiple organ system failure

Heatstroke

Types

BY ALAN DRABKIN, MD

Dr. Drabkin is a clinical editor for DynaMed (www.ebscohost.com/ dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and Assistant Clinical Professor of Population Medicine at Harvard Medical School.

• Classic —— Primarily affects older people or those with chronic medical conditions ——May have gradual onset (days) ——Associated with nervous system dysfunction • Exertional ——Primarily affects younger people, athletes, laborers ——Usually has rapid onset (hours) ——Associated with higher core temperatures Who is most affected

• Elderly • Children • Male athletes • Persons with chronic illnesses Incidence/Prevalence

• About one to two per 1,000 persons in urban U.S. areas during warm periods • 3,442 U.S. deaths between 1999 and 2003 Causes

• Environmental exposure to heat • Dehydration • Poor heat acclimatization • Combination of excessive body temperature and inadequate heat-dissipating mechanisms

© SCIENCE SOURCE / BSIP

Pathogenesis

Headache coupled with flushed skin can be a sign of heatstroke.

• Internal organ tissue temperatures rise above critical levels ——Causes damage to cell membranes and cellular energy systems ——Leads to cell and organ failure • Inability to increase cardiovascular output for central (core) needs Continues on page 100

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Stat Consult Likely risk factors

• Chronic conditions, including ——Cardiac disease and pulmonary disease ——Uncontrolled diabetes, hypertension, thyroid disease • Genetic predisposition • Prior history of heatstroke or heat illness • Acute illnesses or states, including ——Dehydration ——Febrile illness ——Fluid replacement with hypotonic solutions ——Gastroenteritis • Other risks include ——Alcoholism or alcohol/drug abuse ——Anorexia nervosa • Occupational exposure to environmental heat Possible risk factors

• OTC drugs and nutritional supplements containing sympathomimetic compounds • Systematic review of six case-control studies with 1,065 heat-wave-related deaths ——Factors associated with increased risk ■■ Bed confinement ■■ Being homebound ■■ Being unable to care for oneself ■■ Psychiatric illness ■■ Cardiovascular disease ■■ Pulmonary disease ——Factors associated with reduced risk ■■ Working home air conditioning/cool environments ■■ Increasing social contact

Confusion/delirium Coma • Medication History ——Medications that may contribute to heat-related illnesses and/or impair thermoregulation include ■■ Alcohol ■■ Alpha adrenergics ■■ Amphetamines ■■ Anticholinergics ■■ Antihistamines ■■ Benzodiazepines ■■ Beta blockers ■■ Calcium channel blockers ■■ Cocaine ■■ Ephedra (ma huang) ■■ Neuroleptics ■■ Diuretics ■■ ■■

Physical workup

• General physical ——Hyperpyrexia (temperature >40°-41°C [104°-105°F]) ——Hyperventilation ——Shock and/or seizures ——Ataxia • Skin ——Dry, hot, flushed skin (nonexertional-related heatstroke) ——Sweat-soaked pale skin at time of collapse (exertional heatstroke) • Cardiac ——Irregular heart rate Rule out

Complications

• Rhabdomyolysis • Acute renal failure • Cardiac arrhythmias and cardiac arrest • Central nervous system injury • Hepatocellular necrosis • Pulmonary edema • Disseminated intravascular coagulation • Death History

• Chief concern ——Nonspecific symptoms may include ■■ Apathy ■■ Clumsiness ■■ Collapse

• Heat exhaustion • Drug intoxication • Central nervous system abnormality • Hyperthyroidism • Infection (including sepsis psychosis) • Neuroleptic malignant syndrome • Pheochromocytoma Testing overview

• Measure rectal temperature.

• Check electrolytes and renal function.

Blood tests

• Increased blood urea nitrogen • Elevated hematocrit • Elevated creatine phosphokinase

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Stat Consult • Hyperkalemia/hypokalemia • Hypernatremia/hyponatremia • Elevated liver function tests • Hypocalcemia

»»Gastric, colonic, and bladder lavage with iced saline »»IV administration of chilled solutions

• Supportive care ——May need intensive care for airway and circulation support

Urine studies

• Red or white blood cells • Hyaline or white blood cell casts • Elevated protein and myoglobin Electrocardiography

• Look for ST segment and T-wave changes if electrolyte abnormalities or myocardial ischemia are present.

Treatment

• Fluid and electrolytes ——Oral fluids are preferred in conscious athletes able to swallow.

——IV normal saline to improve renal blood flow and tissue perfusion unless hypoglycemic ——Monitor for and treat electrolyte abnormalities.

——May need forced diuresis for rhabdomyolysis • Medications ——Insufficient evidence for use of medications for cooling, including ■■ Antipyretics ■■ Dantrolene (Dantrium) ——Chlorpromazine (Promapar, Thorazine) or muscle relaxants reported to inhibit shivering caused by too-rapid temperature reduction ——Consider benzodiazepines for seizure.

• Cooling ——Immediate cooling to 39.4°C (102.9°F) recommended before emergency transport ——Limited evidence to define optimum cooling method ——Cold-water immersion provides fastest whole-body cooling rate and lowest morbidity and mortality for exertional heatstroke in athletes.

——If water-immersion unavailable ■■ Apply ice-water-soaked towels/sheets to head, trunk and extremities and ice packs to neck, axillae and groin. (Change every two to three minutes.)

■■ Warm-air mist and fanning techniques provide slower whole-body cooling rates but effective only if low relative humidity ■■ Other conductive and evaporation techniques may be useful, including »»Cooling blanket

Follow-up

• Before resuming training and competition ——Refrain from exercise for at least seven days after release from medical care.

——Initiate exercise in cool environment and gradually increase duration, intensity, and heat exposure for two weeks to acclimatize and demonstrate heat tolerance.

——Follow-up in one week for physical exam and repeat lab testing.

——Clear athlete for full competition if heat tolerance exists after two to four weeks of training.

——Consider laboratory exercise-heat tolerance test about one month post-incident if difficulty to exercise persists.

• Good prognosis associated with ——Prompt recognition and appropriate treatment (survival rate 90%-100%) ——Cognitive function returning to normal range within one hour of onset of symptoms • Poor prognosis if treatment is initiated more than two hours after onset • High mortality ——During heat waves ——Among firefighters with heatstroke (up to 80%) Prevention

• Avoid extreme heat.

• Wear loose, light clothes.

• Do not leave children unattended in cars during hot weather.

• Exercise conditioning to reduce risk ——10 to 14 days of exercise training in heat to improve heat acclimatization ——Physical training and cardiorespiratory fitness • Appropriate fluid ingestion before, during and after exercise • Modify physical activity according to air temperature, relative humidity, sun exposure, heat acclimatization status, age, and equipment requirements.

• Heat index chart can be used to estimate when to limit outside activity.

• Fans provide no protection at high temperatures if humidity is high (for example, temperatures >32.2°C [90°F] with associated humidity >35%). n

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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 115

n ADDITIONAL CME/CE: Pages 76, 111

Turn to page 75 for additional information on this month’s CME/CE courses.

CASE #1

Red coalescing lesions on the chest DUSTIN LARSEN AND JULIA R. NUNLEY, MD

A woman, aged 48 years, complained of a rash on her chest that first appeared rather suddenly two months earlier. The lesions were extremely pruritic and had responded minimally to topical steroids prescribed at an urgent-care center. A review of systems revealed episodic flushing, dizziness, abdominal pain, and diarrhea that seemed to be triggered by alcohol consumption or exercise. The woman’s medical history was significant for peptic ulcer disease and type 2 diabetes. Physical examination revealed numerous red 3-to-5-mm coalescing macules on the center of the patient’s chest. Vigorous stroking of individual lesions caused the lesions to urticate.

What is your diagnosis? Turn to page 104

CASE #2

Peeling rash on the trunk and extremities AUDREY CHAN, MD

For the past two months, a man, aged 49 years, experienced persistent nausea, vomiting, and diarrhea. Dermatology was consulted for treatment of a rash that had been present for one month. Medical history was significant for HIV and end-stage renal disease. Physical examination revealed superficial desquamation with underlying erosions on the trunk and extremities with a “flaky paint” appearance. Erythematous plaques were noted in the intertriginous areas, most prominently in the groin. Lab results were significant for an albumin level of 0.8 g/dL. What is your diagnosis? Turn to page 106 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2013 103

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CME CE

CASE #1

Dermatology Clinic

Systemic mastocytosis

The combination of systemic symptoms should trigger the clinician to consider a group of unusual conditions associated with the episodic release of vasoactive cytokines; in combination with the highly characteristic rash described in this patient, the most likely diagnosis is systemic mastocytosis (SM). Indeed, a skin biopsy demonstrated large aggregates of mast cells within the dermis. Subsequent studies included a bone marrow biopsy that revealed a dense infiltrate of mast cells and an elevated serum tryptase level >100 ng/mL. This constellation of findings confirmed the diagnosis of SM. Classified as a myeloproliferative process, mastocytosis develops due to the clonal expansion of normal mast cells in one or more organ systems.1 Because of its rarity and limited epidemiologic data, the true prevalence of mastocytosis is speculative. Overall, the condition is more common in children, but there is a bimodal age of presentation: Approximately 75% of mastocytosis cases occur in infancy or early childhood, with a second peak in the fourth decade of life.2

For most patients, mastocytosis is a benign and self-limited condition that is associated with transient symptoms.

The World Health Organization categorizes mastocytosis into cutaneous and systemic subtypes. The cutaneous form of mastocytosis is more common in all ages; however, SM and malignant transformation is far more common in the adult population.1,3 Skin findings are usually the first clinical sign of mastocytosis. Urticaria pigmentosa (UP) is the most common of the four major cutaneous subtypes (i.e., UP, solitary mastocytoma, diffuse erythrodermic mastocytosis, and telangiectasia macularis eruptiva perstans). UP typically presents as innumerable 3-to-4-mm, oval-to-round, red-brown macules, or papules, most commonly on the chest and proximal extremities.2 Fine telangiectasias can

sometimes be seen in or around primary lesions.4 Solitary mastocytomas, which are more common in children and rare in adults, consist of rather large flesh-colored dermal nodules. Diffuse erythrodermic mastocytosis is also rare but is still more common in children and can be associated with skin thickening and bullae. Telangiectasia macularis eruptiva perstans (TMEP) is similarly rare, more common in adults, and consists of small telangiectasias that can be overlooked because they appear as banal hyperpigmented macules. These macules are also frequently mistaken for spider angiomas or telangiectasias that are attributable to other conditions.2,4,5 Generalized pruritus, dermatographism, and the Darier sign (urtication with light rubbing of the skin) are other clinical clues seen with all mastocytosis subtypes except TMEP.2,6 If firm stroking of a cutaneous lesion results in the formation of a localized hive, the Darier sign is present.

For most patients, mastocytosis is a benign and self-limited condition that is associated with transient symptoms.

However, adults with mastocytosis are more likely to have persistent skin findings and are more likely to develop systemic involvement.6 A small percentage of adults may develop an aggressive form of systemic disease, mast-cell leukemia, or sarcoma.2 The symptoms of SM arise when the infiltrating mast cells degranulate and release various cytokine mediators locally and/or systemically.1 Degranulation can be triggered by a number of stimuli, including local trauma, intense physical exercise, alcohol consumption, excessive stress, insect venom, and various drugs (e.g., opioids, inhaled anesthetics, and topical polymyxins).2 Common symptoms of SM include pruritus, flushing, headache, bone pain, dyspepsia, diarrhea, tachycardia, dizziness, syncope, and hypotensive shock.1,2 Physical findings most commonly seen in individuals with SM include hepatomegaly, splenomegly, osteoporosis, gastrointestinal malabsorption, and dysfunction. Such adverse conditions as peptic ulcers, hepatic failure, bone-marrow failure, and leukemia may also develop.1 Fortunately, 90% of patients will have an indolent form of SM with a good prognosis and normal life expectancy; only a few progress to more advanced forms of disease.2,7 The etiology of SM is not completely understood. Most of the patients studied have had an activating mutation in codon 816 of the c-kit gene, which encodes for the KIT tyrosine kinase receptor. Mast-cell growth and differentiation is triggered when this KIT receptor is bound by a ligand known as stem cell factor; mutation of the KIT

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receptor leads to constitutive activation.1,8 Because a relatively small percentage of patients with SM do not possess this mutation, the mutation is considered only a minor diagnostic criterion.1 The differential diagnosis for SM depends on the cutaneous and/or systemic clinical presentation. For UP, the differential diagnosis includes lentigines and atypical melanocytic nevi. A positive Darier sign would differentiate UP from these conditions. The clinician should be aware that a positive Darier sign may cause UP to be mistaken for urticaria.9 Persistence of hyperpigmented lesions once the hive resolves should be a clinical clue that simple urticaria is not the diagnosis.2,6 Conditions to be considered when a patient presents with systemic symptoms may vary considerably depending on which organ systems are affected. In these cases, recognizing the significance of a rash can be vital in securing the correct diagnosis. Akin et al reported that a subset of 12 patients referred for recurrent idiopathic anaphylaxis actually had SM; of these, physical examination revealed UP in eight individuals.10 Making the diagnosis of SM typically requires suspicion of the condition. Skin biopsies are often the first diagnostic test. Identifying aggregates of mast cells is fairly straightforward, but sometimes the collections are small and require confirming immunohistochemical staining with cell surface markers, tryptase, and, if available, staining for the KIT mutation. All individuals diagnosed with cutaneous mastocytosis should have a complete blood count and have their serum tryptase levels measured. If elevated, the clinician should consider a bone-marrow biopsy, which aids in diagnosis and is necessary for staging the disease. Since children only rarely have extracutaneous involvement, a bone-marrow biopsy should be considered only if the tryptase level is >100 ng/mL or if there are other clinical signs of systemic disease.11 Unfortunately, there is currently no cure for SM. The goal of treatment is symptom control and relief. To avoid triggering symptomatic episodes, patients should always be educated regarding the agents and events that cause mast-cell mediator release. Such symptoms as pruritus, flushing, and tachycardia can be ameliorated with the use of histamine-1 blockers; histamine-2 blockers help mitigate the GI symptoms. Oral cromolyn sodium (Gastrocrom), a specific mast-cell stabilizer, can be used to prevent future GI symptoms. Other medications that can help with symptomatic relief or moderate end-organ damage include glucocorticoids, bisphosphonates, proton-pump inhibitors, and

self-injectable epinephrine for severe anaphylaxis.11 Psoralen with UVA (PUVA) phototherapy has been shown to be highly effective in treating UP and associated pruritus.12 Patients with more aggressive forms of SM may require cytoreductive therapy.11 The patient in this case was placed on cromolyn for control of her GI symptoms. Her skin showed rapid clearing once PUVA was initiated.

Mr. Larsen is a third-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is a professor of dermatology.

References 1. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.

2. Brockow K. Urticaria pigmentosa. Immunol Allergy Clin North Am. 2004;24:287-316.

3. Berezowska S, Flaig MJ, Ruëff F, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2013 Jun 28.

Epub ahead of print.

4. Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537-555.

5. Gordon Spratt EA, DeFelice T, O’Reilly K, et al. Generalized essential telangiectasia. Dermatol Online J. 2012;18:13. Available at escholarship.org/ uc/item/0hx273p5.

6. Caplan RM. The natural course of urticaria pigmentosa. Arch Dermatol.

1963;87:146–157.

7. Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Curr Opin Hematol. 2010;17:125-132.

8. Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol.

2006;19:595-615.

9. Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, N.Y.: McGraw-Hill; 2012.

10. Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007;110:2331-2333. Available at bloodjournal. hematologylibrary.org/content/110/7/2331.long.

11. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435-453.

12. Godt O, Proksch E, Streit V, Christophers E. Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;195:35-39.

All electronic documents accessed October 15, 2013.

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CME CE

CASE #2

Dermatology Clinic

Kwashiorkor

A nutritional disease is caused by either insuff iciency or excess of one or more dietary essentials.1 Kwashiorkor is a nutritional disease in which there is protein deficiency despite normal caloric intake.

The disease is defined as a total body weight of 60% to 80% of ideal body weight with either edema or hypoalbuminemia, or both.2 Nutritional diseases, including kwashiorkor, are endemic in the developing world. In developed countries, protein deficiency occurs predominantly in the chronically ill and in hospitalized patients.3 Protein deficiency can be attributable to either exogenous (primary) causes or endogenous (secondary) causes. Examples of exogenous causes include poverty, old age, alcoholism, psychiatric disorders (e.g., anorexia nervosa, bulimia), diets, and child neglect. Causes of endogenous protein deficiency include intestinal malabsorption (e.g., bowel bypass, cystic fibrosis), gastroenteritis or other GI diseases, metabolic disease, chronic systemic disease (e.g., malignancy), and HIV.3 Kwashiorkor is characterized by skin and hair changes and edema. In children with kwashiorkor, impaired growth and the characteristic potbelly are often seen.

Peeling of the skin is a cutaneous finding specific to kwashiorkor. In mild cases, only a superficial desquamation is seen; it is referred to as “enamel paint spots.” In severe cases, large erosions can be seen underlying the desquamation; these have been described as “flaky paint.”3 Dyschromia is a common finding in kwashiorkor for a multitude of reasons. Pallor caused by skin distension from edema and loss of pigment may be seen in some cases. Hypopigmentation may be seen following abrasions, wounds, and ulcerations. Large “flaky paint” ulcerations often heal with hypopigmentation coupled with a characteristic hyperpigmented border.2 Hyperpigmentation can be seen in areas subject to trauma or friction, including the flexures, groin, buttocks, and elbows.2 Other cutaneous findings of kwashiorkor include erythema, thinning, petechiae, ecchymoses, and purpura.3 The hair in patients with kwashiorkor is often sparse, dry, and brittle. A reddish tinge may be noted as well. Alternating bands of pale and dark coloration along a single strand of hair is a specific hair finding in patients with protein deficiency.

The dark hair corresponds to periods of good nutrition, while the pale hair occurs during periods of poor protein intake. This finding is referred to as “the flag sign.”2,3 Curlyhaired individuals with kwashiorkor may develop straight hair.2 The nails in patients with kwashiorkor are often soft and thin.2,3 The mucosa may often be involved and can present with cheilitis, xerophthalmia, and vulvovaginitis.

Systemic features of kwashiorkor include edema, moon facies, and potbelly. Children are often anorexic, irritable, and apathetic. If there is a prolonged period of deficient protein intake, children may develop failure to thrive with delayed growth and mental development.3 Bilateral parotitis is another possible systemic feature associated with kwashiorkor. As seen in many other nutritional deficiencies, patients with kwashiorkor may develop diarrhea.

By definition, kwashiorkor patients are noted to have hypoalbuminemia with albumin levels <2.5 g/dL. They may have some level of immune deficiency and are often noted to have low alpha and beta globulins. Over time, these individuals may also develop a gamma-globulin deficiency.

Impaired cellular immunity may also develop.3 This deficiency in humoral and cellular immunity may predispose patients to superimposed bacterial and fungal infections.

The diagnosis of kwashiorkor is made based on clinical and laboratory findings. Skin biopsies are useful in confirming an underlying nutritional deficiency; however, a skin biopsy cannot determine which specific nutrient is deficient. The most notable histologic findings for all nutritional deficiencies are pallor of the upper epidermis, a superficial perivascular lymphocytic infiltrate, and confluent parakeratosis.1 If a skin biopsy of the “enamel pain spots” is obtained, a thickened, pigmented stratum corneum with an underlying stratum lucidum may be seen.3 Some patients may develop hepatomegaly. If a liver biopsy or imaging study is performed, fatty-liver change may be noted.3 Given the sparse hair seen clinically in kwashiorkor patients, it is not surprising that histologic examination of scalp biopsies reveal a decreased number of follicles in the growth phase (anagen follicles) and an increased number of follicles in the resting phase (telogen follicles). Scalp biopsies may also reveal severe atrophy, shaft constriction, and depletion of pigment in anagen follicles, which explains the pale, brittle, lusterless hair seen in patients with protein deficiency.

The differential diagnosis of kwashiorkor includes such other nutritional deficiencies as zinc deficiencies and pellagra. Zinc deficiency may be inherited or acquired; the inherited form is known as acrodermatitis enteropathica.

Like patients with kwashiorkor, patients with zinc deficiency

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can present with stomatitis, alopecia, diarrhea, irritabiliy, and failure to thrive. Unlike patients with kwashiorkor, patients with zinc deficiency often present with glossitis and photophobia. A low zinc level will be diagnostic. A quick screening test for zinc deficiency is a low serum alkaline phosphatase level, because alkaline phosphatase is a zinc-dependent enzyme.4 Pellagra is caused by vitamin B3 deficiency and is characterized by the triad of dermatitis, diarrhea, and dementia. The dermatitis seen in pellagra is distinct from that of kwashiorkor because it is photodistributed. When this photosensitive eruption forms a broad band around the neck, it is referred to as “Casal necklace.”3 Diagnosis is often confirmed by the clinical response to niacin supplementation, as niacin levels are typically only obtained for research purposes.

Kwashiorkor is treated through the implementation of a balanced diet with adequate protein and caloric intake.3 Cutaneous findings are all reversible with therapy.3 While awaiting resolution of cutaneous lesions with protein supplementation, symptomatic relief can be achieved with topical moisturizers and ointments. Fatal complications of kwashiorkor include hypoglycemia with hypothermia, coma, and bacterial or parasitic disease, so careful monitoring of these patients is required.3 High mortality rates are seen in patients with HIV. The protein deficiency of the man in this case was felt to be multifactorial, as he was diagnosed with dumping syndrome in addition to chronic active ileitis and cytomegalovirus colitis in the setting of HIV. After several weeks of trophic tube feeds with total parenteral nutrition, improvement in his skin was noted. n

“It helps cut post-op recovery times, as well as health-care costs.”

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

Dr. Chan is a third-year dermatology resident at Baylor College of Medicine in Houston.

References.

1. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:469.

2. Schachner LA, Hansen RC, eds. Pediatric Dermatology. 4th ed.

Philadelphia, Pa.: Mosby Elsevier; 2011:1263-1264.

3. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:661-663.

4. Cho YE, Lomeda RA, Ryu SH, et al. Zinc deficiency negatively affects alkaline phosphatase and the concentration of Ca, Mg and P in rats. Nutr Res Pract. 2007;1:113-119. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC2882585/.

All electronic documents accessed October 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.

Green coffee extract

© THINKSTOCK

Green coffee is simply coffee that has not been “cooked.” Green coffee products are made from unroasted coffee beans, usually from the plant Coffea arabica.1 Most of the world enjoys coffee products that are manufactured from roasted coffee beans.

The most widely known natural component of coffee is caffeine but, in reality, coffee contains hundreds of bioactive chemicals, many of which are more significant than caffeine.1 Green coffee products have become widely popular as a potential weight-loss aid.

Background Green coffee extract contains chlorogenic acid, which is derived from a major group of phenolic compounds.2 Green coffee beans contain nearly twice the concentration of chlorogenic acid as do roasted beans. Chlorogenic acid is a major component of many OTC weight-loss products and acts independently of caffeine.2 The theorized mechanism of action by which green coffee produces weight loss is through the inhibition of the enzyme glucose-6-phosphatase.3 In vitro, glucose-6-phosphatase induces the enzymatic process of glucose production in the liver.3 It is this step in the metabolic pathway that researchers attribute to the known reduction of glycemic disorders in long-term coffee-drinkers.4

Science Green coffee extract is believed to aid weight loss. One trial evaluated the responses of 16 overweight adults who had been

randomized to high-dose extract, low-dose extract, or placebo in a 22-week study.5 Body weight decreased by a mean of 8 lbs, with a mean drop in body fat of more than 4%.5 In another study, 50 volunteers with body mass indices >25 were randomized to placebo or to treatment with green coffee extract.6 After 60 days, members of the treatment group had lost an average of 5.7% of their body weight, with a shift in the muscle-mass-to-fat-mass ratio of +4.1%/-0.7% from baseline.6 In a trial designed to compare the effect of green coffee vs. roasted coffee on BP measurements, researchers randomized more than 200 subjects to either a placebo coffee drink or a drink with low, medium, or high chlorogenic-acid content.7 Each participant drank one cup of the treatment coffee per day and recorded BP readings for one month. At the end of the trial, not only were the BP readings of the placebo group higher than the BP readings of the treatment group, but a definite dose-response curve for the three treatment dose levels also was seen. This indicates that the beneficial effect of coffee intake on BP has nothing to do with caffeine,

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Download the new app for the iPhone, iPad,and Android— created specifically for nurse practitioners and physician assistants from the publishers of the highest rated journal for these health-care professionals.

With the Clinical Advisor app you can: • Take Derm Dx quizzes to learn about difficultto-identify dermatology conditions, and then see how you performed against your peers.

• Use medical calculators to do things like assess liver function, convert HbA1C to mean plasma glucose, evaluate BP, determine BMI and more.

• Read the latest news about breakthrough treatments, disease outbreaks, drug approvals and recalls, and clinical research.

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ALTERNATIVE MEDS UPDATE but rather with the chlorogenic acid content.

These findings have been validated by multiple studies examining different green coffee extract concentrations and populations.8, 9 In each trial, a statistically significant reduction of systolic BP was seen with no documented adverse effects.

Researchers looking at human vasoreactivity monitored nitric oxide activity in individuals after daily intake of a measured amount of green coffee extract. For four months, parameters indicative of endothelial function were monitored daily. At the end of the test period, the vasodilatory response was found to be significantly higher in the test group than in the placebo group, and total plasma homocysteine levels were also lower than at baseline.10 A small lab study using human cell culture lines focused on the chemoprotective and antigenotoxic activities of green coffee extract.11 Human colon and liver cells were treated with a dose-calculated solution of chlorogenic acid and cultured under the same conditions as the placebo cell cultures. Both cell lines were then tested for levels of oxidative stress, such as membrane disruption, DNA damage, and cell death.

Cells exposed to the chlorogenic acid solution showed markedly lower levels of these oxidative injuries than did the untreated cells.

Safety, how supplied, dose, and cost

References 1. van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA. 2005;294:97104. Available at jama.jamanetwork.com/article. aspx?articleid=201177 2. Arion WJ, Canfield WK, Ramos FC, et al. Chlorogenic acid and hydroxynitrobenzaldehyde: new inhibitors of hepatic glucose 6-phosphatase. Arch Biochem Biophys.

1997;339:315-322.

3. Herling AW, Burger HJ, Schwab D, et al.

Pharmaco­dynamics profile of a novel inhibitor of the hepatic glucose-6-phosphatase system. Am J Physiol.

Green coffee extract is believed to assist in weight loss.

Marketed green coffee extract is often standardized to contain more than 50% chlorogenic acid.

1998;274(6 Pt 1):G1087-1093. Available at ajpgi.physiology. org/content/274/6/G1087.

4. Greenberg J, Boozer CN, Geliebter A. Coffee, diabetes, and weight control. Am J Clin Nutr. 2006;84:682693. Available at ajcn.nutrition.org/content/84/4/682.long.

5. Vinson JA, Burnham BR, Nagendran MV. Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects. Diabetes Metab Synd Obes. 2012;5:21-27. Available at www.ncbi.nlm.nih.gov/ pmc/articles/PMC3267522/.

6. Dellalibera O, Lemaire B, Lafay S. Svetol, green coffee extract, induces weight loss and increases the lean to fat mass ratio in volunteers with overweight problem. Exper Phytother. 2006;4:194-197.

7. Yamaguchi T, Chikama A, Mori K, et al.

Hydroxyhydro­quinone-free coffee: a double-blind, randomized controlled dose-response study of blood pressure. Nutr Metab Cardiovasc Dis. 2008;18:408-414.

8. Watanabe T, Arai Y, Mitsui Y, et al. The blood pressure-

Few adverse reactions have been noted with green coffee extract use. The extract is supplied in a variety of ways, including as liquid extract, powder or liquid-filled capsules, or a drink. The dose is widely variable based both on body mass and age.

Marketed green coffee extract is often standardized to contain more than 50% chlorogenic acid.

Average cost for a typical month’s supply ranges from $20 to $30, regardless of the dosage form.

Summary

lowering effect and safety of chlorogenic acid from green coffee bean extract in essential hypertension. Clin Exp Hypertens. 2006;28:439-449.

9. Kozuma K, Tsuchiya S, Kohori J, et al. Antihypertensive effect of green coffee bean extract on mildly hypertensive subjects. Hypertens Res. 2005;28:711-718. Available at www.nature.com/hr/journal/v28/n9/pdf/hr200591a.pdf.

10. Ochiai R, Jokura H, Suzuki A, et al. Green coffee bean extract improves human vasoreactivity. Hypertens Res. 2004;27:731-737.

11. Glei M, Kirmse A, Habermann N, et al. Bread enriched antigenotoxic activities in human cells. Nutr Cancer.

2006;56:182-192.

All electronic documents accessed October 15, 2013.

© THINKSTOCK

with green coffee extract has chemoprotective and

While further study is needed, green coffee extract appears to be safe and somewhat effective in increasing the efficacy of regular weight-loss methods. n 110 THE CLINICAL ADVISOR • NOVEMBER 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 115

n ADDITIONAL CME/CE: Pages 76, 103

Turn to page 75 for additional information on this month’s CME/CE courses.

Young boys with desquamating skin CHRISTOPHER CHU AND ADAM REES, MD

CASE #1

CASE #2

A boy, aged 4 years, was brought to the emergency department (ED). His parents reported that he had experienced recurrent ear infections over the past eight months, the most recent of which had occurred two weeks earlier and had been treated with sulfamethoxazole/trimethoprim (Bactrim, Septra, Sulfatrim). Three days before presenting to the ED, the boy had a low-grade fever, tender skin erythema, and a sore throat. Examination revealed blistering and desquamating skin over approximately 10% of the boy’s body. Conjunctivitis and oral erosions were also noted.

The parents of a 5-year-old boy brought their son to the ED. Two days prior to presentation, the boy had developed a low-grade fever and his skin had become pink. The next day, his parents noticed that his skin was peeling slightly around his groin. On the morning of presentation, the boy’s skin was peeling in the groin folds, axilla, neck, back, and face. The patient was afebrile on examination, and desquamation was noted in the flexural areas and back. Slight purulence was noted in the nasal passages.

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CME CE

CASE #1

Dermatologic Look-Alikes

Stevens-Johnson syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are lifethreatening mucocutaneous diseases associated with certain groups of medications.

Use of potential offender medication is reported in more than 80% of cases of TEN and in up to 50% of cases of SJS, although this may be an underestimation. SJS and TEN are diseases of unclear pathology and result in extensive keratinocyte cell death and separation of significant areas of skin and mucous membranes at the dermalepidermal junction.1,2 SJS and TEN are now considered to be on a spectrum. SJS is defined as <10% body surface area involvement, and TEN is defined as >30% body surface area involvement. Body surface area involvement between 10% and 30% constitutes an SJS/TEN overlap syndrome.3 Clinically, initial symptoms of SJS include fever, stinging eyes, and dysphagia, all of which can precede cutaneous manifestations. Tender skin lesions appear first on the trunk before spreading to the neck, face, and proximal upper extremities.

While the distal extremities are often spared, the palms and soles are also a site of early involvement.1,2 Approximately 90% of patients have erythema and painful erosions of the buccal, ocular, and genital mucosa. Less commonly, the mucosa of the respiratory and GI tract are involved.4

In patients with SJS, the skin resembles wet cigarette paper and reveals raw and bleeding dermis when pulled away.

Lesions first appear as an erythematous and purpuric macule with a tendency to coalesce. SJS should be suspected in any patient with these lesions plus the presence of mucosal involvement. Clinicians should look for the Nikolsky sign by applying tangential pressure with a finger on any erythematous lesions. The Nikolsky sign is positive if dermal-epidermal cleavage is seen.4 Within hours to days, epidermal involvement progresses towards full-thickness necrosis. The necrotic epidermis then detaches from the underlying dermis, and fluid fills the space between the dermis and the epidermis, producing

blisters. The blisters are flaccid and can be extended sideways with pressure of the thumb, as more necrotic epidermis is displaced laterally (Asboe-Hansen sign). The skin resembles wet cigarette paper and reveals raw and bleeding dermis when pulled away.1,2 Certain patient populations have an increased risk of developing SJS. Such populations include the immunocompromised and those with specific human leukocyte antigen (HLA) types. The HLA-DQB1* 0601 allele is reported disproportionately in white patients with SJS and ocular complications.5 HLA-B *1502 in Asians and East Indians predisposes these individuals to SJS caused by carbamazepine. The FDA recently recommended genotyping all Asians for the HLA allele before administering the drug to these patients.6 In patients with AIDS, the risk of developing SJS is 1,000-fold higher.4 More than 100 drugs have been identified as being associated with SJS, the most common of which are nonsteroidal anti-inflammatory drugs, anticonvulsants, antibiotics (especially sulfonamides), and allopurinol (Aloprim, Lopurin, Zyloprim).4 In general, risk is highest during the initial weeks of therapy.

Because delayed withdrawal of the causative drug is associated with increased mortality, identifying the causative drug is extremely important. Currently, no reliable test for identification of the causative drug is available. Clinicians must rely on previously reported cases while taking into account the use of a given medication in relationship to the onset of SJS. SJS usually occurs seven to 21 days after initiation of the causative drug in the setting of a first exposure. In a case of re-exposure, SJS can occur as early as two days later.1,2 Staphylococcal scalded skin syndrome (SSSS), another disease of skin desquamation, can usually be clinically distinguished from SJS. SSSS occurs in newborns and young children but can also rarely occur in adults who are in renal failure or who are immunosuppressed. SSSS tends to spare the palms, soles, and the mucous membranes, unlike SJS, in which the mucous membranes are always affected. While the Nikolsky sign may be positive, it results in a superficial subcorneal cleavage, as opposed to the dermal-epidermal separation seen in SJS. This superficial exfoliation leaves behind an intact epidermal layer instead of the wet and bright-red dermal tissue observed in SJS. Also, in SSSS, a purulent nasal discharge is frequently present. Histologically, SJS shows a full-thickness epidermal necrolysis, whereas SSSS shows a subcorneal split with a normal underlying epidermis.1,2 Successful treatment of SJS requires early diagnosis, immediate discontinuation of the causative drug, supportive care

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in an intensive care unit, and specific therapy. Supportive care for SJS is similar to that of a thermal burn and is aimed at the associated complications that cause mortality (i.e., hypovolemia, electrolyte imbalance, renal insufficiency, and sepsis).1,2 Wound care is important in the treatment of SJS. Manipulation should be kept to a minimum. Detached areas should be covered with petrolatum (Vaseline) gauze and silicone dressings.

All SJS patients should have regular ophthalmological exams. Scarring and other ocular complications are potential adverse sequelae of SJS, and the ophthalmologist is a key member of the medical team in the management of SJS. No specific therapy for SJS has yet shown efficacy in a controlled clinical trial. High-dose systemic corticosteroids are often used, with pulse therapy proving the most successful.7 Recent evidence supports the use of high-dose intravenous immunoglobulin (IVIG), which has become the treatment of choice at many institutions, but this remains controversial.8 The patient in this case was admitted to the hospital, where the sulfamethoxazole/trimethoprim was immediately stopped. An infusion of IVIG was administered. The hospital’s wound care and ophthalmology services evaluated the patient. Two days after being admitted, the body surface area affected was up to 25%. The patient was maintained on a regimen of daily wound care. By the third day, the skin loss has stabilized. The patient remained hospitalized for 12 days. Four weeks after discharge, the boy had made a complete recovery with no anticipated long-term sequelae.

CASE #2

Staphylococcal scalded skin syndrome

Formerly known in the past as Ritter’s disease or dermatitis exfoliativa neonatorum, SSSS is a generalized, confluent, and superficially exfoliative disease. The syndrome triggers fever and causes the skin to exfoliate rapidly in sheets.

SSSS usually occurs in neonates and in young children.

Rarely, adults with chronic renal insufficiency or immune suppression are affected.9 SSSS is primarily attributable to hematogenous dissemination of the exfoliative toxins (ETs) type A and type B

(ETA and ETB). The same toxins, when produced locally, lead to bullous impetigo. However, in SSSS, hematogenous dissemination leads to extension of the lesions beyond the area of actual staphylococcal infection.10 Staphylococcus aureus is usually transmitted through humanto-human contact. A carrier with asymptomatic colonization of the strain is responsible for the transmission. Outbreaks that occur in neonatal nurseries are usually secondary to asymptomatic carriage of a toxogenic strain of S. aureus by health-care workers or parents.

Most cases of SSSS are caused by phage-group II strains type 71 or 55 of S. aureus.11 This group can be either methicillin-sensitive or methicillin-resistant, but always produces ETA or ETB. ETA (chromosomally encoded) and ETB (plasmid encoded) are serine proteases that bind and cleave desmoglein-1. This binding causes the desmosomes to split, which leads to disruption at the epidermal granular layer and blister formation. In bullous impetigo, however, the effects of the ETs are limited to the site of infection.

In contrast, the hematogenous diffusion of the ET in SSSS from a focus of infection produces widespread effects. In children, the most common infectious focus is usually in the nasopharynx or conjunctivae. In adults, SSSS is most likely due to a staphylococcal pneumonia or bacteremia.1,2 The clinical characteristics of SSSS begin with a prodrome of malaise, fever, irritability, skin erythema, and severe tenderness of the skin. The patient may have purulent rhinorrhea or conjunctivitis as a manifestation of the underlying staphylococcal infection. Erythema typically first appears on the head with facial edema and in intertriginous sites (i.e., the groin and axilla). The erythema typically becomes diffuse within 48 hours. The skin develops a wrinkled appearance due to the formation of flaccid and sterile bullae within the superficial epidermis. As in SJS, a positive Nikolsky sign can be elicited by applying tangential pressure to bullae, which leads to subcorneal cleavage.1 Classically, the flexural areas are the first to exfoliate, leaving behind moist skin and thin, varnish-like crusting.

Patients demonstrate characteristic periorificial crusting and radial fissuring. However, unlike in SJS, intraoral lesions do not occur. Scaling and desquamation with large sheets of epidermis separating continue for the next three to five days, followed by re-epithelialization without scarring. With proper treatment, SSSS resolves in one to two weeks without sequelae. The mortality rate is only 3% in children but >50% in adults.12 Continues on page 114

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CME CE

Dermatologic Look-Alikes

SSSS is usually diagnosed clinically. To confirm the diagnosis or to rule out other causes, skin biopsy may be performed. Cultures taken from the intact bullae will be negative, because the skin erythema and desquamation of SSSS are caused by the distant effects of the ET. If cultures are taken, the clinician should focus on the conjunctiva, nasopharynx, feces, or pyogenic foci on the skin.

Skin biopsy shows a sharply demarcated zone of cleavage at or below the stratum granulosum. There are usually no inflammatory cells in the bullae. The upper dermis also lacks an inflammatory infiltrate, and no organisms are seen on gram stain of biopsy specimens.

Individuals diagnosed with severe, generalized forms of SSSS require hospitalization and parenteral antibiotics.13 Initial treatment for such patients at the authors’ institution consists of intravenous clindamycin (Cleocin Phosphate IV) before transitioning to oral clindamycin (Cleocin).

The patient in this case was admitted to the hospital and started on IV clindamycin. A culture taken from the nasal passages grew methicillin-sensitive S. aureus. The patient remained stable and afebrile without any progression of skin desquamation. He was discharged after 24 hours on oral clindamycin. At the two-week follow-up, the boy had made a complete recovery. n

7. Araki Y, Sotozono C, Inatomi T, et al. Successful treatment of Stevens-Johnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009;147:1004-1011.

8. Momin SB. Review of intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis. J Clin Aesthet Dermatol. 2009;2:51-58. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC2958184/.

9. Patel GK, Finlay AY. Staphylococcal scalded skin syndrome: diagnosis and management. Am J Clin Dermatol. 2003;4:165-175.

10. Ladhani S. Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus. FEMS Immunol Med Microbiol.

2003;39:181-189.

11. Dajani AS. The scalded-skin syndrome: relation to phage-group II staphylococci. J Infect Dis. 1972;125:548-551.

12. Ladhani S, Evans RW. Staphylococcal scalded skin syndrome. Arch Dis Child. 1998;78:85-88. Available at adc.bmj.com/content/78/1/85.long.

13. Knowles SR, Shear NH. Cutaneous drug reactions with systemic features. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed.

Philadelphia, Pa.: Saunders Elsevier; 2013:747-756.

All electronic documents accessed October 15, 2013.

Mr. Chu is third-year student at Baylor College of Medicine in Houston, where Dr. Rees is a resident in the Department of Dermatology.

References 1. Sobera JO, Elewski BE. Fungal diseases. In: Bolognia JL, Jorizzo JL, 2008:1135-1164.

2. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-Elsevier; 2011:114-116, 252-253.

3. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and StevensJohnson syndrome: a review. Crit Care Med. 2011;39:1521-1532.

4. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:39. Available at www.ojrd.com/ content/5/1/39.

5. Power WJ, Saidman SL, Zhang DS, Vamvakas et al. HLA typing in patients with ocular manifestations of Stevens-Johnson syndrome.

Ophthalmology. 1996;103:1406-1409.

6. Ferrell PB Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008;9:1543-1546. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2586963/.

“I lost the hand to a shark, the leg to a barracuda, and the gallbladder to Dr. Steven Erlich.”

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

Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby;

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CE

POSTTEST Expiration date: November 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 0.5 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

Dermatology Clinic

Dermatologic Look-Alikes

page 103

page 111

Case #1: Systemic mastocytosis

Case #1: Stevens-Johnson syndrome

1. A clinical clue associated with systemic mastocytosis (SM) is the Darier sign, which is described as a. A white line that turns red with applied pressure b. Pinpoint bleeding when the lesion is scraped c. Urtication with light rubbing of the skin d. Development of new lesions with trauma

1. What location is often spared in individuals with Stevens-Johnson syndrome (SJS)? a. Proximal upper extremities b. Distal extremities c. Palms and soles d. Chest

2. What is a common symptom of SM? a. Pruritus b. Bone pain c. Dyspepsia d. All of the above

2. What antibiotic class is commonly associated with SJS? a. Sulfonamides b. Fluoroquinolones c. Aminoglycosides d. Cephalosporins

Case #2: Kwashiorkor

Case #2: Staphylococcal scalded skin syndrome

3. Where is the hyperpigmentation associated with kwashiorkor often found? a. Groin b. Back c. Scalp d. Face

3. Although rare, adults with which of the following conditions are affected by staphylococcal scalded skin syndrome (SSSS)? a. Inflammatory bowel disease b. Rheumatoid arthritis c. Chronic obstructive pulmonary disease d. Chronic renal insufficiency

4. What sign of zinc deficiency helps distinguish this condition from kwashiorkor? a. Alopecia b. Diarrhea c. Glossitis d. Stomatitis

4. The erythema associated with SSSS typically first appears on the a. Oral mucosa b. Head c. Joint surfaces d. Trunk

TO TAKE THE POSTTEST please go to CliniAd.com/1aDivhl

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice 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 infor-­­ mation 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.

ADDITION OF CO-TRIMOXAZOLE TO CEPHALEXIN DOES NOT INCREASE CURE RATE OF UNCOMPLICATED CELLULITIS Level 1: Likely reliable evidence The recommended treatment for non-purulent cellulitis (without abscess) is a beta-lactam antibiotic (e.g. cephalexin [Keflex]) (Clin Infect Dis. 2011;52:e18). However, antibiotics that target methicillin-resistant Staphylococcus aureus (MRSA) are often added for patients with uncomplicated cellulitis.To assess the benefits of adding antibiotics to specifically target MRSA, a new randomized trial compared the efficacy of combined treatment with co-trimoxazole (Bactrim, Septra, Sulfatrim) and cephalexin vs. cephalexin alone in 153 patients with uncomplicated cellulitis.

Patients aged 3 years to 74 years (median age 29 years) with symptoms of uncomplicated cellulitis for less than one week were randomized to cotrimoxazole plus cephalexin vs. cephalexin alone (with placebo) for at least seven days and followed for 30 days. Patients were instructed to continue antibiotic treatment for three days after resolution of treatment, up to a total of 14 days. Exclusion criteria included hospitalization, diabetes, renal insufficiency, immunosuppression, peripheral arterial disease, or purulent discharge >1 mL. MRSA was endemic in the areas in which the patients lived, and 13% of patients in the trial had associated purulence.

At the end of follow-up, the cure rate was 85% with combination treatment and 82% with cephalexin alone (not significant). The infection progressed to abscess in 6.8% in each group (not significant).There were also no significant differences in the rates of diarrhea, nausea and vomiting, or other adverse events. Neither the presence of purulence nor nasal colonization with MRSA appeared to influence outcomes.

In patients who have uncomplicated skin abscesses, the use of antibiotics that target MRSA did not appear to increase cure rates over incision and drainage alone (Emerg Med J. 2013 May 18.

[Epub ahead of print]). These two reports suggest that although MRSA is a significant clinical concern, providers should be judicious in their use of MRSA-targeted antibiotics.

In patients who have uncomplicated skin abscesses, the use of antibiotics that target MRSA did not appear to increase cure rates over incision and drainage alone.

APIXABAN IS AS EFFECTIVE AS CONVENTIONAL THERAPY FOR TREATMENT OF ACUTE VENOUS THROMBOEMBOLISM AND REDUCES BLEEDING RISK Level 1: Likely reliable evidence Standard therapy for venous thromboembolism (VTE) includes short-term treatment with a parenteral heparin-type anticoagulant (e.g. enoxaparin [Lovenox]) and long-term treatment with warfarin (Coumadin, Jantoven), which requires frequent monitoring and dose adjustment. Newer anti­coagulants, such as fixed-dose oral factor Xa inhibitors, could simplify VTE management by reducing the need for injections and monitoring.

The AMPLIFY trial compared the efficacy of the factor Xa inhibitor apixaban (Eliquis) to conventional therapy for treatment of acuteVTE in adults.

Patients with acute symptomatic proximal deep vein thrombosis or pulmonary embolism were randomized to one of two interventions and followed for seven months. The conventional therapy group received enoxaparin 1 mg/kg subcutaneously every 12 hours for five 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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© SCIENCE SOURCE / ST BARTHOLOMEW’S HOSPITAL

Apixaban has proven useful in the treatment of VTE (shown above).

or more days plus warfarin with target international normalized ratio (INR) 2.0-3.0 for six months.The apixaban group received 10 mg orally twice daily for the first seven days, then 5 mg twice daily for six months. Blinding was maintained through placebo subcutaneous injections and placebo warfarin with sham INR monitoring.The primary outcome was a composite of recurrent symptomatic VTE and VTE-related death.

Primary outcome events occurred in 2.3% with apixaban vs.

2.7% with conventional therapy (not significant).The apixaban group had lower rates of major bleeding (0.6% vs. 1.8%, p <0.001, NNT 84) and clinically relevant nonmajor bleeding (3.8% vs.

8%, p <0.05, NNT 24). There were no significant differences in all-cause mortality or in serious adverse events. These data in patients with acuteVTE add to recently published evidence regarding the efficacy and safety of long-term apixaban use for prevention of recurrent VTE (DynaMed EBM FocusVolume 8, Issue 11).Apixaban is currently FDA-approved only for use in patients with nonvalvular atrial fibrillation.

ADDITION OF VASOPRESSIN PLUS STEROIDS TO EPINEPHRINE INCREASES SURVIVAL TO DISCHARGE WITH FAVORABLE NEUROLOGIC OUTCOMES AFTER IN-HOSPITAL CARDIAC ARREST Level 1: Likely reliable evidence The addition of vasopressin and steroids to epinephrine during resuscitation has previously been shown to improve survival following in-hospital cardiac arrest compared with the use of epinephrine alone (Arch Intern Med. 2009;169:15). A new randomized trial further assessed the efficacy of combined treatment with vasopressin plus steroids in addition to epinephrine in 300 adult patients with in-hospital cardiac arrest.

Patients with in-hospital cardiac arrest requiring epinephrine

by European resuscitation guidelines were randomized to vasopressin plus steroids plus epinephrine (VSE) vs. epinephrine alone during resuscitation and were followed until death or hospital discharge.The VSE group received vasopressin 20 units/ cycle plus epinephrine 1 mg/cycle for the first five resuscitation cycles plus methylprednisolone 40 mg on first cycle. The epinephrine-alone group had epinephrine 1 mg/cycle plus normal saline placebo for the first five cycles.All patients could receive additional epinephrine as needed. Patients in the VSE group who had postresuscitation shock also received hydrocortisone IV 300 mg daily for up to seven days with gradual taper. (Patients in the epinephrine group with postresuscitation shock received placebo saline.) Favorable neurologic outcome was defined as a Cerebral Performance Category score of 1 (conscious, alert, and able to work, with possible mild neurologic or psychologic deficit) or 2 (moderate disability, but sufficient cerebral function for independent activities of daily living). The intention-to-treat analysis included all patients who received the allocated treatment. (Sixteen patients in each group had confirmed return of spontaneous circulation before administration of study treatment and were excluded from analyses.) The rate of survival to discharge with favorable neurologic outcome was 13.9% with VSE vs. 5.1% with epinephrine alone (p = 0.02, NNT 12).VSE was also associated with a higher rate of return of spontaneous circulation for at least 20 minutes (83.9% vs. 65.9%, p = 0.005, NNT 6). In a subgroup analysis of 149 patients who had postresuscitation shock, 21.1% of the VSE group and 8.2% of the epinephrine group survived to discharge with good neurologic outcome (p = 0.02, NNT 8).There were no significant differences in the rates of complications, postarrest morbidity, or causes of death in analyses of 162 patients who survived four or more hours.

GENTLE WIPING OF FACE, NOSE, AND MOUTH APPEARS AS EFFECTIVE AS SUCTION FOR CLEARANCE OF SECRETIONS AT BIRTH OF TERM NEONATES Level 3: Lacking direct evidence Oronasopharyngeal suction is frequently used immediately following routine delivery to clear the airway secretions of neonates both to prevent aspiration and to stimulate spontaneous respiration.

However, due to increases in the risks of bradycardia and apnea, guidelines from the American Heart Association recommend suction for babies born through clear amniotic fluid only in cases of obvious obstruction or need for mechanical

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Evidence-Based Medicine

Oronasopharyngeal suction is frequently performed in neonates.

ventilation (Circulation. 2010;122[18 Suppl 3]:S909).A recent randomized trial assessed the efficacy of simply wiping the mouth and nose at birth in 506 term neonates.

Infants born at ≥35 weeks gestational age (median 39 weeks) at a single hospital were randomized to gentle wiping of the face, mouth, and nose with a towel vs. suctioning of mouth and nostrils with a bulb syringe immediately after cutting of the umbilical cord and were followed for 24 hours. After randomization, 15 nonvigorous neonates with meconium-stained amniotic fluid were intubated and excluded from analysis.The primary outcome for assessing successful clearance of secretions was mean 24-hour respiratory rate.The rates of crossover to the alternate treatment were high in both groups: 26% in the wiping group received suction, and 14% in the suction group received wiping.The mean 24-hour respiratory rates were 51 breaths/minute with wiping vs. 50 breaths/minute with suction in the intention-to-treat analysis (not significant). Respiratory rates also showed no significant differences in per-treatment and per-protocol analyses.There were also no significant differences in incidence of tachypnea (respiratory rate >60 breaths/ minute) (46% vs. 46%), need for advanced resuscitation at birth (10% vs. 7%), or 5-minute Apgar scores (9 vs. 9).Wiping was associated with a nonsignificant increase in need for admission to neonatal intensive care (18% vs. 12%, p = 0.07).

FOR PRESSURE ULCERS, AIR-FLUIDIZED MATTRESSES, PROTEIN SUPPLEMENTS, RADIANT HEAT DRESSINGS, OR ELECTRICAL STIMULATION MAY IMPROVE HEALING Level 2: Mid-level evidence Pressure ulcers are common in hospitalized patients and may lead to further morbidity, increased costs, and death. A wealth

of research has been conducted to evaluate numerous treatment and prevention strategies, but the relative efficacy of different approaches remains unclear.Two recent systematic reviews commissioned by the Agency for Healthcare Research and Quality assessed the evidence for the benefits and harms of multiple strategies.

Pressure ulcer treatments were investigated in a review of 174 randomized trials and observational studies.The quality of the randomized trials was limited, and both clinical and statistical heterogeneity limited the viability of meta-analyses. Followup times varied widely, and in many studies were inadequate to assess complete wound healing. Categories of treatment strategies included support surfaces, nutritional supplements, local wound applications, and other adjunctive therapies.

There was no strong evidence in favor of any intervention, and no comparisons showed significant differences in rates of complete wound healing. However, a number of treatments had moderate evidence for partial healing assessed by reduction in wound size.

Air-fluidized mattresses appeared more effective than standard mattresses in five studies with 908 patients followed for four days to 36 weeks.The results of these studies were described as “highly consistent,” but no meta-analysis was performed. Protein supplements were more effective than no supplementation in 12 studies involving 562 patients and seven days to 10 months of follow-up. Radiant heat dressings (noncontact dressings with heating elements to increase capillary blood flow) appeared to reduce wound size compared with other dressings in four studies with 160 patients (4-12 weeks’ follow-up), and electrical stimulation with surface electrodes to apply current directly to the ulcer was more effective than sham stimulation in nine studies with 397 patients (3-16 weeks’ follow-up).

There were no significant differences in most other comparisons of treatment strategies. Hydrocolloid dressings were associated with greater reductions in wound size compared with standard care but also were associated with higher risks of skin reactions including inflammation, erythema, and wound deterioration. No comparisons showed significant differences in rates of complete wound healing. There was insufficient evidence to assess risk of harms in most comparisons.

In a companion systematic review of 62 trials evaluating pressure ulcer prevention strategies, advanced static support surfaces were associated with decreased risk of pressure ulcers compared with standard mattresses in five trials. Insufficient evidence was found regarding the efficacy of repositioning, nutritional support, and use of creams, dressings, or pads compared with usual care. No meta-analyses were performed for any interventions due to heterogeneity of treatment settings and comorbidities. n

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COMMENTARY Judi Greif, RN, MS, APN-C, is author of AIDS Care at Home: A Guide for Caregivers, Loved Ones, and People with AIDS.

HIV complacency can be deadly It has now been 32 years since the Centers for Disease Control and Prevention (CDC) issued a report of five cases of a rare type of pneumonia, Pneumocystis carinii, seen in previously healthy young homosexual men living in Los Angeles (MMWR. 1981;30[21]:1-3; available at www.cdc .gov/mmwr/preview/mmwrhtml/june_5.htm, accessed October 15, 2013). That seemingly minor case report, of course, was the start of what was eventually to be known as acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV).

Too many Americans have become complacent, no longer viewing HIV as a serious disease.

I was living in New York City and practicing in a Bronx hospital at the time, and I can still remember the agony of seeing so many patients, some colleagues, and even close friends succumb to the disease or suffer through the loss of loved ones. Those horrible memories flood back whenever I think about those years of ignorance, fear, sadness, pain, and helplessness as we struggled to find a treatment and cure, and as we attended funerals almost weekly.

Today, as younger generations come of age, they do not have those memories embedded in their psyches. Too many Americans have become complacent, no longer viewing HIV as a serious disease. In 2011, a Kaiser Family Foundation report detailing the foundation’s survey of more than 2,500 adults (HIV/AIDS at 30: A Public Opinion Perspective) noted, “Thirty years into the epidemic, there is a declining sense of national urgency and visibility of HIV/AIDS” (available at http://kff.org/hivaids/poll-finding/hivaidsat-30-a-public-opinion-perspective/; accessed October 15, 2013). Furthermore, according to the Kaiser report, HIV testing rates have not changed since 1997—even among some higher-risk groups.

Earlier this year, the United States Preventive Services Task Force (USPSTF) updated its 2005 recommendations for HIV screening (available at www.uspreventiveservicestaskforce.org/ uspstf13/hiv/hivfinalrs.htm#update; accessed October 15, 2013). The 2005 guidelines

recommended that clinicians offer HIV screening to all adults and adolescents at increased risk for infection, including all pregnant women, but for patients with no risk factors, the USPSTF recommended counseling regarding the benefits and harms of testing. Now, the task force wants all adolescents and adults aged 15 to 65 years, including all pregnant women, to be screened for HIV infection. Younger adolescents and older adults who are at increased risk should also be tested. (However, the USPSTF agrees with the CDC recommendation that HIV screening should be voluntary on the part of the patient, and done only with the patient’s knowledge and understanding.) The USPSTF concluded that the overall harms of screening for and treatment of HIV infection in adolescents, adults, and pregnant women are small.

Today, the CDC estimates that 1.1 million people in the United States are living with HIV. Studies have shown that HIV prevention programs can significantly reduce risk, and we have more HIV-related resources than ever before.

Yet we still face substantial challenges. For example, nearly 1 in 5 HIV-positive individuals are unaware that they are infected (available at www.cdc.gov/hiv/statistics/basics/ataglance. html, accessed October 15, 2013). Complacency now haunts us. Each new generation needs to be reminded of the potentially fatal nature of HIV and the importance of prevention—our lives depend on it. n

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