November 2012 Full Issue by The Clinical Advisor

THE CLINICAL ADVISOR • NOVEMBER 2012

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

■ Two-part gout guidelines ■ Preventing “silent” MIs ■ HPV vaccine deemed safe ADVISOR FORUM

■ Foul-smelling urine ■ Endometrial biopsy ■ Help for victims of bullying LEGAL ADVISOR

An ED clinician is sued after an unattended patient dies

✶ FREE CE COURSES!

■ CE Feature: Part 3 of 3

UPDATED CCHD SCREENING PAGE 28

VOLUME 15, NUMBER 11

■ Dermatologic Look-Alikes

PINK PLAQUES WITH INFLAMMATION PAGE 65 Expanded job listings! www.ClinicalAdvisor.com/Jobs

| N OV E M B E R 2 012 | www.ClinicalAdvisor.com

MANAGING INFANTS WITH

BRONCHIOLITIS Infection with respiratory syncytial virus (shown) manifests as bronchiolitis or viral pneumonia.

t REE app app F r u o t e G /a dvisor.com alA www.Clinic

Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Group production director Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6075. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only.

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LEVEL

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 5

CONTENTS NOVEMBER 2012

NEWS AND COMMENT

■ A man presented with firm red lesions

and very xerotic skin on both legs. 12

Newsline ■ Gout guidelines cover prevention to therapy ■ Preventive efforts for “silent” heart attacks ■ And more

Alternative Meds Update Eucalyptus oil is thought to be anti-inflammatory and antimicrobial.

CME/CE Dermatologic Look-Alikes Can you differentiate between these erythematous, pruritic plaques?

CME/CE Posttest

Commentary Neonatal screening for heart disease 28

FEATURES 18

Managing infants with bronchiolitis The symptoms of this common lung infection usually dissipate after a week, but some cases require hospitalization. CME/CE Updated standards for CCHD screening: pulse-oximetry pearls and statewide protocols The last of a three-part series designed to improve detection of critical congenital heart disease in newborns.

ADVISOR FORUM 40

Consultations ■ Foul-smelling urine caused by supplements ■ When to do an endometrial biopsy ■ Diarrhea in an elderly man in an assisted-living facility Clinical Pearls ■ Minimize pain during an eye exam ■ Use distilled water when taking

Bullae spare the face, trunk, and arms 53

thyroid medication

DEPARTMENTS 44

■ Gassing up at the gynecologic exam

Derm Dx Read the clinical descriptions, view the images, and make your diagnosis.

Legal Advisor An unattended patient is found cyanotic and unresponsive in the ED.

CME/CE Dermatology Clinic ■ A woman developed tense bullae on her legs after spending time outdoors.

MAKING CONTACT

Your Comments ■ More help for victims of bullying

Eucalyptus oil is used to treat severe asthma 59

Like us on Facebook facebook.com/TheClinicalAdvisor

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

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While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “ If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit www.aan.com/guidelines. Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria. AAN=American Academy of Neurology. LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP485919-01

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention). Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. Click here for Full Prescribing Information and Medication Guide. Please see the Brief Summary of Prescribing Information on adjacent pages. Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2012

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LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL)

Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1). Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)*

Dose Regimen

≥60

150

300

450

600

BID or TID

30–60

150

225

300

BID or TID

15–30

25–50

100–150

150

QD or BID

<15

25–50

50–75

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebocontrolled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebotreated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy Psychiatric Other Total

1.0 5.7 1.0 2.4

3.4 8.5 1.8 4.3

3.5 1.5 1.9 1.8

2.4 2.9 0.9 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report

behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when coadministering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the longterm cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

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Table 3. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with Diabetic Peripheral Neuropathy (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal† 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision‡ 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia. Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis. Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement. In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications. DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal

variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide 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 efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeateddose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. LAB-0294-22.0 June 2012 This brief summary is based on LYRICA Prescribing Information LAB-0294-22.0, revised June 2012.

September 2012

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Newsline N O V E M B E R 2 0 12

“Silent heart attacks” merit more attention page 14

Use antibiotics against group A streptococcus page 16

No safety concerns with HPV vaccine page 16

Gout guidelines cover prevention to therapy

CLINICIANS SHOULD educate patients with gout regarding diet, lifestyle choices, treatment objectives, and management of concomitant disease, and should aim for a urate level <6 mg/dL to improve gout symptoms. These are two of several recommendations made in new guidelines for the management of gout issued by the American College of Rheumatology. Gout has been on the rise over the past 20 years and affects 8.3 million people in the United States. The increased prevalence may be attributable to such factors as hypertension, obesity, metabolic syndrome, type 2 diabetes, and thiazide and loopdiuretic therapies for cardiovascular disease. A panel comprised of two primary-care physicians as well as seven rheumatologists, a nephrologist, and a patient representative developed the two-part guidelines

Gout (shown) is caused by the accumulation of uric acid in the joints.

(Arthritis Care Res [Hoboken]. 64:1431-1446 and 1447-1461). Part I covers the systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. For example, clinicians are advised to use a xanthine oxidase inhibitor (XOI) such as allopurinol (Lopurin, Zyloprim) as a first-line pharmacologic approach to lowering urate, and to use combination therapy with one XOI and one uricosuric agent when target urate levels are not achieved. Part II of the guidelines focuses on therapy and prophylactic anti-inflammatory treatments for acute gouty arthritis. Clinicians are advised to: (1) initiate pharmacologic therapy within 24 hours of onset of acute gouty arthritis attack; (2) continue urate-lowering therapy, without interruption, during flares; (3) use nonsteroidal antiinflammatory drugs (NSAIDs),

corticosteroids, or oral colchicine (Colcrys) as first-line treatment, and combinations of these medications for severe or unresponsive cases; and (4) use oral colchicine or low-dose NSAIDs as the firstline therapy options to prevent gout attacks when initiating uratelowering therapy if there is no medical contraindication or lack of tolerance. The guidelines suggest that clinicians explain exactly which foods should be eaten, limited, and avoided. One food that may belong on the “encourage” list is cherries, according to a recent study published online ahead of print by Arthritis & Rheumatism. Yuqing Zhang and colleagues found that among persons with gout, cherry intake over a twoday period was associated with a 35% lower risk of gout attacks compared with no intake.

Age-specific prevalence of hypertension among adults The age-adjusted prevalence of hypertension among U.S. adults aged 18 years and older was 28.6% .

Age (years) 18 -39

6.8%

40-59

30.4%

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

66.7%

12 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

Newsline GIVEN THE high prevalence of unrecognized myocardial infarction (UMI) and its association with increased mortality uncovered in a recent study, people at greater risk for these so-called “silent” heart attacks may benef it from following cardiovascular disease prevention methods, note researchers ( JAMA.2012;308:890-896). In the study of older adults, conducted in Iceland, 936 persons aged 67 to 93 years were either randomly selected for participation or were selected because they were known to have diabetes. A data analysis showed that 91 of the 936 participants (9.7%) had recognized MI (RMI) and 157 (17%) had UMI as detected by cardiac magnetic resonance (CMR) imaging.

This was more prevalent than the 46 UMI (5%) detected by electrocardiography. More UMI also was detected by CMR than by ECG among the 337 persons with diabetes (72 participants, or 21%, compared with 15 participants, or 4%, respectively). Over a median of 6.4 years, 30 (33%) of the RMI patients and 44 (28%) of the UMI patients died—both higher rates than the 119 of 688 (17%) persons with no MI who died. UMI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Persons with UMI by CMR used statins, aspirin, and other cardiac medications less often than did persons with RMI (36% vs. 73%).

Preventive efforts for “silent” heart attacks

In MI (shown), a blocked artery leads to a lack of oxygen.

After adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (absolute risk increase 8%) and significantly improved risk stratification for mortality, but UMI by ECG did not.

New process for managing low back pain A team of radiologists has developed evidence-based templates designed to assist practitioners that have been through the process of managing patients with acute low back pain ( J Am Coll Radiol. 2012;9:704-712). Low back pain is one of the most common reasons for patient visits in the ambulatory-care setting. However, the approach to workup and management of this condition is inconsistent. “These templates may be reasonably expected to improve patient care, decrease inappropriate imaging utilization, reduce

Low back pain is categorized into one of three groups.

the inappropriate use of steroids and narcotics, and potentially decrease the number of inappropriate invasive procedures,” the authors wrote. The researchers presented their method to help providers choose, develop, and implement clinical decision support interventions based on the best available scientific evidence. At the initial visit, after the clinician has taken a thorough history and performed a physical examination, he or she must categorize the patient with low back pain into one of three groups: (1) nonspecific low back

14 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

pain; (2) low back pain potentially associated with radiculopathy or spinal stenosis; or (3) low back pain potentially associated with a specific cause. Evidence-based order sets are provided for each category to help practitioners through the process of evaluation, management, and follow-up of patients. Order-set templates for use at the initial follow-up visit—four weeks later—offer recommendations for appropriate imaging, laboratory workup, referral for invasive procedures, and surgical consultation.

Newsline ALTHOUGH THE quadrivalent human papillomavirus (HPV4) vaccine (Gardasil) was associated with same-day syncope and skin infections in the two weeks after vaccination in a retrospective observational study, no evidence of new safety concerns among females aged 9 to 26 years receiving the shots was detected. The study, funded by Gardasil manufacturer Merck & Co., Inc., involved 189,629 females who received a total of 346,972 HPV4 doses through Kaiser Permanente in California. As Nicola P. Klein, MD, PhD, and fellow investigators explained in Archives of Pediatrics & Adolescent Medicine, outcomes were emergencydepartment visits and hospitalizations, grouped into predefined diagnostic categories. Compared with results from a control group, 50 predefined diagnostic categories ref lected significantly elevated odds ratios during at least one of three postvaccination risk intervals (days

Fainting has a known association with injections in general.

1–60, days 1–14, and day 0), but a review of medical records indicated that most diagnoses were present before immunization or diagnostic workups were initiated at the vaccine visit. An independent safety-review committee found only syncope on the day of vaccination and skin infections during days 1–14 to be likely related to HPV4. The authors noted that fainting has a known association with immunizations and injections in general, and that the medicalrecord review suggested some skin infections might have been local injection-site reactions.

IDSA updates group A strep guidance Penicillin or amoxicillin remain the treatments of choice for group A streptococcal (GAS) pharyngitis, and clindamycin (Cleocin) is now on the list of drugs recommended for penicillin-allergic patients, according to updated guidelines from the Infectious Diseases Society of America (available at cid.oxfordjournals.org/content/early/2012/09/06/cid. cis629.long, accessed October 15, 2012). Diagnosis should include swabbing the throat and testing for GAS pharyngitis by

rapid antigen detection and/or culture. Clinical features alone do not reliably discriminate between GAS and viral pharyngitis except when overt viral features are present. Patients should be treated with an appropriate antibiotic, usually for 10 days. Penicillin-allergic individuals should receive a first-generation cephalosporin for 10 days, clindamycin or clarithromycin (Biaxin) for 10 days, or azithromycin (Zithromax, Zmax) for five days.

16 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

Vitamin D did not stop colds A STUDY has demonstrated that a monthly dose of 100,000 international units (IU) of vitamin D3 did not reduce the incidence or severity of upper-respiratorytract infections (URTIs) in adults ( JAMA 2012;308:1333-1339). To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults, the researchers enrolled 322 persons in Christchurch, New Zealand, in a randomized, double-blind, placebo-controlled trial. Half of the participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU one month later, followed by another 100,000 IU monthly, all over the course of 18 months. The remaining enrollees received placebo administered in an identical dosing regimen. A total of 593 URTI episodes occurred in the vitamin D group, compared with 611 among the placebo takers. No significant differences were seen in number of URTIs per participant (mean 3.7 per person for vitamin D and 3.8 per person for placebo) number of days of missed work (mean 0.76 days in each group); duration of symptoms per episode (mean 12 days in each group), or severity of URTI episodes. These results remained unchanged when the analysis was repeated by season and by baseline 25-hydroxyvitamin D levels. ■

HPV vaccine deemed safe

FEATURE: CHRISTINA ROBOHM, MS, PA-C

Managing infants with bronchiolitis The symptoms of this common lung infection usually dissipate after a week, but some cases can become severe and require hospitalization.

ronchiolitis is the most common lowerrespiratory-tract infection that affects children in the first two years of life and the most common reason for hospitalization in this age group.1 More than one-third of children develop bronchiolitis between birth and age 2 years, and the cost of hospitalization is more than $500 million annually.2-4 In most cases, the disease responds well to home care. Risk factors include exposure to cigarette smoke, age younger than 6 months, crowded living conditions, not being breastfead, and premature birth (before 37 weeks’ gestation).

Definition

Bronchiolitis, a disease of the lung’s smallest airways (bronchioles) usually caused by a viral infection, generally occurs in a seasonal pattern over the winter months. More than 50% of cases result from respiratory syncytial virus (RSV). Other causes include parainfluenza, adenovirus, human metapneumovirus, and influenza. The pathophysiology of bronchiolitis results from the infection of epithelial cells in the respiratory tract.This infection leads to inflammation, edema, mucus production, bronchospasm, and necrosis of the respiratory tract’s epithelial lining. Because the bronchioles are so small in infants, they may easily become blocked, causing respiratory distress. Respiratory syncytial virus (shown) causes respiratory tract infections in all ages.

18 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

Clinical assessment

Bronchiolitis is diagnosed clinically based on history and physical examination.5 The disease can be recognized from clinical signs and

BRONCHIOLITIS

symptoms, starting with several days of upper-respiratory symptoms of mild rhinorrhea, cough, and fever followed by tachypnea, wheezing, and increased respiratory effort. Physical examination should include respiratory rate and such evidence of increased work of breathing as retractions, nasal flaring, and grunting. Auscultation will typically reveal wheezes or inspiratory crackles as a result of inflammation and epithelial debris in the airway. Assessment of disease severity in an otherwise healthy infant aged 60 days or older should be based on the history and physical examination (Table 1). Several features of the history and physical exam must be considered when determining severity. One key is evaluation of the respiratory rate; for an accurate measurement, count the respiratory rate for one full minute rather than estimating by counting for a partial minute.6 In addition, nasal suctioning may be required prior to counting, as the respiratory rate may be increased due to obstruction. Tachypnea (i.e., respiratory rate >70 breaths per minute) may be associated with risk for severe disease and may warrant additional evaluation for pneumonia or other lower-respiratory-tract infection.6 Radiologic and laboratory testing

It is not necessary to use radiologic or laboratory testing in the diagnosis of bronchiolitis.2,7 Ask yourself, “Will the result of the test change my clinical management?” When a child has the classic presentation of disease, chest x-ray, viral testing, and blood work is not required. Generally, children with bronchiolitis will have hyperinflation, atelectasis, and infi ltrates on chest radiograph. However, the findings typically do not correlate with disease severity and are not useful in determining treatment or predicting the clinical course.8 Because risk of serious bacterial infection in children aged 60 days or older is low, additional laboratory testing in these patients is not indicated.9 In those younger than age 60 days, the question of serious bacterial illness in febrile infants becomes more complicated. In such cases, urinary tract infection is the most commonly reported serious bacterial infection. Many clinicians may screen children in this age group in accordance with suggested guidelines for febrile infants.10

POLL POSITION

Do you educate new parents on the importance of proper hand washing?

n=264

Yes No 91%

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Treatment

Children with uncomplicated bronchiolitis may be appropriately managed with supportive care (Table 2). No pharmacologic therapies for acute bronchiolitis have been shown to change the natural progression of the disease. Many pharmacologic treatments have been studied, including bronchodilators, corticosteroids, antibiotics, and antivirals, but no significant evidence of efficacy has been found. The mainstays of treatment are ensuring adequate rest, hydration, and oxygenation. A humidifier can be used to help loosen sticky mucus. The decision to admit a child to the hospital is made on the basis of the clinical assessment. Previously healthy children with mild disease typically do not require hospitalization. Those with moderate disease may be managed at home if there is no oxygen requirement. However, younger patients, patients with pre-existing medical conditions, or those with a concerning social situation may require inpatient disease management (Table 3). Because of increased respiratory rate, poor feeding, and fever, children with bronchiolitis may become dehydrated. In cases of mild-to-moderate disease, nasal obstruction and mucus plugging may cause difficulty feeding. Nasal

For more on bronchiolitis and other childhood illnesses, visit our new Pediatrics Information Center at

ClinicalAdvisor.com/Pediatrics. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 21

BRONCHIOLITIS

CLINICAL SLIDESHOW For more information on what can trigger an asthma attack, visit ClinicalAdvisor.com/AsthmaSlideshow.

suctioning can easily be performed by parents using a bulb syringe and may help to clear secretions. Intravenous fluids may be needed for children who tire quickly or are unable to feed due to respiratory distress. In such cases, hospitalization is indicated. Oxygen supplementation should be used in children with oxygen saturations persistently <90%.2 Once oxygen therapy has been started, spot-checks for oxygen saturation are adequate for monitoring. Supplemental oxygen may be discontinued once saturation rises above 90%, there is only mild respiratory distress, and the infant is feeding well. Continuous pulse oximetry is not needed and may contribute to longer hospital stays.11 Following a period of careful observation, home oxygen therapy is a reasonable alternative to hospitalization in cases of uncomplicated bronchiolitis. Home therapy could decrease the economic burden of disease in low-risk children.12 Bronchodilator use has not been shown to improve clinical outcomes in children with bronchiolitis. The American Academy of Pediatrics does not recommend the routine use of bronchodilators in the treatment of this condition. Only one in four children at most may have transient improvement in symptoms with albuterol (Proventil, Ventolin, Volmax, Vospire) or epinephrine. A review of 29 studies showed that most bronchodilators do not improve oxygen saturation, reduce hospital stay, or decrease length of disease.13 However, a recent review of racemic epinephrine (Micronefrin, VapoNefrin, Nephron) provided preliminary evidence of reduced hospitalization for children with mild-to-moderate disease, provided a dose was received within the first 24 hours of symptoms.14 Although further research is needed, this may show promise for the future. Short-term adverse effects of bronchodilators are common and must be weighed against the benefit of their use. Bronchodilators may be considered in a child with moderate or severe disease. Inhaled and systemic corticosteroids have not been shown to reduce clinical symptoms, hospitalizations, or length of hospital stays in children with bronchiolitis.15,16

Epinephrine combined with dexamethasone (Decadron, Dexamethasone Intensol, Dexpak) may reduce the number of hospital admissions and shorten stays, but additional study is needed.14 There is no evidence that epinephrine or corticosteroids alone improve clinical outcomes for inpatients with bronchiolitis. Although the cause of bronchiolitis is viral, antibiotics are commonly prescribed for children with uncomplicated disease.17 Antibiotic use may be appropriate for children at high risk of complications or those with proven bacterial infection, but this modality has no role in healthy children with uncomplicated bronchiolitis. Judicious use of antibiotics in the treatment of bronchiolitis will help reduce the risk of developing resistant bacteria. Prognosis

Children with bronchiolitis generally recover without complications or wheezing episodes. The average length of illness is 12 days, but some children may continue to cough for weeks. Children who are hospitalized are usually discharged in fewer TABLE 1. Bronchiolitis severity classification Mild disease

• Infant is alert, active • Feeding well • No to minimal intercostal retractions • Respiratory rate normal to mildly elevated (<50 breaths/minute)

Moderate disease

• Infant is alert, able to be consoled • Feeding decreased • Minimal to moderate intercostal retractions • Respiratory rate mildly to moderately elevated (50–70 breaths/minute)

Severe disease

• Infant is fussy, difficult to console • Poor feeding • Moderate to severe intercostal retractions • Respiratory rate moderately to severely elevated (>70 breaths/minute)

Adapted from Schuh S, Lalani A, Allen U, et al. Evaluation of the utility of radiography in acute bronchiolitis. J Pediatr. 2007;150:429-433.

TABLE 2. Bronchiolitis treatment modalities Indicated • Oxygen, suctioning, fluids • Careful clinical monitoring • Passive-smoke avoidance Not routinely indicated • Antibiotics • Chest radiograph • Viral testing • Inhaled medications (unless proven benefit) • Steroids

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TABLE 3. Common risk factors for hospitalization in bronchiolitis • Age younger than 3 months • Prematurity • Congenital heart disease • Chronic respiratory disease • Immunocompromised • In utero exposure to tobacco smoke • Low socioeconomic status • Neuromuscular disease Adapted from Wagner T. Bronchiolitis. Pediatr Rev. 2009;30:386-395; Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis hospitalizations. Arch Pediatr Adolesc Med. 2004;158:527-530; and Tie SW, Hall GL, Peter S, et al. Home oxygen for children with acute bronchiolitis. Arch Dis Child. 2009;94:641-643.

TABLE 4. Eligibility for palivizumab prophylaxis • Infants born at 28 weeks’ gestation or earlier during RSV season, whenever that occurs during the first 12 months of life • Infants born at 29–32 weeks’ gestation if they are younger than age 6 months at the start of the RSV season • Infants born at 32–35 weeks’ gestation who are younger than age 3 months at the start of the RSV season or who are born during RSV season if they have at least one of the following risk factors: (1) infant attends child care; (2) infant has a sibling younger than age 5 years • Infants and children younger than age 2 years with cyanotic or complicated congenital heart disease • Infants and children younger than age 2 years who have been treated for chronic lung disease within six months of the start of the RSV season. • Infants born before 35 weeks’ gestation who have either congenital abnormalities of the airway or neuromuscular disease that compromises handling of respiratory secretions Adapted from American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:560-569.

palivizumab may reduce the incidence rate of RSV bronchiolitis by 39% to 82% in high-risk infants.19 If hospitalized during RSV season, eligible children should receive a dose prior to discharge. The specific indications for palivizumab administration are listed in Table 4. The viral infections that cause bronchiolitis are quite contagious. Additional preventive measures include handwashing and reduction of exposure to tobacco smoke. Educating parents and staff on the importance of handwashing is an essential component to reducing the spread of the disease.2 Similarly, counseling parents on the importance of reduction of smoke exposure and the availability of smoking-cessation resources may help reduce infant morbidity. Evidence shows increased rates of lower-respiratory-tract illness, ear infections, cough, asthma, and hospitalizations in children who are exposed to secondhand smoke.20 Conclusion

Evidence-based reviews suggest limited use of diagnostic testing and treatment modalities in the management of bronchiolitis. Although most studies have shown a lack of efficacy for the use of pharmacologic treatments, preliminary research shows promise with a combination of bronchodilators and corticosteroids. Clinicians must remain cognizant of current practice recommendations in the diagnosis and treatment of bronchiolitis. ■ Ms. Robohm is Clinical Professor and Director of Physician Assistant Studies at Carroll University in Waukesha, Wisc. References 1. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syn-

than five days. Following severe bronchiolitis infection, subsequent asthma has been reported in 30% of children hospitalized with the disease. Increased severity of infant bronchiolitis may be associated with increased chances of developing childhood asthma, but this relationship is not well understood.18 It is unclear whether bronchiolitis causes or triggers asthma or if children who are prone to asthma are more likely to develop bronchiolitis as infants. Further research is needed to clarify the relationship between bronchiolitis and the development of asthma later in childhood.

cytial virus infection in young children. N Engl J Med. 2009;360:588-598. Available at www.nejm.org/doi/full/10.1056/NEJMoa0804877. 2. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118:1774-1793. Available at pediatrics.aappublications.org/ content/118/4/1774.long. 3. Yorita KL, Holman RC, Sejvar JJ, et al. Infectious disease hospitalizations among infants in the United States. Pediatrics. 2008;121:244-252. Available at pediatrics.aappublications.org/content/121/2/244.long. 4. Pelletier AJ, Mansbach JM, Camargo CA Jr. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006;118:2418-

Prevention

2423. Available at pediatrics.aappublications.org/content/118/6/2418.long.

Although there is currently no vaccine against bronchiolitis, the monoclonal antibody palivizumab (Synagis) can be given to high-risk infants to help prevent RSV during respiratory season. Given in once-monthly intramuscular doses,

5. Zorc JJ, Hall CB. Bronchiolitis: recent evidence on diagnosis and management. Pediatrics. 2010;125:342-349. Available at pediatrics.aappublications. org/content/125/2/342.long. References continue on page 26

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6. Berman S, Simoes EA, Lanata C. Respiratory rate and pneumonia in infancy. Arch Dis Child. 1991;66:81-84. Available at www.ncbi.nlm.nih.gov/ pmc/articles/PMC1793190/. 7. Schuh S, Lalani A, Allen U, et al. Evaluation of the utility of radiography in acute bronchiolitis. J Pediatr. 2007;150:429-433. 8. Bordley WC, Viswanathan M, King VJ, et al. Diagnosis and testing in bronchiolitis: a systematic review. Arch Pediatr Adolesc Med. 2004;158:119126. Available at archpedi.jamanetwork.com/article.aspx?articleid=485626. 9. Wagner T. Bronchiolitis. Pediatr Rev. 2009;30:386-395. 10. Ralston S, Hill V, Waters A. Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis: a systematic review. Arch Pediatr Adolesc Med. 2011;165:951-956. Available at archpedi.jamanetwork. com/article.aspx?articleid=1107617. 11. Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis hospitalizations. Arch Pediatr Adolesc Med. 2004;158:527-530. Available at archpedi. jamanetwork.com/article.aspx?articleid=485734. 12. Tie SW, Hall GL, Peter S, et al. Home oxygen for children with acute bronchiolitis. Arch Dis Child. 2009;94:641-643. Available at adc.bmj.com/ content/94/8/641.long. 13. Gadomski AM, Brower M. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2010;12:CD001266. 14. Hartling L, Bialy LM, Vandermeer B, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev. 2011;6:CD003123. 15. Corneli HM, Zorc JJ, Mahajan P, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med. 2007;357:331-339. Available at www.nejm.org/doi/full/10.1056/ NEJMoa071255. 16. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev. 2010;10:CD004878.

17. Spurling GK, Doust J, Del Mar CB, Eriksson L. Antibiotics for bronchiolitis in children. Cochrane Database Syst Rev. 2011;6:CD005189. 18. Carroll KN, Wu P, Gebretsadik T, et al. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J Allergy Clin Immunol. 2009;123:1055-1061. Available at www.ncbi. nlm.nih.gov/pmc/articles/PMC2703291/. 19. American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:560-569. 20. Best D; Committee on Environmental Health; Committee on Native American Child Health; Committee on Adolescence. From the American Academy of Pediatrics: Technical report—Secondhand and prenatal tobacco smoke exposure. Pediatrics. 2009;124:e1017-e1044. Available at pediatrics.aappublications.org/content/124/5/e1017.long. All electronic documents accessed October 15, 2012.

26 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

“Spoiler alert.”

CME CE

PROGRAM OUTLINE NOVEMBER 2012

0.5 CREDITS

Page 28 FEATURE Updated standards for CCHD screening: pulse-oximetry pearls and statewide protocols Gerard R. Martin, MD; Alex R. Kemper, MD, MPH, MS; and Elizabeth A. Bradshaw, MSN, RN, CPN ■ LEARNING OBJECTIVES: • Describe current technologies for pulse-oximetry screening of newborns. • Analyze screening procedures that optimize pulse-oximetry performance. • Illustrate screening protocols and surveillance support from various state public-health systems.

0.5 CREDITS

Page 53 DERMATOLOGY CLINIC Itchy leg bullae after a trip outdoors Audrey Chan, MD

Firm, red plaques and xerotic skin Kerri Robbins, MD ■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 65 DERMATOLOGIC LOOK-ALIKES Erythematous, pruritic leg plaques Adam Rees, MD ■ LEARNING OBJECTIVE: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 70 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 2012. 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. The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). 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

■ EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Describe current technologies for pulse-oximetry screening of newborns. • Analyze screening procedures that optimize pulse-oximetry performance. • Illustrate screening protocols and surveillance support from various state public-health systems. ■ COMPLETE THE POSTTEST: Page 36 ■ ADDITIONAL CME/CE CREDIT: Pages 53, 65

FEATURED COURSE

Turn to page 27 for additional information on this month’s CME/CE courses.

This continuing medical education/continuing education (CME/CE) activity, Updated Standards for CCHD Screening, the third in a 3-part series, Taking the Pulse of Neonatal Screening for Critical Congenital Heart Disease (CCHD), is directed to physicians, nurse practitioners, and physician assistants and designed to take the learner from a comprehensive understanding of CCHD, the imperatives of appropriate neonatal screening for CCHD, and implementation of standardized protocols nationwide, to discussion of the continuum of care from assessment and diagnosis to management decisions and follow-up post-discharge. Faculty Gerard R. Martin, MD (CHAIR) Co-Director, Children’s National Heart Institute, Children’s National Medical Center Professor of Pediatrics George Washington University, Washington, DC Alex R. Kemper, MD, MPH, MS Department of Pediatrics, Community and Family Medicine Duke University School of Medicine, Durham, NC Elizabeth A. Bradshaw, MSN, RN, CPN Coordinator for the Congenital Heart Disease Screening Program Children’s National Medical Center, Washington, DC Release Date: November 2012 Expiration Date: November 2013 Estimated time to complete the educational activity: 30 minutes This activity is supported by an educational grant from Covidien and jointly sponsored by Medical Education Resources (MER), Nurse Practitioner Associates for Continuing Education (NPACE), and Haymarket Medical Education (HME). Target Audience: This activity has been designed to meet the educational needs of physicians, nurse practitioners (NPs), and physician assistants (PAs) in family practice, pediatrics, obstetrics, women’s health, neonatology, and cardiology specialties. 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 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Credit Designation: NPACE 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. 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 It is the policy of Nurse Practitioner Associates for Continuing Education to ensure balance, independence, objectivity, and scientific rigor in all of its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that the participants may evaluate the objectivity of the presentations. In addition, any discussion of off-label, experimental, or investigational use of drugs or devices will be disclosed by faculty. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty Reporting Financial Relationship Gerard R. Martin, MD, has no financial relationships to disclose. Alex R. Kemper, MD, MPH, MS, has no financial relationships to disclose. Elizabeth A. Bradshaw, MSN, RN, CPN, has no financial relationships to disclose. Name of Content Managers Reporting Financial Relationship Joe Kopcha, Marina Galanakis, Nick Zittell, Susan Basilico, Anne Jacobson, of HME, and Victoria C. Smith, MD, of Medical Education Resources 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 2012 through November 2013, 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 2012); 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.

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.

28 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

Jointly Sponsored by

Supported by an educational grant from:

GERARD R. MARTIN, MD; ALEX R. KEMPER, MD, MPH, MS; AND ELIZABETH A. BRADSHAW, MSN, RN, CPN

TAKING THE PULSE OF NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE (CCHD)

Updated standards for CCHD screening: pulse-oximetry pearls and statewide protocols

niversal screening for critical congenital heart disease (CCHD) using pulse oximetry is becoming the standard of care for newborns in the United States. In 2012, the U.S. Department of Health and Human Services (HHS) endorsed recommendations from the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) to add CCHD to the Recommended Uniform Screening Panel, an established public health tool used to detect a range of heritable disorders.1 Individual hospitals and birthing facilities will be responsible for implementing CCHD screening programs based on national recommendations and, in many cases, new state-level legislation. Taking the Pulse of Neonatal Screening for Critical Congenital Heart Disease is a three-part educational activity designed to facilitate the implementation of screening for CCHD in newborns. The first two articles described the burden of CCHD, introduced screening for CCHD using pulse oximetry as an effective strategy for improving detection, and summarized current guideline recommendations for universal CCHD screening. The fi nal article examines improved pulse-oximetry standards that translate into more sensitive screening. The article also looks ahead to the future of CCHD screening with case studies of individual states that have started to implement programs.

Screening for CCHD using pulse oximetry

CCHD screening of the right foot

In the United States, approximately 1.3 infants per 1,000 live births will be affected by CCHD, a type of cardiac defect in which surgical or catheter interventional therapy within the first year of life is mandatory to achieve survival.2 Early detection and follow-up are critical for preventing the morbidity and mortality associated with CCHD. Detection is www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 29

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challenging, however, due to the subtlety of clinical presentation. For instance, half of all newborns with CCHD, particularly those with ductal-dependent defects, have no distinctive murmur, and in many cases the symptoms of CCHD do not present until after hospital discharge.2,3 CCHD is missed in 1 in 3 affected newborns; missed cases are at an increased risk of life-threatening complications.4 Pulse oximetry is a simple, noninvasive, painless test that can detect mild hypoxemia, a feature of many forms of CCHD that is easy to miss on physical examination.5 As an adjunct to the standard newborn physical examination, pulse oximetry can identify cases of CCHD that escape routine clinical diagnosis. The current approach to universal screening for CCHD using pulse oximetry reflects the efforts of multiple agencies and collaborative groups, including the American Academy of Pediatrics (AAP), the American Heart Association, and the SACHDNC. Key features of the screening recommendations are outlined in Table 1. TABLE 1. Key recommendations for pulse-oximetry screening • Screen healthy newborn infants. • Screen at 24-48 hours of life, or as late as possible if earlier discharge is planned. • Obtain oxygen saturation readings in the right hand and one foot. — A reading of ≥95% in either extremity with a ≤3% absolute difference between the upper and lower extremity is considered normal, and no further screening is required. — Repeat measurements when the initial screening result is positive. — Refer any infant with oxygen saturation <90% for immediate diagnostic evaluation. — Adjust thresholds for positive findings in high-altitude areas. • Exclude CCHD with a diagnostic echocardiogram in infants with positive screening results and no infectious or pulmonary causes of hypoxemia. Source: Kemper AR, et al. Pediatrics. 2011;128:e1259-e1267.

TABLE 2. Device standards for CCHD screening Pulse oximeters used for CCHD screening should comply with the following standards: • Indicated for use in motion and non-motion conditions* • Reports functional oxygen saturation† • Validated in low-perfusion conditions† • Cleared by the FDA for use in newborns† • 2% root mean-square accuracy† • Must be calibrated regularly based on manufacturer guidelines† *

U.S. Food and Drug Administration. www.in.gov/isdh/files/Instructions_for_FDA_ Clearance_in Neonates.pdf; †Kemper AR, et al. Pediatrics. 2011;128:e1259-e1267.

Evolution of pulse-oximetry standards

Individual hospitals, birthing centers, and other facilities are responsible for selecting appropriate equipment for screening. In practice, implementing pulse oximetry as a screening tool has been fraught with complexities due to the lack of standardization of pulse-oximetry technologies and other standards across hospital settings. Historically, commercially available pulse oximeters have been labeled by manufacturers according to generation of technology (e.g., “next generation”), yet this designation has not been standardized and may not correlate with test validity or reliability. In 2011, the SACHDNC, which assembled an independent group of experts in the area of CCHD screening in an advisory capacity, published technological standards for pulse-oximetry equipment to ensure reliable and reproducible outcomes with devices available at the time.1 In 2012, those standards were updated through the issuance of a Food and Drug Administration (FDA) guidance document that addresses devices currently in use.6 (Table 2) The historical context and evolution of technological standards in pulse oximetry are described below. Concern over motion artifact with early pulse oximetry, for instance, prompted the development of motion-tolerant devices, which were recognized as the standard of care in the 2011 SACHDNC guidelines.1 With additional advances in hardware and software, the technological standards for pulse oximetry are expected to continuously evolve. LOOKING AHEAD: FUTURE DEVICE TECHNOLOGY

Technological standards for pulse oximetry are rapidly advancing. In 2011, the HHS endorsed the SACHDNC standards for pulse-oximetry screening, including the recommendation to utilize motion-tolerant devices.7 In 2012, the AAP published a policy statement to guide the implementation of these technological standards in clinical practice.8 In addition, several states have passed CCHD screening legislation and implemented CCHD screening protocols based on the SACHDNC technological standards,9-12 and other states have legislation pending.12 Future guidelines from experts will reflect evolving standards of care in CCHD screening using pulse oximetry, including updated standards for device technology. For instance, all new devices are expected to meet federal performance standards (e.g., sensitivity and specificity for CCHD), regardless of their designation regarding motion tolerance. The FDA, through the issuance of the guidance document, has endorsed the use of all oximetry equipment for CCHD screening that is approved for neonatal patients.6 The adoption of new standards into universal newborn

30 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

screening protocols will require collaborative efforts from states, hospitals, and health-care providers. Standardizing screening protocols

Based on national guidance and state legislation, hospitals and birthing centers will be required to implement CCHD screening programs. The particular screening strategy should reflect the conditions within each particular facility, as well as the needs of infants, families, and the health-care providers. On a practical level, caregivers should understand the requirements related to sensor type and placement. SENSOR TYPE

Pulse oximetry can be performed with disposable or reusable sensors, and hospitals and birthing centers must select the type of sensor that best meets the needs of their facility.1 The SACHDNC recommendations state that either disposable or reusable pulse-oximetry sensors are appropriate for CCHD screening.8 Reusable sensors have the advantage of reducing the overall cost of screening for CCHD. However, the reusable sensors must be cleaned between uses to minimize the risk of infection. The Maryland State Advisory Council on Hereditary and Congenital Disorders estimates that the cost of reusable sensors can be amortized to approximately $1 per use compared with approximately $12 per disposable sensor.9 Partially reusable sensors, which require less cleaning than standard reusable sensors and cost less than fully disposable sensors, are another option. For newborn patients, sensors with close coupling to the skin, such as those that are taped rather than clamped, show better performance for CCHD screening.1 Clinicians should keep in mind that sensor type can influence the performance of pulse oximetry, and therefore only recommended combinations of devices and sensors should be used.1 SENSOR PLACEMENT

Newborn fingers and toes are often too small for proper attachment of pulse-oximeter sensors, requiring sensor placement on the sole of the foot or palm of the hand. (It should be noted, however, that the finger or toe may be suitable for probe placement, if in the judgment of the clinician the child is large enough.) According to the current SACHDNC recommendations for CCHD screening, oxygen saturation readings should be obtained in the right hand and one foot.8 Moreover, the sensors should be used according to the specifications outlined by the manufacturer, with the palm, foot, great toe, or thumb serving as the optimal sites for placement.

In addition to the ideal placement of sensors in newborns, it is essential that the operator obtain pre-ductal and postductal sensor measurements to ensure an accurate oxygensaturation reading. For instance, researchers have placed a sensor on one foot as well as the right hand to determine any difference between readings, with a difference of >3% considered abnormal. The strategy of using two sensor readings may improve detection of left outf low tract obstructions, such as coarctation of the aorta or interrupted aortic arch, which may result in an arm saturation of 99% and a leg saturation of 95%.2 One large study identified two patients whose diagnosis of CCHD would have been missed if only the foot SpO2 reading had been recorded.2 Ongoing research will continue to evaluate the optimal approach to CCHD screening. Toward this goal, several recent studies explored different options for sensor placement.13,14 In one study, researchers evaluated the accuracy and precision of pulse oximetry at five different sensor locations (the finger, palm, toe, sole, and ear) in infants and children with known cyanotic heart disease.13 In this study, the sole was the most accurate sensor location. Regardless of sensor placement, however, the accuracy of pulse oximetry deteriorated at low saturation states (<90%) and tended to overestimate oxygen saturation. Another study showed that pulse-oximetry sensors were less accurate when used on the sole of the foot or palm of the hand when oxygen saturation fell below 90% in newborns and children up to 2 years of age.15 Clinicians should keep in mind that this limitation can be mitigated if the sensors are used as instructed by the manufacturer. Additional practice pearls

These guidelines offer additional practice pearls for optimal pulse-oximetry use, including the following: • Adult pulse-oximetry clips should not be used when obtaining an SpO2 reading for an infant. An adult pulse-oximetry clip in a newborn will yield an inaccurate reading.10 • Blood flow is necessary to obtain an accurate SpO2 reading. Therefore, do not attempt to obtain a reading on the same extremity as an automatic blood-pressure cuff, which impedes normal blood flow.10 • Bilirubin lamps, surgical lights, and other bright or infrared lights can affect the accuracy of the pulse-oximetry reading. Therefore, avoid placing the infant in bright or infrared light while pulse oximetry is being performed.10 • Substances with dark pigmentation, such as dried blood and nail-polish dyes, can alter pulse-oximetry readings. Therefore, confirm that the skin is clean and dry before

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NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE

Case study: New Jersey In 2011, the New Jersey Department of Health and Senior Services (NJDHSS) signed legislation requiring each birthing facility licensed by the NJDHSS to perform pulse-oximetry screening on every newborn in its care.11 Lorraine Freed Garg, MD, MPH, Medical Director of Newborn Screening and Genetic Services, NJDHSS, recently described New Jersey’s experience with CCHD screening. The NJDHSS law was signed on June 2, 2011, and became effective on August 31, 2011. In preparation for launching the statewide screening program, the NJDHSS convened the Critical Congenital Heart Disease Screening Working Group to develop a recommended screening protocol (Figure 1). In addition, to train clinicians in CCHD screening, the NJDHSS distributed protocols, communicated with hospitals, identified pulse-oximetry contacts and each birthing facility, and conducted educational webinars. The NJDHSS screening initiative includes surveillance to collect data related to CCHD screening, including the total number of births and the total number of screens. Discrepancies between total births and total screens in each quarterly reporting period should be explained as follows: infant death; transferred out of the birthing center at <24 hours of age; not medically appropriate; <24 hours of age at end of current reporting period; and born in prior reporting period. In addition, the NJDHSS Birth Defect Registry will compile data on all failed screens, including symptom history, upper-extremity (UE) and lower-extremity (LE) pulse-oximetry readings x 3, prenatal ultrasound and postnatal echocardiogram results, and final diagnosis explaining the failed screen.

placing the sensors. Skin color and jaundice, however, will not affect the SpO2 reading.10 • When using disposable pulse-oximetry sensors, use a new, clean sensor for every newborn. Likewise, when using reusable sensors, be sure to clean the sensor with the recommended disinfectant between each infant. In addition to increasing the risk of transmitting infection, dirty sensors can decrease the accuracy of the pulseoximetry reading. In each case, the sensor should be secured to the sensor site with a disposable wrap.10 Understanding screening performance

Pulse oximetry is not 100% accurate, however, and some readings will result in false-positive or false-negative screens.1 Understanding the limitations of pulse-oximetry screening is important for interpreting screening results.

In November 2011, the NJDHSS conducted a preliminary survey of 52 hospitals and 18 birthing facilities to assess initial efforts related to protocol implementation. Most facilities were utilizing the NJDHSS screening protocol and found no major barriers to successful implementation. Within the first 90 days of the CCHD screening program, more than 95% of infants underwent pulse-oximetry screening according to the NJDHSS protocol.11 The challenges were primarily in the areas of infrastructure and cost. For instance, while 83% of hospitals had the ability and expertise to conduct echocardiograms in newborns, 17% did not have this on-site capability.11 One hospital noted the burden of having to purchase an additional pulse oximeter as well as disposable wraps for reusable sensors, which were not accounted for in initial cost estimates.11 Hospitals also identified the need for educational materials and more intensive training to support clinicians across the spectrum of newborn care. While the mechanisms for data collection and surveillance were praised overall, some participants faced a steep learning curve related to data reporting.11 Any up-front errors may adversely affect the accuracy of surveillance data and should be addressed as part of ongoing quality-assurance efforts. The NJDHSS attributed the successful implementation to the Critical Congenital Heart Disease Screening Working Group, dedicated hospital staff, and strong connections with birthing facilities. Follow-up surveys with participating hospitals and birthing centers should identify additional areas for improvement in CCHD screening.

FALSE-POSITIVES

A small percentage of infants who have a positive pulseoximetry screen will not have CCHD, and some may have other conditions that require intervention. In a recent metaanalysis of data on pulse-oximetry screening in 229,421 asymptomatic newborns, pulse oximetry was highly specific (99.9%) and moderately sensitive (76.5%) for the detection of CCHD.16 The false-positive rate was 0.14%, but fell to 0.05% when pulse oximetry was performed after 24 hours from birth, without any compromise in overall sensitivity. Although the goal of pulse oximetry was to detect CCHD, other life-threatening disorders of noncardiac origin were also identified via screening, including group B streptococcal pneumonia and pulmonary hypertension. Current CCHD screening algorithms include steps to decrease the rate of false-positive readings. For instance,

32 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

both extremities, or if there is >3% absolute difference in oxygenation between the right hand and foot.1 These second and third measurements are included to reduce the risk of a false-positive screen by confirming the presence of low oxygenation. Infants with oxygen saturation <90% in any screen do not need repeat pulse oximetry, however. These infants should be referred immediately for further evaluation. Follow-up echocardiography and pediatric cardiology consultations are a major source of secondary costs related to CCHD screening.2 Therefore, there is a major cost incentive for hospitals and birthing centers to reduce the false-positive

screening after 24 hours of life is a key step toward enhancing the performance of CCHD screening.1 Some evidence suggests that screening infants who are alert (rather than sleeping) will decrease the risk of false-positive results by reducing the likelihood of low oxygen saturations caused by hypoventilation in deep sleep.1 In addition, performing pulse oximetry around the time of the newborn hearing screening may improve the efficiency of CCHD screening.1 The SACHDNC screening protocol recommends taking a second SpO2 measurement—and if needed, a third reading— for infants with an initial SpO 2 reading <95% in

Screening Algorithm for Critical Congenital Heart Disease Recommendations from the New Jersey Department of Health and Senior Services All babies 24-48 hours of age or shortly before discharge if <24 hours

Perform and document pulse oximetry in both RIGHT HAND and either FOOT.

Is pulse oximetry reading <90% in either the HAND or FOOT? NO

YES

Are both HAND and FOOT 95%-100%?

Is the difference between the two measurements 3% or less?

YES

FAIL Do not rescreen.

YES

PASS

FAIL Repeat the above pulse-oximetry screening algorithm in 1 hour by obtaining new measurements from both right hand and either foot. If baby does not pass after a total of three screenings (initial screen and two repeat screens), notify responsible medical practitioner and follow recommendations in box below.

• Notify responsible medical practitioner of the failed screen and of need for further evaluation. • Evaluate for other causes of low oxygen saturation (e.g., persistent pulmonary hypertension, pneumonia, infection, etc.). • In the absence of a clear cause of hypoxemia, obtain a diagnostic echocardiogram by an expert in the interpretation of infant echocardiograms and review the report prior to discharge home. This may require transfer to another institution or use of telemedicine. • If saturation is <90% in either the hand or foot, the baby should have immediate clinical assessment and immediate referral to pediatric cardiology. In this case, do not wait and rescreen.

• A pass on the screen does not exclude the existence of a cardiac disorder. • If cardiac evaluation is otherwise indicated (e.g., clinical signs, prenatal diagnosis of critical congenital heart disease, dysmorphic features, etc.), proceed with cardiac evaluation even if baby receives a pass on the pulseoximetry screen.

Source: Garg LF. Screening for critical congenital heart disease in newborns using pulse oximetry—New Jersey’s experience. March 22, 2012. Adapted from the Secretary’s Advisory Committee on Heritable disorders in Newborns and Children (SACHDNC) Expert Panel Workgroup’s Preliminary Recommendations. Jan. 2011.

FIGURE 1. New Jersey Department of Health and Senior Services pulse-oximetry screening algorithm for CCHD

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 33

CME CE

NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE

Case study: Maryland Based on recommendations from the Maryland State Advisory Council on Hereditary and Congenital Disorders, in 2011 the Maryland legislature signed into law a bill to facilitate the implementation of CCHD screening for all newborns in the state.9 Each year, Maryland has approximately 74,000 live births. By implementing a CCHD screening program, the state anticipates identifying 10 newborns with CCHD each year who would have otherwise been undetected by current prenatal and newborn examination protocols. A key feature of the Maryland CCHD screening legislation is a quality-assurance initiative that includes ongoing surveillance and program evaluation. The Maryland Department of Health and Mental Hygiene will employ a half-time nurse to develop a dedicated surveillance system for the CCHD screening program. The surveillance initiative will track screening rates—including total screens, false-positive rates, and false-negative rates—as well as follow-up data on infants with positive pulse-oximetry screens. Once launched, the ongoing surveillance component will consist of monitoring the electronic database to identify hospitals with unusual rates of failed or missed screens and providing technical assistance to those hospitals.

rates of pulse oximetry by implementing standardized protocols for CCHD screening. Although current protocols include steps to enhance the efficiency of screening, they do not remove the possibility of a false-positive screen entirely. By comparison, though, the false-positive rate with a standard physical examination alone for CCHD is nearly 10 times higher than with the addition of pulse oximetry.17,18 Additional technological advances should improve the performance of screening tests in the future. FALSE-NEGATIVES

Pulse oximetry does not detect all types of CCHD, so it is possible for a newborn with a negative screening result to have CCHD or other congenital heart defects. Data from large studies provide some insight into the patterns of falsenegative screens. In the large Swedish study of nearly 40,000 newborn screens, 5 out of 60 ductal-dependent lesions were not detected by pulse oximetry.17 In each case of a falsenegative screen, the newborn had coarctation of the aorta, a type of CCHD that can present late and, therefore, be missed during the recommended screening window.4,17 A

Norwegian study of 50,008 newborn screenings involved 49,684 infants with SpO2 readings ≥95%, including eight with false-negative screens.19 Of these, four were diagnosed with CCHD before discharge on the basis of clinical findings. Therefore, the overall false-negative rate was 4 of 49,684 screens, or 0.008%. Missing a diagnosis of CCHD has significant clinical and financial costs. In the Swedish trial, newborns who were discharged with undiagnosed CCHD had a higher proportion of severe acidosis than those who were diagnosed in hospital, resulting in a longer stay in the intensive-care unit and a higher mortality rate during corrective surgery.17 Although current pulse-oximetry technology cannot detect every cardiac defect, the rate of missed CCHD diagnoses is much higher when screening is based on physical examination alone. Health-care providers and families also must understand limitations of pulse-oximetry monitoring to detect CCHD, that a negative screening result does not exclude the possibility of CCHD or other congenital heart disease, and that there is a potential for false-positive screen results.1 Implementation of screening programs

According to the SACHDNC recommendations, it is the responsibility of individual states to develop and implement screening protocols to enhance the detection of CCHD.7 State departments of public health will lead comprehensive efforts to standardize screening practices, for instance, by disseminating screening protocols to all hospitals and birthing centers in their jurisdiction. States will also perform ongoing data surveillance to monitor CCHD screening rates and the appropriateness of follow-up care in newborns with positive screens. As of September 1, 2012, nine states—California, Connecticut, Indiana, Maryland, New Hampshire, New Jersey, Tennessee, Virginia, and West Virginia—had passed legislation mandating CCHD screening for newborns in their states.12 Another 18% of states had legislation introduced, and 10% had legislation pending. States including Tennessee, Massachusetts, Arizona, California, Iowa, Montana, and Washington have initiated pilot multicenter screening programs to determine the needs of local hospitals and birthing facilities. To date, 42% of states have not yet taken action to implement recommendations for CCHD screening.12 Future of CCHD screening

Pulse oximetry is a simple, safe, cost-effective tool for improving the early detection of CCHD in newborns. When added to the standard newborn physical examination,

34 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

current pulse-oximetry protocols are associated with high sensitivity for CCHD, with low false-positive and falsenegative rates.15-18 The FDA guidance document on the safety and effectiveness of pulse oximeters will further clarify the technical standards of care in CCHD screening.6 When the FDA guidance document is finalized, any pulse oximeter considered for screening should meet the revised technical recommendations.6 Future advances will continue to improve the clinical utility of screening by further decreasing false-negative and falsepositive rates. Manufacturers are making frequent improvements both in hardware and software in an effort to enhance the performance of pulse oximeters, and future guidelines from the SACHDNC are expected to reflect these new technological standards. Moreover, findings from state surveillance programs may also reveal important gaps in pulse-oximetry screening for CCHD that can be addressed with revised protocols. Given the importance of feedback for continuous quality improvement, it is critical that caregivers participate and provide detailed information to surveillance programs.

5. O’Donnell CP, Kamlin CO, Davis PG, et al. Clinical assessment of infant colour at delivery. Arch Dis Child Fetal Neonatal Ed. 2007;92:F465-F467. 6. U.S. Food and Drug Administration. Draft guidance for industry and FDA staff: pulse oximeters—premarket notification submissions [510(k)s]. www.in.gov/isdh/files/Instructions_for_FDA_Clearance_in_ Neonates.pdf. 7. Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children. Recommendations and responses from the HHS Secretary. www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/ recommendations/index.html. 8. Mahle WT, Martin GR, Beekman RH, et al. Endorsement of Health and Human Services recommendation for pulse oximetry screening for critical congenital heart disease. Pediatrics. 2012;129:190-192. 9. Maryland State Advisory Council on Hereditary and Congenital Disorders. Recommendations on implementation of screening for critical congenital heart disease in newborns: 2011 Legislative Report. 10. Congenital Heart Disease Screening Program Toolkit. Children’s National Medical Center, Washington, D.C. www.childrensnational. org/PulseOx/request-tool-kit.aspx. 11. Garg LF. Screening for critical congenital heart disease in newborns using pulse oximetry— New Jersey’s experience. March 22, 2012.

Conclusions

www.amchp.org/Calendar/Webinars/ArchivedWebinars/Pages/

Backed by evidence-based recommendations, endorsements from the HHS and national medical societies, and state-level legislation, pulse-oximetry screening for CCHD is poised to change the standard of care for infants born in the U.S. Successful screening will require the standardization of protocols across hospitals and other care settings, as well as commitment from state public-health systems to support surveillance. Ongoing quality-assurance initiatives will continue to enhance the performance of pulse-oximetry screening across health-care settings. By participating in the implementation of screening programs in their institutions, health-care providers can contribute to the early detection of CCHD in affected newborns. ■

default.aspx. 12. Newborn Coalition. CCHD Screening Map. www.cchdscreeningmap.com. 13. Das J, Aggarwal A, Aggarwal NK. Pulse oximeter accuracy and precision at five different sensor locations in infants and children with cyanotic heart disease. Indian J Anaesth. 2010;54:531-534. 14. Phattraprayoon N, Sardesai S, Durand M, et al. Accuracy of pulse oximeter readings from sensor placement on newborn wrist and ankle. J Perinatol. 2012;32:276-280. 15. Sedaghat-Yazdi F, Torres A Jr, Fortuna R, et al. Pulse oximeter accuracy and precision affected by sensor location in cyanotic children. Pediatr Crit Care Med. 2008;9:393-397. 16. Thangaratinam S, Brown K, Zamora J, et al. Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis. Lancet. 2012;379:2459-2464.

References

17. de-Wahl Granelli A, Wennergren M, Sandberg K, et al. Impact of pulse

1. Kemper AR, Mahle WT, Martin GR, et al. Strategies for implementing screening for critical congenital heart disease. Pediatrics. 2011;128:e1259-e1267.

oximetry screening on the detection of duct dependent congenital heart disease: a Swedish prospective screening study in 39,821 newborns. BMJ. 2009;338:a3037.

2. Hoffman JI. It is time for routine neonatal screening by pulse oximetry. Neonatology. 2011;99:1-9.

18. Ewer AK, Middleton LJ, Furmston AT, et al. Pulse oximetry screening for congenital heart defects in newborn infants (PulseOx): a test accuracy

3. Mahle WT, Newburger JW, Matherne GP, et al. Role of pulse oximetry in examining newborns for congenital heart disease: a scientific statement from the AHA and AAP. Pediatrics. 2009;124:823-836. 4. Wren C, Reinhardt Z, Khawaja K. Twenty-year trends in diagnosis of

study. Lancet. 2011;378:785-794. 19. Meberg A, Brügmann-Pieper S, Due R Jr, et al. First day of life pulse oximetry screening to detect congenital heart defects. J Pediatr. 2008;152:761-765.

life-threatening neonatal cardiovascular malformations. Arch Dis Child Fetal Neonatal Ed. 2008;93:F33-F35.

All electronic documents accessed October 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 35

CME CE

POSTTEST Expiration date: November 2013

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 Credits™. 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. 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 myCME.com/neonatal or ClinicalAdvisor.com/CMEFeatureNov2012.

CREDITS: 0.5

| CCHD screening guidelines: pulse-oximetry performance and statewide protocols

1. Future guidelines for pulse-oximetry screening devices are projected to: a. Reflect state and local performance and protocol standards for sensitivity and specificity b. Reduce the number of false-negatives for newborns undergoing critical congenital heart disease (CCHD) screening c. Reduce the number of false-positives for newborns undergoing CCHD screening d. Meet FDA criteria for performance standards for sensitivity and specificity 2. In a study evaluating the accuracy and precision of pulse oximetry at five different sensor locations in infants and children with known cyanotic heart disease, which site was the most accurate? a. Finger c. Sole b. Palm d. Foot

4. A Swedish study reported that compared with newborns who were diagnosed in the hospital, those infants who were discharged with undiagnosed CCHD had a higher proportion of: a. Severe sepsis b. Severe acidosis c. Ductal-dependent lesions d. Similar mortality rates 5. The New Jersey Department of Health and Senior Services Birth Defects Registry data on failed pulse-oximetry screens include: a. Upper-extremity and lower-extremity pulse-oximetry x 3 b. Upper-extremity and lower-extremity pulse-oximetry x 2 c. Postnatal ultrasound d. Prenatal echocardiogram

3. The false-positive rate with a standard physical examination alone for CCHD is approximately how many times greater than with the addition of pulse oximetry? a. 5 times c. 20 times b. 10 times d. 30 times

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, and/or Covidien. 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 Covidien. 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.

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureNov2012

36 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

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 2012

Consultations Foul-smelling urine caused by supplements . . . . . . . . . . . . . . . .40 When to do an endometrial biopsy . . .40 Diarrhea in an elderly man in an assisted-living facility . . . . . . . .41

Clinical Pearls Minimize pain during an eye exam . . .42 Use distilled water when taking thyroid medication. . . . . . . . . . . . . .42 Gassing up at the gynecologic exam . .42

Your Comments

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.

More help for victims of bullying . . . .42

CONSULTATIONS FOUL-SMELLING URINE CAUSED BY SUPPLEMENTS I recently underwent surgery to repair a cracked femoral head. Ever since the injury, I have been taking vitamin D and calcium. My urine is foul-smelling but clear, and there is no dysuria. Could the foul smell be caused by the supplements? – MARIA BIPS, PA-C, Decatur, Ga. Foul-smelling urine can be due to dehydration, dietary intake (e.g., asparagus), uncontrolled diabetes, genetic conditions (e.g., maple sugar urine disease, phenylketonuria), or infections of the urinary tract. Vitamin supplements have also been associated with foul-smelling urine, especially B vitamins. In such cases, the urine typically takes on a bright-yellow color as well. Other supplements, especially water-soluble ones, can also cause a foul smell. Be sure to remain well hydrated; if further symptoms develop, a urinalysis and urine culture would be the first step in the investigation.—Claire Babcock O’Connell, MPH, PA-C (169-1)

WHEN TO DO AN ENDOMETRIAL BIOPSY I have a patient in her early 20s who continues to have breakthrough bleeding (BTB) while taking oral contraceptive pills (OCPs). She has changed pills at least two times with no improvement. Assuming negative Pap results, would

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.

40 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

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

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

Maria Kidner, DNP, FNP-C,

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

you advise endometrial biopsy on this patient?—BETSY SCHRADER, ARNP-BC, EdD, Stillwater, Okla. BTB is one of the more common side effects of using OCPs. An endometrial biopsy is not necessary in this case. The clinician should (1) obtain a thorough history of the woman’s current bleeding pattern as well as her bleeding pattern prior to OCP use (e.g., ask if the bleeding is postcoital or if she has any other symptoms associated with the bleeding); (2) screen for sexually transmitted infections or other forms of vaginitis; (3) do a thorough pelvic exam looking for cervical polyps, cervicitis, or cervical ectropion, as well as a bimanual exam to feel for an enlarged uterus, which could indicate uterine fibroids; (4) rule out pregnancy; (5) ensure the patient is taking the pill consistently, as missing pills or being late on pills is one of the most common causes of BTB; and (6) ask if the woman smokes, as smoking cessation may improve cycle control. Endometrial biopsies are a screening tool used to assess for endometrial hyperplasia (and ultimately endometrial carcinoma), a condition found almost solely in peri- and postmenopausal, overweight, and anovulatory women. Endometrial biopsies should be performed on postmenopausal women who have any vaginal bleeding, women age 35 years and older who have abnormal bleeding for more than three months prior to starting contraception, and women who have a history of prolonged anovulation and thus, unopposed estrogen stimulation (e.g., obese women with polycystic ovary syndrome [PCOS]). OCPs actually decrease the risk of endometrial carcinoma by keeping the endometrium thin (the likely reason for much of the BTB in OCP users). Women who have PCOS and other unopposed estrogenic states are prescribed OCPs to protect their endometrium from the hyperplasia that would otherwise result from their anovulatory cycles. Once other causes of her BTB are ruled out, Ms. Schrader’s patient has the option to: (1) change birth-control methods altogether; (2) switch to a pill containing norethindrone acetate (Aygestin) as

opposed to levonorgestrel, as this may decrease the duration of her BTB; (3) try a seven-day course of 1.25 mg conjugated estrogen or 2 mg estradiol in addition to her OCP; or (4) continue her current method after being counseled that BTB is a common finding and that unscheduled bleeding may improve over time with consistent pill use.—Mary Newberry, CNM, MSN (169-2)

DIARRHEA IN AN ELDERLY MAN IN AN ASSISTED-LIVING FACILITY For several months, 99-year-old white man in an assistedliving facility has experienced bouts of explosive diarrhea. It occurred every day and only after breakfast. Restricting the patient’s dairy intake led to some improvement. After being placed on a gluten-free diet, the frequency has lessened to two to three times per week, but the diarrhea has not resolved. The patient’s medications are furosemide [Delone, Furocot, Lasix, Lo-Aqua], low-dose aspirin, and vitamin D. His weight and vital signs have been stable; physical examination was unremarkable except for cool extremities and trace pitting edema to the legs. A complete blood count (CBC) and comprehensive metabolic profi le (CMP) were within normal limits. A stool culture taken three years ago was negative for Clostridium difficile. The family does not want any invasive testing. An abdominal CT taken four years ago was unremarkable. Where can I go from here?—MARY KEANE, GNP-BC, Saginaw, Mich. This patient’s condition may be related to dietary issues. I recommend eliminating any artificially sweetened foods, which can also contribute to diarrhea in older adults living in long-term-care facilities. Although the diagnostic tests are not current, it is unlikely that this man would be suffering from C. difficle or other infectious causes while maintaining a normal weight, vital signs, CBC, and CMP.

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

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

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

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

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

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 41

Advisor Forum Lactose malabsorption is more prevalent in individuals older than age 74 years. Restricting foods that contain milk and milk products should continue to be helpful. Be sure that the patient is not impacted. If impaction is not present, an empiric trial of such bile-acid-binding resins as cholestyramine is the least expensive way to diagnose bile-acidinduced diarrhea and increase bulk in his stools. Consider repeating stool cultures, including C. difficle and ova and parasites.—Deborah L. Cross, MPH, CRNP, ANP-BC (169-3)

CLINICAL PEARLS MINIMIZE PAIN DURING AN EYE EXAM When conducting a slit-lamp examination, set the light all the way to the lowest setting and have the patient close his or her eyes until you are ready to begin. This will help the patient stay still and result in far less eye pain caused by an overly bright lamp.—KATHLEEN DUPONT, PA-C, Santa Barbara, Calif. (169-4)

down toward the anus, I tell the student to open up the speculum and slowly tilt his or her wrist upward until the cervix is fully visualized.—AIMEE HOLLAND, DNP, WHNP, FNP, RD, Birmingham, Ala. (169-6)

YOUR COMMENTS MORE HELP FOR VICTIMS OF BULLYING Thank you for the wonderful suggestions in the Commentary, “Help kids who are bullied or are bullies” (September 2012). Acknowledging and validating the child’s fears and concerns is also helpful. Letting the child know, “Anyone in this situation could feel the same way,” authenticates his or her feelings and can help calm the emotions.—LORNA McDOUGALL, NP, Toronto (169-7) ■

GASSING UP AT THE GYNECOLOGIC EXAM I precept in the obstetrics/gynecology clinic, and teaching students how to insert a speculum into the vagina and locate the cervix can often be a challenge. An analogy I came up with has really helped. Instruct the student to gently insert the speculum into the vagina like he or she was inserting a gas nozzle into a car. Insert the speculum into the vagina while gently pointing it downward toward the anus. When the speculum is inserted all the way into the vagina pointed

USE DISTILLED WATER WHEN TAKING THYROID MEDICATION If a patient on thyroid hormone replacement therapy has fluctuating levels of thyroid-stimulating hormone, advise him or her to take thyroid medication with distilled water. The minerals in tap and bottled water can deactivate some of the thyroid hormone. Since the mineral level in the water varies, so will the amount of thyroid hormone the patient receives. Some patients are especially sensitive to these small fluctuations and do much better when taking medication with distilled water. As always, remind your patient to take thyroid medication on an empty stomach and at least four hours before or after taking any mineral (e.g., calcium) supplements.—MELISSA DONAIS, FNP, North Reading, Mass. (169-5)

“Thanksgiving is politically incorrect, turkey is politically incorrect, yams with marshmallow fluff are politically incorrect—and disgusting.”

42 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

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 ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Yellowish papules on the upper and lower eyelids A 66-year-old man presented complaining of yellowish papules on his eyelids that had been present for several years. The papules were asymptomatic, but he was bothered by the cosmetic appearance. WHAT IS YOUR DIAGNOSIS?

• • • •

Xanthelasma Eruptive xanthoma Tuberous xanthoma Tendinous xanthoma

● See the full case at ClinicalAdvisor.com/DermDx1112A

Focal area of sparse scalp hair present since birth A toddler presented with an area of sparse hair at the left anterior hairline. This abnormality was noted at birth. No complications during pregnancy or in the perinatal period were reported. A skin exam was normal. WHAT IS YOUR DIAGNOSIS?

• • • •

Temporal triangular alopecia Alopecia areata Tinea capitis Traction alopecia

● See the full case at ClinicalAdvisor.com/DermDx1112B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s other cases. White spots on the legs

44 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

Ulcer associated with leukemia

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LEGAL ADVISOR CASE

A critical mistake in the ED

BY ANN W. LATNER, JD

The emergency department (ED) of a large hospital can often be a busy, chaotic place. The very nature of medical emergencies means that treatment often has to be instantaneous and that the health status of a patient can change quickly. Clinicians who work in the ED have to be able to multitask, parse information from several sources at once, juggle numerous patients, and make splitsecond decisions. It is a difficult job, and, as one clinician found out, a job in which inattention— just for a short time—can mean the difference between life and death. Mr. O was a nurse practitioner employed in the ED of an urban medical center. Located in a busy metropolitan area, the hospital’s ED had a steady flow of patients. Mr. O had been working in the ED for the past five years, and the stress was beginning to wear on him. Everything shifted for Mr. O when he got married. His priorities changed. Mr. O and his wife now had a child at home, and long shifts in the ED were draining. In addition, he no longer wanted to pull double shifts that kept him from spending time with his family. Mr. O was on

Who is at fault when an unattended patient is found cyanotic and unresponsive?

The patient had trouble focusing and was belligerent, so questions had to be asked repeatedly to get an answer.

46 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

the verge of leaving the hospital to work in a physician’s office. During Mr. O’s shift one night, two paramedics wheeled in an obviously intoxicated man. “A woman walking her dog found him lying on the street—semiconscious and incoherent— and called us,” said the lead paramedic. “He was physically and verbally combative when we tried to help him, and he is having difficulty speaking and walking.” The patient looked familiar to Mr. O, but that was not terribly surprising. Local drunks were often brought to the ED. Mr. O started a fi le, noting that the patient, Mr. J, arrived in the ED at 10:45 pm. Mr. O then tried to question Mr. J, but the patient was too intoxicated to answer coherently. Because Mr. J had trouble focusing and was belligerent, the questions had to be asked repeatedly to elicit an 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.

When a hug hurts, LYRICA® (pregabalin) can make a difference in reducing Fibromyalgia pain.

Access downloadable resources for managing Fibromyalgia and learn more about LYRICA at www.FMMGMT.com LYRICA is indicated for the management of Fibromyalgia in adults 18 years and older. Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebo-treated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA clinical trials are PBP491706-01

dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention). Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. Patients with a history of drug or alcohol abuse may have a higher chance of misuse or abuse of LYRICA. Withdraw LYRICA gradually over a minimum of 1 week. Discontinue LYRICA immediately in patients with symptoms of hypersensitivity or angioedema. Click here for Full Prescribing Information and Medication Guide. Please see Brief Summary of Prescribing Information on adjacent pages. September 2012

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of fibromyalgia DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Fibromyalgia: • Administer in 2 divided doses per day • Begin dosing at 150 mg/day • May be increased to 300 mg/day within 1 week • Maximum dosage of 450 mg/day • Dose should be adjusted in patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: CLCr =

[140 - age (years)] x weight (kg) 72 x serum creatinine (mg/dL)

(x 0.85 for female patients)

Dose Regimen BID or TID

30–60

150

225

300

BID or TID

15–30

25–50

100–150

150

QD or BID

<15

25 25–50 50–75 75 Supplementary dosage following hemodialysis (mg)†

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent

association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when coadministering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICArelated dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebotreated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in shortterm, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worseningpreexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to visionrelated events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 103/µL, compared to 11 × 103/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 × 103/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/ µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Fibromyalgia Adverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150–600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with fibromyalgia in the ‘all pregabalin’ treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".

Table 3. Treatment-emergent adverse reaction incidence in controlled trials in Fibromyalgia (events in at least 2% of all LYRICA-treated patients and occurring more frequently in the all pregabalin-group than in the placebo treatment group) 150 mg/d 300 mg/d 450 mg/d 600 mg/d All PGB* Placebo System Organ Class [N=132] [N=502] [N=505] [N=378] [N=1517] [N=505] - Preferred term % % % % % % Ear and Labyrinth Disorders Vertigo 2 2 2 1 2 0 Eye Disorders Vision blurred 8 7 7 12 8 1 Gastrointestinal Disorders Dry mouth 7 6 9 9 8 2 Constipation 4 4 7 10 7 2 Vomiting 2 3 3 2 3 2 Flatulence 1 1 2 2 2 1 Abdominal distension 2 2 2 2 2 1 General Disorders and Administrative Site Condition Fatigue 5 7 6 8 7 4 Edema peripheral 5 5 6 9 6 2 Chest pain 2 1 1 2 2 1 Feeling abnormal 1 3 2 2 2 0 Edema 1 2 1 2 2 1 Feeling drunk 1 2 1 2 2 0 Infection and Infestations Sinusitis 4 5 7 5 5 4 Investigations Weight increased 8 10 10 14 11 2 Metabolism and Nutrition Disorders Increased appetite 4 3 5 7 5 1 Fluid retention 2 3 3 2 2 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 3 6 4 2 Muscle spasms 2 4 4 4 4 2 Back pain 2 3 4 3 3 3 Nervous System Disorders Dizziness 23 31 43 45 38 9 Somnolence 13 18 22 22 20 4 Headache 11 12 14 10 12 12 Disturbance in attention 4 4 6 6 5 1 Balance disorder 2 3 6 9 5 0 Memory impairment 1 3 4 4 3 0 Coordination abnormal 2 1 2 2 2 1 Hypoaesthesia 2 2 3 2 2 1 Lethargy 2 2 1 2 2 0 Tremor 0 1 3 2 2 0 Psychiatric Disorders Euphoric Mood 2 5 6 7 6 1 Confusional state 0 2 3 4 3 0 Anxiety 2 2 2 2 2 1 Disorientation 1 0 2 1 2 0 Depression 2 2 2 2 2 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 2 1 3 3 2 2 *PGB: pregabalin Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, GuillainBarré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis. Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement. In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications. DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin

exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide 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 efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The noeffect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. LAB-0294-22.0 June 2012 This brief summary is based on LYRICA Prescribing Information LAB-0294-22.0, June 2012.

September 2012

LEGAL ADVISOR answer. Mr. O was able to ascertain that the patient was aged 26 years and that he had ingested alcohol. Mr. J denied drug use. Mr. O noted that the patient was responsive to pain and able to move his extremities. Several ambulances then arrived with the victims of an automobile accident, and Mr. O was needed elsewhere. He placed Mr. J on his side—on a stretcher—and put him in a holding area between the waiting room and the exam room. Mr. O then attended to the incoming patients. When Mr. O later returned to check on Mr. J’s status, the patient was unresponsive, not breathing, cyanotic, and had fi xed and dilated pupils. Mr. J was rushed into the exam room and quickly treated by the head ED physician, Dr. F.

Memory can be faulty, which is why hard evidence—such as a written record—is more credible than individual testimony. The clinicians worked furiously for 30 minutes but were unable to save the patient. Respiratory failure was deemed the cause of death. Several months after the incident, Mr. O was served with papers informing him that Mr. J’s father was suing him, Dr. F, and the hospital for the wrongful death of his son. “I’ve looked at the patient’s file,” said the attorney, “and I don’t see anywhere in the chart that you noted taking Mr. J’s vital signs before leaving him on the stretcher.” Mr. O felt a surge of panic. “I’m not sure if I did,” he said. “Ordinarily I would, but he was hard to examine because of his extreme intoxication, and then a trauma case came in. I may have neglected to check his vitals. Or maybe I did, but I didn’t write it in the chart. I’m just not sure.” “The patient’s records indicate that he arrived in the ED at 10:45 pm and was found unresponsive at 11:30 pm,” stated the attorney. “Did you check on him at any time between 10:45 and 11:30?” “I don’t remember,” answered Mr. O. “There was a lot going on that night.” “What is the hospital policy on how often you should be checking vitals on a patient in the ED?” the attorney asked. “We are supposed to check every 15 minutes,” explained Mr. O. “But sometimes it gets very busy and 20 minutes or so might go by before we get a chance.” “In the physician’s report, prepared after the patient died, Dr. F wrote that he was told that the patient had been checked

on by a nurse at around 11:05 pm. Do you remember telling the physician that?” “Honestly, no,” said Mr. O. “I wish I did.” After several more discussions, and after depositions had begun, Mr. O’s attorney advised him that settling the case would be the best option. The case was later settled for an undisclosed amount. Legal background

Memory can be faulty, which is why hard evidence—such as a written medical record—is given more credibility than individual testimony. The defense attorney in this case consulted Mr. O to settle because there was no record of the clinician checking on the patient before 11:30 pm or taking the patient’s vital signs. The document prepared by Dr. F was created after the incident and contained secondhand information indicating that Mr. O had checked on the patient. But the patient’s medical fi le showed no record of this, nor did Mr. O recall monitoring the patient. The evidence at trial would have shown that the hospital has a policy mandating that a patient’s vital statistics be checked every 15 minutes, which the patient record indicates did not occur. In light of these facts, and the fact that Mr. O should have known that alcohol consumption depresses the respiratory system, Mr. O would likely have been found negligent in his care of the patient had the case gone to trial. Settling out of court avoided the time, money, and emotional strain involved with a trial. Protecting yourself

It is vital to comply with hospital policy. Protocol in this case clearly mandated that a clinician check an ED patient’s vital signs every 15 minutes. Had there been only a five-minute deviation, this lag in response time probably would have been overlooked. Yet, there was no record of Mr. O taking Mr. J’s vitals at initial intake, and no documentation supporting a follow-up within 45 minutes. In court, these factors attest to the fact that Mr. O (and, by extension, the hospital) did not meet the appropriate standard of care. Record-keeping is crucial as well. Notes in Mr. J’s chart as to when the initial exam took place, what the results were, and timed/dated entries regarding follow-up could have helped Mr. O—a busy practitioner—remember this particular case. Had he rendered treatment, this documentation could have avoided a lawsuit altogether. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

50 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

For the early treatment of recurrent herpes labialis to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time.

In a controlled clinical trial:

• 42% of patients treated with XERESE® did not progress to the ulcerative stage vs vehicle (26%) (p<0.0001)2 • 50% smaller lesion area vs vehicle (p<0.0001); 1.6 days faster healing vs vehicle (p=0.0001)1-3 • Combines antiviral acyclovir with antiinﬂammatory hydrocortisone

WHEN A COLD SORE STARTS

STOP IT BEFORE IT GETS UGLY

Indication and Important Safety Information: XERESE (acyclovir and hydrocortisone) Cream 5%/1% is indicated for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and adolescents (12 years of age and older). XERESE Cream is intended for cutaneous use only, on the lips and around the mouth. XERESE should not be used in the eye, inside the mouth or nose, or on the genitals. Patients should be encouraged to seek medical advice when a cold sore fails to heal within 2 weeks. The effect of XERESE Cream has not been sufficiently established in immunocompromised patients. XERESE Cream has a potential for irritation and contact sensitization. In clinical trials, the most common adverse reactions in the area of the application site included drying or flaking of the skin; burning or tingling following application; erythema; pigmentation changes; application site reaction including signs and symptoms of inflammation. Each event occurred in less than 1% of patients. Please see brief summary of Prescribing Information on adjacent page. References: 1. XERESE [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2012. 2. Hull CM, Harmenberg J, Arlander E, et al. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol. 2011;64(4):696.e1-11. 3. Data on file, Valeant Dermatology. © 2012 Valeant Dermatology, a division of Valeant Pharmaceuticals North America LLC XER1260312

Learn more at www.XERESE.com

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XPERTISE in action

A19170x02E_300ucr.tif

VALXR10289 - Xerese 4C Bleed Journal Ad with b/w PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.375"w × 11.125"h Trim: 7.75"w × 10.5"h Live: 6.875"w × 9.875"h Output @ 100% Giant Creative Strategy

The only FDA-approved agent proven to help prevent cold sore progression1

USE IN SPECIFIC POPULATIONS Pregnancy

XERESE®

Category B

(acyclovir and hydrocortisone) Cream 5%/1% for topical use

Teratogenic Effects

IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing information provided with the product and therefore should not be used as the basis for prescribing the product. This summary has been prepared by deleting information from the complete prescribing information such as certain text, tables, and references. The physician should be thoroughly familiar with the complete prescribing information before prescribing the product.

Acyclovir was not teratogenic in the mouse, rabbit or rat at exposures greatly in excess of human exposure. There are no adequate and well-controlled studies of systemic acyclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy between 1984 and 1999 followed 749 pregnancies in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximated that found in the general population. However, the size of the registry was insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.

INDICATIONS AND USAGE XERESE is indicated for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and adolescents (12 years of age and older). CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS General XERESE is intended for cutaneous use only for herpes labialis of the lips and around the mouth. XERESE should not be used in the eye, inside the mouth or nose, or on the genitals. There are other orofacial lesions, including bacterial and fungal infections, which may be difficult to distinguish from a cold sore. Patients should be encouraged to seek medical advice when a cold sore fails to heal within 2 weeks. XERESE has a potential for irritation and contact sensitization (see Adverse Reactions). ADVERSE REACTIONS Overall Adverse Reaction Profile The safety data derived from XERESE clinical studies reflect exposure to XERESE in 1002 subjects with recurrent herpes labialis treated 5 times daily for 5 days. The majority of the adverse reactions were local skin reactions and occurred in the area of the application site. Adverse Reactions in Clinical Studies Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. The majority of the adverse reactions were local and occurred in the area of the application site. Skin and Subcutaneous Tissue Disorders The following most common adverse reactions (< 1%) were local skin reactions, and occurred in the area of the application site: — Drying or flaking of the skin; burning or tingling following application; erythema; pigmentation changes; application site reaction including signs and symptoms of inflammation. Contact dermatitis following application has been observed when applied under occlusion in dermal safety studies. Where contact sensitivity tests have been conducted, the reactive substances were hydrocortisone or a component of the cream base. A study enrolling 225 healthy adults was conducted to evaluate the contact sensitization potential of XERESE using repeat insult patch testing methodology. Of 205 evaluable subjects, one confirmed case (0.5%) of sensitization to hydrocortisone and 2 additional cases (1.0%) of possible sensitization to the XERESE base were identified. Additionally, one subject developed a contact allergy in the photosafety study to propylene glycol, one of the inactive ingredients of the cream base. Dermal tolerance was assessed in a 21-day cumulative irritation study in 36 healthy subjects. XERESE, its cream base and Zovirax® (acyclovir) Cream 5% all showed a high and cumulative irritation potential under occlusive and semiocclusive conditions.

Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Animal reproduction studies have not been conducted with XERESE. No studies have been performed in pregnant women. Systemic exposure of acyclovir and hydrocortisone following topical administration of XERESE is minimal. Nursing Mothers It is not known whether topically applied acyclovir or hydrocortisone is excreted in breast milk. Systemic exposure following topical administration of either drug is expected to be below detection limits. Because many drugs are excreted in human milk, caution should be exercised when XERESE is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric subjects less than 12 years of age have not been established. Geriatric Use In clinical studies, there were insufficient subjects above 65 years of age to reach a firm conclusion regarding safety and efficacy of XERESE in this group, although the available results were similar to lower age subjects. Immunocompromised Subjects Even though the safety of XERESE has been studied in immunocompromised subjects, data are insufficient to support use in this population. Immunocompromised subjects should be encouraged to consult a physician concerning the treatment of any infection. Benefit has not been adequately assessed in immunocompromised patients. A randomized, double-blind study was conducted in 107 immunocompromised subjects with stable HIV infection and recurrent herpes labialis. Subjects had on average 3.7 episodes of herpes labialis in the previous 12 months. The median age was 30 years (range 19 to 64 years), 46% were female, and all Caucasian. Median CD4+ T-cell count at screening was 344/mm3 (range 100-500/mm3). Subjects were treated with XERESE or 5% acyclovir in XERESE vehicle. The primary objective was to exclude a doubling of the healing time in either treatment arm. The mean healing time for cold sores was similar between the two treatment groups: 6.6 days for XERESE and 6.9 days for 5% acyclovir in XERESE vehicle. HOW SUPPLIED XERESE is supplied in a plastic-laminated aluminum tube containing 5 gm of XERESE. NDC 0187-5104-01: 5 gm tubes Revised: 01/2012 Manufactured for: Valeant Pharmaceuticals North America LLC Bridgewater NJ 08807 Produced under license MEDA Pharma SARL, Luxembourg, by Valeant International (Barbados) SRL, Barbados, West Indies Made in Canada

Manufactured by: Contract Pharmaceuticals Limited (CPL) 7600 Danbro Crescent Mississauga, Ontario Canada L5N 6L6

Photoallergic potential and phototoxicity were assessed in two studies in 50 and 30 healthy volunteers, respectively. No photoallergic or phototoxicity potential was identiﬁed for XERESE. DRUG INTERACTIONS No drug interaction studies have been performed with XERESE.

XERESE is a registered trademark of Meda Pharma SARL under license by Valeant. U.S. Patents RE39,264 and 7,223,387 Part No. 2005525

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XER1250312

ValeantNAInc_NORTH_gs_outline.ai Xerese_Logo_4C+KO_®.ai

VALXR10289 - Xerese PI Colors: Black Trim/live: DO NOT PRINT Bleed: None Trim: 7.75"w × 10.5"h Live: 6.875"w × 9.875"h Output @ 100% Giant Creative Strategy

BRIEF SUMMARY OF PRESCRIBING INFORMATION

CME CE

Dermatology Clinic ■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 70

■ ADDITIONAL CME/CE: Pages 28, 65

Turn to page 27 for additional information on this month’s CME/CE courses.

CASE #1

Itchy leg bullae after a trip outdoors AUDREY CHAN, MD

A black woman, aged 65 years, presented with a one-week history of pruritic bullae. The patient reported participating in outdoor activities in the days prior to the eruption. Her medical history included type 2 diabetes mellitus but was notably negative for any history of lymphoproliferative disorders. The woman had begun taking colestipol (Colestid) three weeks earlier. Otherwise, no new medications were noted. On physical examination, several 2- to 3-cm tense bullae were appreciated on the distal lower extremities with no pitting edema. The face, trunk, and proximal extremities were not involved. What is your diagnosis? Turn to page 54

CASE #2

Firm, red plaques and xerotic skin KERRI ROBBINS, MD

A 52-year-old man with a history of type 2 diabetes, hypertension, and hyperlipidemia presented with a rash on his bilateral lower extremities. He stated that he often gets edema on his lower extremities, especially after standing for long periods of time. He recently developed pruritic reddish areas that became progressively more indurated and complained of very xerotic skin. No previous treatments or OTC medications or moisturizers were reported. Physical exam revealed brown to erythematous/violaceous indurated plaques on bilateral lower extremities What is your diagnosis? Turn to page 55 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 53

CME CE

CASE #1

Dermatology Clinic

Arthropod bite reaction

The woman was diagnosed with bullous arthropod bite reaction (BABR). Arthropod bite reaction can produce a wide array of clinical lesions. The most characteristic reaction is erythematous edematous papules that are markedly pruritic and often excoriated.1 Occasionally, vesicles and bullae may develop in response to insect saliva in a previously sensitized individual.2 There are no epidemiologic studies regarding the incidence or prevalence of BABR, nor are there any known risk factors based on ethnicity, gender, or age.There is, however, a well-accepted association of exaggerated arthropod reaction in individuals with chronic lymphocytic leukemia.3 It is often difficult to determine the culprit arthropod, as a vast majority of patients are unaware of the initial insect bite.3 However, certain arthropods have characteristic bite or reaction patterns. Bedbug (Cimex lectularius) bites are often noted in linear groups of three (commonly referred to as breakfast, lunch, and dinner).1 Blister beetles (order Coleoptera) have caused epidemics of bullous skin disease in hospital wards worldwide.1 Flea (order Siphonaptera) bites are usually located on the lower legs. Scabies (Sarcoptes scabiei var. hominis) infestations may rarely cause a bullous reaction with characteristic involvement of the interdigital webbing of the hands, flexural wrists, axillae, waist, feet, buttocks, and belt area.1 The differential diagnosis of tense bullae includes autoimmune blistering disorders, drug-induced bullous pemphigoid, contact dermatitis, bullosis diabeticorum, and edema bullae. Bullous pemphigoid (BP) is the most common autoimmune blistering disorder, with the vast majority of patients presenting after age 60 years. Although there is a rare variant localized to the pre-tibial area, most cases of BP have a symmetrical distribution, usually affecting the flexural limbs and abdomen. Drug-induced BP must also be considered as a differential. Medications commonly implicated include furosemide (Delone, Furocot, Lasix, Lo-Aqua), ibuprofen, phenacetin, d-penicillamine (Cuprimine, Depen), ampicillin (Omnipen, Polycillin, Principen), penicillin derivatives, and captopril (Capoten).4 A careful review of the patient’s medication list is imperative, but such a review can be challenging, as the time from initiation of medication to bullae development is variable. Acute allergic contact dermatitis (ACD) may also present with tense bullae; however, these lesions will almost

invariably develop in an erythematous background. One of the most common allergens that cause acute ACD is the OTC antibacterial Neosporin. Clinicians should specifically inquire about its use because patients often fail to mention it due to its ubiquity. Bullosis diabeticorum is a rare manifestation of diabetes and is also characterized by tense bullae most commonly located on the feet. A helpful distinguishing feature is the general lack of symptoms in bullosis diabeticorum, unlike BABR, which is most often pruritic. Finally, the differential diagnosis can include edema bullae; by definition, however, pitting edema must be present for this diagnosis. BABR can sometimes be diagnosed clinically. A thorough history regarding potential exposures (e.g., outdoor activities, pets, home infestations) must be obtained. A comprehensive physical exam should also be performed to assess for areas of involvement and to look for stigmata of such underlying causes as lymphadenopathy and peripheral edema. A detailed medication history should also be obtained, including use of such OTC medications as Neosporin and ibuprofen, which patients often fail to report. In a healthy young patient on no medications with a suggestive history (i.e., recent outdoor exposure or known arthropod infestation), the diagnosis sometimes can be made on clinical grounds. However, in many cases, two biopsies are required for hematoxylin and eosin (H&E) and direct immunofluorescence (DIF) to rule out other etiologies, including autoimmune bullous conditions, which will have a positive DIF. Treatment is supportive, as BABR will resolve with time. Pruritus can be managed with topical corticosteroids. Class 1 topical corticosteroids (e.g., clobetasol 0.05% ointment) are usually necessary to control pruritus on the extremities. Class 1 topical corticosteroids are a relative—but not absolute— contraindication on the face, so a less potent class is recommended. Antihistamines, including diphenhydramine and hydroxyzine, are helpful adjuncts for controlling pruritus. If the bullae are painful or located on the feet and interfering with ambulation, the fluid can be aspirated with a sterile needle in the clinic. Alternatively, patients can puncture the bullae at home with a sterilized needle to release the fluid. Instruct patients to leave the roof of the bullae intact to prevent open erosions, which can be a nidus for infection. This woman’s history was notable for recent outdoor exposure. Although she had recently started colestipol, a literature review revealed no association with drug-induced BP. None of the woman’s antihypertensives were commonly associated with drug-induced BP. Although the history and distribution of her lesions was suggestive of an arthropod reaction, her age and history of diabetes precluded making a diagnosis

54 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

on clinical grounds alone. Two biopsies were obtained; a lesional biopsy for H&E was notable for an intraepidermal vesicle with spongiosis and eosinophils, and a perilesional biopsy for DIF was negative. Taken together, these findings were consistent with BABR. A normal complete blood count ruled out an underlying lymphoproliferative disorder. The woman was managed with antihistamines and topical corticosteroids for symptomatic relief. Dr. Chan is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. References 1. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 3rd ed. St. Louis, Mo.: Elsevier-Mosby; 2012:431-438, 1292-1293, 1303-1318. 2. Lane K, Lumbang W. Pruritic blisters on legs and feet. J Fam Pract. 2008;57:177-180. Available at www.jfponline.com/Pages.asp?AID=5980. 3. Rosen LB, Frank BL, Rywlin AM. A characteristic vesiculobullous eruption in patients with chronic lymphocytic leukemia. J Am Acad Dermatol. 1986;15:943-950. 4. Fellner MJ. Drug-induced bullous pemphigoid. Clin Dermatol. 1993;11:515-520. All electronic documents accessed October 15, 2012

CASE #2

Stasis dermatitis

First described in the 1950s,1 stasis dermatitis causes inflammation on the lower extremities in people who have chronic venous insufficiency. Although not all patients with chronic venous insufficiency will develop stasis dermatitis, most will experience episodes of this skin disease. Stasis dermatitis is a complex and multifactorial condition influenced by many etiologic factors that act together over time.Although there are no direct reports on the prevalence of stasis dermatitis, researchers studying the prevalence of chronic venous insufficiency and venous ulcers have estimated that slightly more than 1% of the world population has the disease.2 Stasis dermatitis tends to be seen in older individuals, and women are affected more than men.The age of onset is usually in the fifth decade of life but may occur earlier if the patient has suffered trauma or thrombosis, which can give rise to venous insufficiency.

The disease may be a precursor to such problematic conditions as venous leg ulcers and lipodermatosclerosis. Chronic venous insufficiency is the most common factor for the onset of stasis dermatitis. Venous hypertension is caused by a malfunction of the one-way valvular system in the deep venous plexus of the legs. This incompetence causes a backflow of deoxygenated blood into the deep and superficial regions of the legs, which distends the capillaries and damages the capillary permeability barrier. The damage allows plasma fluid and plasma proteins into the tissue, causing edema. Stasis purpura and hemosiderin deposition also occur secondary to erythrocyte extravasation. The combination of these events causes microangiopathy.3 Metabolic exchange and oxygen diffusion ceases when the tissue becomes edematous and the protein (fibrin) becomes deposited around the vessels (i.e., forms a cuff around dermal capillaries). This slow blood flow causes upregulation of L-selectin on neutrophils, vascular intercellular adhesion molecule ICAM-1, and vascular cell adhesion molecule VCAM1.4,5 These adhesion molecules act as chemoattractants that keep leukocytes (neutrophils and macrophages) alive and active in the perivascular environment. Upregulation causes an increase in neutrophils, which have been reported to be up to 40 times their normal level in those with stasis dermatitis.6 Additionally, pericapillary inflammation is caused by neutrophils releasing inflammatory mediators, free radicals, and proteases. This can trigger focal thrombosis by platelet accumulation in the microvasculature. All of these imbalances in the capillary network will cause fibrosis and tissue remodeling, dysfunction of the lymphatics, and lipoderatosclerosis.2 It is believed that the chronic inflammation and microangiopathy lead to the development of stasis dermatitis. Stasis dermatitis is typically seen in the medial supramalleolar region, which is most susceptible to microangiopathy. The areas of dermatitis occur over dilated varicose veins, and areas that are affected with dermal inflammation may cause hyperproliferation, barrier impairment, and desquamation of the epidermis. Xerosis is also a common feature. Patients sometimes report severe pruritus, a feeling of heaviness, tingling in the legs, and a burning sensation, which is most likely caused by the release of inflammatory mediators in the dermis and the repeated congestion and decongestion.7 Excoriation at these areas will perpetuate the dermatitis. Such additional factors as contact sensitization and irritant dermatitis due to wound secretion and topical medications may also aggravate the dermatitis. In the early stages, stasis dermatitis is very mild and may present with xerosis and pruritis of the lower extremities. Due to the chronic venous insufficiency, pitting edema is

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CME CE

Dermatology Clinic

often appreciated, with greatest severity around the major communicating veins on the shin, calf, and proximal side of the ankle. As the disease progresses, it may be associated with inflammation and mimic cellulitis.The skin, adipose tissue, and deep fascia become indurated and adhere to each other.7,8 This creates a cuff around the distal calf, giving it the appearance of an inverted champagne bottle. The skin may also show hemosiderin pigmentation, venous ulcers, and the changes of atrophic blanche (stellate sclerotic areas depleted of capillaries with the formation of peripheral giant capillaries). In cases of longstanding stasis dermatitis, scaly papules and plaques will develop on the lower legs. By this stage, the affected area is severely pruritic, and oozing and crusting caused by excoriations will be present. Secondary contact sensitization to components of topical therapies is seen in 58% to 86% of individuals with venous leg ulcers.9 This sensitization will often lead to secondary dissemination that may become generalized and wax and wane for long periods of time. The stages of stasis dermatitis have different histologic appearances. In acute stasis dermatitis, edema predominates, and large macrovesicles may be seen within the epidermis. Perivascular and superficial lymphocytes are seen in the dermis with occasional exocytosis of lymphocytes into the epidermis. During the subacute phase, the spongiosis is subtle, and the epidermis begins to thicken and develop parakeratosis. Lymphocytes are still present in the dermis during this stage, but in fewer numbers. In chronic stasis dermatitis, the thickening of the epidermis is pronounced and often appears psoriasiform.2 The presence of lymphocytes and spongiosis is minimal to nonexistent. All biopsies of stasis dermatitis may reveal such signs of venous hypertension as dilated capillaries surrounded by cuffs of fibrin, hemosiderin deposits, and hyperplastic venules.2,10 During the chronic stages, fibrosis and sclerosis may occur. Stasis dermatitis is easily diagnosed if signs of venous hypertension are present (e.g., dilated venules, hemosiderin deposits, edema, inverted-champagne-bottle appearance of the calf). Difficulties may arise in differentiating stasis dermatitis from asteatotic eczema, allergic or irritant contact dermatitis, nummular eczema, psoriasis, or mycosis fungoides.Allergic contact dermatitis may be excluded by patch testing. Histologic assessment can differentiate among the other diagnoses. There are many treatment options for stasis dermatitis; however, the major aim of therapy involves the treatment of such underlying factors as venous hypertension and venous insufficiency. Compression stockings are helpful, but it is important to properly examine peripheral arterial circulation using a Doppler study before starting the treatment in select individuals. Compression of a compromised arterial circulation could

cause more problems. Compression therapy uses compression stockings; there are also specialized compression bandages and boots. In conjunction with compression therapy, such surgical measures as ligation of incompetent communicating veins and removal of insufficient saphenous veins can be taken. Other treatments include topical therapies, particularly corticosteroids and emollients. Topical calcineurin inhibitors are added to individuals with refractory disease.2 Stasis dermatitis is a chronic condition that requires significant life changes to treat effectively.The patient must comply with treatment using leg elevation, compression stockings, and topically applied therapies. Complications that may arise with stasis dermatitis include nonhealing venous ulcers, increased episodes of allergic contact dermatitis, and lipodermatosclerosis. Ulcers produced by stasis dermatitis should be routinely checked for superinfection. Patient knowledge and education are the most powerful tools available. The man in this case was treated with compression stockings, leg elevation and triamcinolone 0.1% ointment to be used as needed for pruritus. He was also advised to apply a heavy, bland emollient to the area at least three times a day. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. References 1. Pillsbury DM. The Pathogenesis of Eczema. Proc X Int Congress Dermatol (London, 1952). London: British Medical Association; 1953:58. 2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 3rd ed. St. Louis, Mo.: Elsevier-Mosby; 2012:201-202. 3. Scharffetter-Kochanek K, Schüller J, Meewes C, et al. [Chronic venous venous ulcus cruris. Pathogenesis and the significance of “aggressive micromilieus”]. J Dtsch Dermatol Ges. 2003;1:58-67. 4. Peschen M, Lahaye T, Hennig B, et al. Expression of the adhesion molecules ICAM-1,VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency. Acta Derm Venereol. 1999;79:27-32. 5. Jünger M, Steins A, Hahn M, Häfner HM. Microcirculatory dysfunction in chronic venous insufficiency (CVI). Microcirculation. 2000;7(6 Pt 2):S3-S12. 6. Scurr JH, Coleridge-Smith PD. The microcirculation in venous disease. Angiology. 1994;45:537-541. 7. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, N.Y.: McGraw-Hill; 2009:476-477. 8. RP Rapini. Practical Dermatopathology. 2nd ed. Philadelphia, Pa.: Elsevier Health Sciences; 2012:45-47. 9. Tavadia S, Bianchi J, Dawe RS, et al. Allergic contact dermatitis in venous leg ulcer patients. Contact Dermatitis. 2003;48:261-265. 10. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:243.

56 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

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.

Eucalyptus

Many generations of children remember the strong, aromatic smell of eucalyptus. Our mothers were quick to bring out the family supply of whatever eucalyptus product was available at the time and liberally slather it on our chests when we were in the throes of a bad cold or had the croup or bronchitis. While Mom may not have understood the chemical activity that helped us to breathe easier, the relief that eucalyptus provided was enough to continue the practice. Today, there are multiple brandname products that contain eucalyptus oil for medicinal uses.

Background Australia is the world’s main producer of eucalyptus oil.1 Also called the “gum tree,” eucalyptus is an evergreen, and its leaves are broad, whitish-green, and waxy. It is the leaves of Eucalyptus globulus that are harvested for the distillation of its essential oil. The active ingredient of eucalyptus oil is 1.8-cineol, or eucalyptol.2

Science The actual mechanism of action in eucalyptus oil is still unclear. Generally, eucalyptus oil is thought to be antiinflammatory and antimicrobial. There is some evidence that it can be used as an antifungal agent.3 One study examined the effect of eucalyptus oil on human monocytes, specifically its ability to stimulate protective macrophage activity.4 The substance was also studied for its effect on the release of pro-inflammatory cytokines.

Eucalyptus oil significantly induced macrophage activation and reduced the release of inflammatory cytokines.4 Steroid-dependent asthma patients were studied to determine the potential for steroid reduction when treated with an oral preparation of eucalyptus oil.5 After randomization, patients’ daily steroid doses were reduced by 2.5 mg every three weeks. At the end of 12 weeks, 36% of the patients on the active eucalyptus-oil therapy tolerated an average of 3.5 mg/day reduction in oral steroid use while only 7% of the placebo-treated patients were able to decrease their daily dose with an average reduction of 0.91 mg/day. Eucalyptus oil has also been studied for its potential as an antimicrobial. A study of 56 respiratory isolates from 200 symptomatic patients showed definite antimicrobial activity with eucalyptus oil.6 Isolates included Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. With the rise in antimicrobial resistance, a potential new method for treating these infections is welcome news. Continues on page 60

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 59

ALTERNATIVE MEDS UPDATE A separate study examining the use of eucalyptus oil in asthmatic patients explored the extract’s effect on nitric oxide in respiratory cells.7 Previous studies have shown an increase in exhaled nitric oxide in cases of eosinophilic infl ammation and other indices of asthmarelated inflammation. If eucalyptus oil is found to mitigate inflammation in such patients, this could lead to significant nonsteroidal treatment options for asthma. This trial showed that the extract was highly effective at inhibiting the induction of nitric oxide and the concomitant pro-inflammatory effects, further suggesting that eucalyptus extract may be a clinically viable option for asthmatic patients. E. globulus has also been tested to determine its analgesic and anti-inflammatory effects in rat models.8 Eucalyptus-oil extract induced analgesic effects in this animal cohort, and was designed to show both peripheral and central pain relief. Another arm of the same trial measured—and confirmed—the anti-inflammatory benefits of eucalyptus oil.

Safety, interactions

at least 70% to 85% of 1.8-cineol.9 Eucalyptus extract is supplied in multiple formulations, most for topical or inhaled use.

Summary Developing research suggests that a chemical in eucalyptus may be able to break up mucus in persons with severe asthma, thus allowing for lowered steroid maintenance in such patients.3 But overall research to date suggests that more evidence is needed to rate the effectiveness of eucalyptus as complementary therapy. ■ Eucalyptus oil is being studied as a nonsteroidal treatment for asthma.

References 1. Centre for Plant Biodiversity Research: The history of

Eucalyptus oil is unsafe when taken by mouth or applied directly to the skin without being diluted.

Eucalyptus oil is unsafe when taken by mouth or applied directly to the skin without being diluted.3 Fatal allergic reactions have occurred with ingestion of eucalyptus products. Even though eucalyptus use in asthma and bronchitis has been shown to be beneficial, bronchospasm can result with inhalation. 3 Eucalyptus oil is not recommended for use in pregnant or nursing women or in infants. If using a topical formulation for the fi rst time, a patch test is recommended. This involves applying the extract to the upper arm. If no rash occurs after 24 hours, it is typically safe to proceed. Clinicians considering the use of diluted oral eucalyptus should proceed with caution. There is little data regarding drug interactions.

Eucalyptus page. Euclid website. Available at www.anbg .gov.au/cpbr/cd-keys/Euclid/sample/html/history.htm. 2. University of Maryland Medical Center. Eucalyptus. Available at www.umm.edu/altmed/articles /eucalyptus-000241.htm. 3. MedlinePlus. Eucalyptus. Available at www.nlm.nih.gov /medlineplus/druginfo/natural/700.html. 4. Serafino A, Sinibaldi Vallebona P, Andreola F, et al. Stimulatory effect of Eucalyptus essential oil on innate cellmediated immune response. BMC Immunol. 2008; 9:17. Available at www.biomedcentral.com/1471-2172/9/17. 5. Juergens UR, Dethlefsen U, Steincamp G, et al. Antiinflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial. Respir Med. 2003;97:250-256. 6. Salari MH, Amine G, Shirazi MH, et al. Antibacterial effects of Eucalyptus globulus leaf extract on pathogenic bacteria isolated from specimens of patients with respiratory tract disorders. Clin Microbiol Infect. 2006;12:194-196. 7. Vigo E, Cepeda A, Gualillo O. Perez-Fernandez R. In-vitro anti-inflammatory effect of Eucalyptus globulus and Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophages. J Pharm Pharmacol. 2004;56:257-263. 8. Silva J, Abebe W, Sousa SM, et al. Analgesic and antiinflammatory effects of essential oils of Eucalyptus. J Ethnopharmacol. 2003;89:277-283.

How supplied, dosage

Chemical composition and antimicrobial activity of the

There is no standardization for the dosing of eucalyptus oil. The literature states that for the oil to be medicinally effective, it must contain

2007;21:231-233.

essential oils from two species of Eucalyptus. Phytother Res.

60 THE CLINICAL ADVISOR • NOVEMBER 2012 • www.ClinicalAdvisor.com

All electronic documents accessed October 15, 2012.

9. Sartorelli P, Marquioreto AD, Amarol-Baroli A, et al.

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64 THE CLINICAL ADVISOR â&#x20AC;˘ NOVEMBER 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 70

■ ADDITIONAL CME/CE: Pages 28, 53

Turn to page 27 for additional information on this month’s CME/CE courses.

Erythematous, pruritic leg plaques ADAM REES, MD

CASE #1

CASE #2

A 75-year-old woman with a history of hypothyroidism presented with extremely itchy red plaques on her trunk and extremities. The eruption started on her shins and generalized. She had been treated previously with both oral and topical antifungals for presumed tinea corporis, but the eruption had worsened and began blistering. A skin biopsy demonstrated a subepidermal blister with eosinophils. Fluorescent stains for complement and immunoglobulin (Ig) G showed a linear staining pattern along the dermal-epidermal junction.

A man, aged 65 years, presents with itchy red patches on his trunk and extremities. He was previously diagnosed with “dermatitis” and had been using a topical corticosteroid for the past two weeks. The ointment relieved some of the itchy sensation, but the the rash had not resolved. History was significant for poorly controlled type 2 diabetes. Physical exam showed large pink plaques with inflamed borders. Toenails were thickened and yellow with subungual debris. A skin scraping from the border of the leg lesion demonstrated hyphael elements.

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CME CE

CASE #1

Dermatologic Look-Alikes

Bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune blistering disease in which circulating autoantibodies bind to the proteins in the skin that attach the dermis to the epidermis.The autoantibody implicated in BP is against a protein called BP180, which is a component of the hemidesmosome. Hemidesmosomes are responsible for attaching the basal keratinocytes of the epidermis to the dermis. Patients may also have autoantibodies against a second protein called BP230, but BP180 is considered to be the pathogenic antibody in this disease. When the autoantibodies bind to their targets in the skin, an inflammatory reaction ensues; this accounts for the clinical manifestations of the disease.1,2 Rarely present in children, BP is generally a disease of the elderly and typically presents after age 60 years. The risk of developing BP increases with age. Someone aged 90 years has a 300-fold greater risk of developing BP than does an individual younger than age 60 years. Men may be at greater risk than women.1.2 There is a broad spectrum of clinical presentations.The classic presentation is a pruritic eruption with the development of tense blisters. Prior to the onset of blisters, patients may suffer for weeks to months with the prodromal nonbullous phase of the disease, which may be quite variable. Manifestations of the nonbullous phase include pruritis without rash, eczematous plaques, or excoriated urticarial lesions.A percentage of patients will never progress to the bullous phase of the disease. In the bullous phase of BP, vesicles and bullae develop on normalappearing skin or are associated with urticarial or eczematous plaques.The vesicles and bullae may rupture, leaving crusted erosions. The characteristic distribution includes the trunk, thighs, groin, axilla, and volar forearms. The shins frequently serve as the initial site of the eruption. The oral mucosa is involved in 20% of cases. Other mucous membranes are rarely involved. A peripheral blood eosinophilia is present in 50% of patients.1,2 BP has are several clinical variants. Vesicular pemphigoid features small, tense, grouped vesicles. In pemphigoid nodularis— a variant that may resemble prurigo nodularis—pruritic papules and nodules occur on the scalp and extremities. In erythrodermic pemphigoid, patients present with erythroderma. Rarely, BP may occur in association with lichen planus in a

variant termed lichen planus pemphigoides. BP localized to the palms and soles may resemble dyshidrotic eczema but is called dyshidrosiform pemphigoid. In vulvar childhood pemphigoid, young girls present with lesions limited to the vulva. In gestational pemphigoid, women present in the second or third trimester of pregnancy with urticarial plaques that subsequently develop vesicles and bullae. Most commonly, the lesions in gestational pemphigoid involve the abdominal region, including the umbilicus.This contrasts with pruritic urticarial papules and plaques of pregnancy, another pregnancy dermatosis that characteristically spares the umbilicus. All variants of BP share common histologic features and are attributable to autoantibodies to BP180.1,2 BP generally is not believed to be a paraneoplastic syndrome; however, there are rare instances in which BP is clearly associated with the onset of a malignancy. Additionally, other autoimmune diseases (e.g., autoimmune thyroid diseases and collagen vascular diseases) are not clearly associated with BP. Occasionally, systemic medications are implicated in the development of BP. These medications include furosemide (Delone, Furocot, Lasix, Lo-Aqua), penicillamine (Cuprimine, Depen) and captopril (Capoten), among others.1,2 Because of the polymorphic presentation of BP, establishing the diagnosis requires a high degree of clinical suspicion.Typically, establishing the diagnosis involves two punch biopsies. One biopsy is taken from an obviously diseased skin area, such as a blister or urticarial plaque.This specimen will be sent for routine hemotoxylin and eosin staining. If a frank blister is present, the blister will be in a subepidermal location, and the blister cavity will have eosinophils and occasionally neutrophils. If the biopsy is taken from an urticarial or nonbullous area, then the findings are less specific and may include subepidermal clefting and eosinophilic spongiosis. The second biopsy is taken from perilesional skin (normalappearing skin immediately adjacent to clinically involved skin). This specimen will be sent for direct immunofluorescent (DIF) microscopy. In DIF microscopy, the specimen is processed with a fluorescent stain for complement (C3) and various immunoglobulins (IgG, IgM, and IgA). In BP, the DIF microscopy demonstrates linear deposits of C3 and IgG along the epidermal basement membrane. When the diagnosis is in doubt, the specimen can be split at the dermal-epidermal junction. In BP, the fluorescent staining will appear on the epidermal side of the split. This contrasts with such other subepidermal autoimmune blistering diseases as epidermolysis bullosa acquisita, in which the stain appears on the dermal side of the split. Another way to establish the diagnosis is through

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testing of the patient’s serum for the circulating autoantibodies against BP180 or BP230.There is now a commercially available enzyme-linked immunosorbent assay (ELISA) to assess for these autoantibodies.1,2 The differential for BP includes drug reactions, contact dermatitis, prurigo, and urticarial eruptions. BP can be distinguished from these dermatoses by the characteristic findings on immunofluorescence and histopathology.Additionally, ELISA may be useful in supporting the diagnosis of BP.1,2 There are few controlled clinical studies pertaining to the treatment of BP. Treatment guidelines are based on clinical experience and consensus opinion. Oral prednisone at a dose of 0.5-1.0 mg/kg/day will typically control the disease within weeks. The prednisone is subsequently tapered over a period of months. It is important to monitor (and provide prophylaxis when applicable) for such side effects of longterm oral corticosteroid therapy as osteoporosis, hypertension, infection, and cataracts. Potent topical corticosteroids may be as effective as oral corticosteroids with fewer side effects. Additional treatments include such other oral immunosuppressive medications as azathioprine (Azasan, Imuran), methotrexate (Rheumatrex,Trexall), cyclosporine (Gengraf, Neoral, Sandimmune, Sangcya), mycophenolate mofetil (Cellcept), cyclophosphamide (Cytoxan), and chlorambucil (Leukeran). Novel therapies include the combination of niacinamide and tetracycline.1,2 The patient in this case was treated with oral prednisone at an initial dose of 60 mg daily.Within four weeks, her skin was clear.The steroids were tapered over the next four weeks. Her skin has remained clear for six months.

CASE #2

Tinea corporis

The term tinea indicates an infection of the most superficial layer of the skin (stratum corneum) caused by species of fungus known as dermatophytes. The commom term for tinea is ringworm. Dermatophyte infections of the hands are termed tinea mannum; tinea pedis refers to the feet; tinea cruris refers to the groin; tinea facei refers to the face; tinea capitis refers to the scalp; and tinea unguinum refers to the nails.

The patient in this case was diagnosed with tinea corporis, a dermatophyte infection of the trunk and extremities. Tinea corporis most commonly presents as round, sharply demarcated patches that sometimes have central clearing and frequently feature an inflammatory or active border with scale and pustules. Patients may complain of itching or burning. In the setting of topical-corticosteroid use, the scale and pustules are absent or subtle and the patient may be entirely asymptomatic, a condition referred to as tinea incognito. Although topical corticosteroids may mask the scale, pustules, and pruritus, they ultimately lead to an exacerbation of the infection.3,4 The most common cause of tinea corporis is Trychophyton rubrum, followed by T. mentagrophytes. Tinea corporis can be spread from human to human, from soil to human, or from animal to human. Patients at risk for tinea corporis may have a personal history of (or a close contact with) tinea capitis, tinea pedis, or tinea unguinum. Other risk factors include close contact with domestic animals, immunosuppression, and recreational or occupational exposures to such facilities or activities as locker rooms, military housing, and wrestling. Immunosuppression does not lead to an increased incidence of tinea infections, but it will lead to increased severity and greater risk of recurrence of such an infection.3,4 Variants of tinea corporis include Majocchi’s granuloma, tinea profunda, and tinea imbricata. Majocchi’s granuloma is caused by T. rubrum and presents as perifollicular pustules. This condition is frequently seen in people with tinea pedis or onychomycosis who shave their legs and subsequently develop an infection of the hair follicles. Tinea profunda results when an individual develops an excessive inflammatory respose to the dermatophyte infection. Tinea profunda may appear verrucous or granulomatous, mimicking a deep fungal infection, squamous cell carcinoma, or cutaneous mycobacterial infection. Found only in equatorial regions, tinea imbricata is caused by T. concentricum and appears as concentric annular rings that have the appearance of wood grain. The diagnosis of tinea corporis frequently can be made clinically by the classic appearance of annular patches with an inflammatory border. When the diagnosis is in doubt, a skin scraping will demonstrate fungal elements when examined under the microscope. Skin biopsies are occasionally required. In the skin biopsy, fungal hyphae are seen in the stratum corneum. With routine staining, this finding may be quite subtle. Such special stains as the periodic acid-Schiff will help with the pathologic diagnosis. Additionally, the specimen may be cultured to identify the particular microorganism.3,4 Continues on page 68

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Dermatologic Look-Alikes

The differential diagnosis includes common forms of dermatitis, including contact dermatitis, nummular dermatitis, atopic dermatitis, seborrheic dermatitis, and stasis dermatitis. Additionally, psoriasis and superficial staphylococcal infections (impetigo) may mimic tinea corporis. Rarer diseases that may mimic tinea corporis include pityriasis rosea, erythema annulare centrifugum, subacute cutaneous lupus erythematosus, granuloma annulare, and parapsoriasis. Skin scrapings, culture, and biopsy can help distinguish tinea corporis from these other dermatoses when the diagnosis is in doubt.3,4 Topical antifungals are considered first-line therapy for limited disease. Selection of the topical antifungal is important, as the various medications do not have equal anti-dermatophyte potency. According to in-vitro studies, topical butenafine (Mentax) and terbinafine (Lamisil, Terbinex) are the most effective (butenafine may be more potent than terbinafine). Other therapies, in order of effectiveness, include ciclopirox (Penlac nail lacquer), naftifine (Naftin), and the topical azoles (e.g., clotrimazole, miconazole).5 In practice, many patients require systemic antifungal therapy with oral therapy (e.g., terbinafine or itraconazole [Sporanox]), especially for extensive disease or when there is a significant inflammatory component, such as in Majocchi’s granuloma or tinea profunda. Tinea corporis infections require a oneto two-week course of oral terbinafine or oral itraconazole. Other treatment options include oral fluconazole (Diflucan) or griseofulvin for one to two weeks. In all cases, a full-body skin exam is warranted to identify other areas with tinea infection. For example, tinea infections of the nails will serve as reservoirs for reinfection, and require prolonged systemic therapy (i.e., 12 weeks of oral terbinafine).3,4,6 Treatment with systemic antifungal therapy requires an understanding of key medication interactions, as many patients are on multiple medications for such comorbidities as hypertension and hyperlipidemia. Some of the most common drug interactions that guide systemic antifungal selection include: terbinafine, contraindicated with all classes of betablockers; itraconazole, contraindicated with simvastatin (Zocor) and atorvastatin (Lipitor); and fluconazole, contraindicated with rosuvastatin (Crestor), fluvastatin (Lescol), and warfarin (Coumadin, Jantoven). Griseofulvin is a CYP3A4 inducer and has the potential to lower the levels of multiple medications. Caution is advised with patients taking warfarin and such phosphodiesterase type 5 (PDE5) inhibitors as sildenafil (Revatio, Viagra), tadalafil (Adcirca, Cialis) and vardenafil (Levitra, Staxyn).4 This list is by no means comprehensive, and a thorough medication reconciliation is required when prescribing any systemic therapies.

In this case, the patient’s immunosuppressed status due to his poorly controlled diabetes and use of topical corticosteroids likely contributed to his presentation of tinea corporis. He also had thickened yellowish dystrophic toenails with subungual debris, clinically indicative of tinea unguinum. He was treated with 12 weeks of oral terbinafine for tinea unguinum.After the second week of therapy, the lesions on his trunk and extremities had cleared. Twelve months after therapy, the man’s toenails were completely clear of infection. Unfortunately, by 18 months after therapy, he had redeveloped a tinea infection in his toenails.This highlights the difficulty in maintaining remission in patients with diabetes and other immunosuppressive conditions. ■ Dr. Rees is a first-year dermatology resident at Baylor College of Medicine in Houston. References 1. Borradori L, Bernard P. Pemphigoid group. In: Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:431-445. 2. Chronic blistering dermatoses. In: James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-Elsevier; 2011:448-467. 3. Sobera, JO, Elewski BE. Fungal diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1135-1163. 4. Diseases resulting from fungi and yeasts. In: James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-Elsevier; 2011:287-321. 5. Phillips RM, Rosen T. Topical antifungal agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia, Pa.: Saunders-Elsevier; 2007:547-568. 6. Gupta AK. Systemic antifungal agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia, Pa.: Saunders-Elsevier; 2007:75-99.

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CME

POSTTEST Expiration date: November 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of November 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken. CREDITS: 0.5

Dermatology Clinic

Dermatologic Look-Alikes

page 53

page 65

Case #1: Arthropod bite reaction

Case #1: Bullous pemphigoid

1. There is an association of an exaggerated arthropod reaction in individuals with a. Crohn disease b. Chronic lymphocytic leukemia c. Rheumatoid arthritis d. Hepatitis C

1. What is a manifestation of the nonbullous phase of bullous pemphigoid (BP)? a. Pruritis without rash b. Eczematous plaques c. Excoriated urticarial lesions d. All of the above

2. One of the most common allergens that cause acute allergic contact dermatitis is OTC a. Hydrocortisone b. Benzocaine c. Neosporin d. Vitamin A

2. What is used to establish the diagnosis of BP? a. Two punch biopsies b. Skin scrapings in potassium hydroxide c. Wood’s lamp examination d. Tzanck smear Case #2: Tinea corporis

Case #2: Stasis dermatitis 3. What is a characteristic associated with stasis dermatitis? a. Age of onset is usually in the third or fourth decade of life b. Men are affected more frequently than women c. Presents as plaques with central clearing d. Occurs earlier with trauma or thrombosis 4. What should be used to examine peripheral arterial circulation before starting treatment of stasis dermatitis in select individuals? a. CT angiogram b. Magnetic resonance angiogram c. Doppler ultrasound d. Contrast angiogram

3. What is the classic appearance of tinea corporis? a. Annular patches with an inflammatory border b. Small, grouped vesicles coalesced to form plaques c. Discrete flesh-colored umbilicated papules d. Pruritic burrows with excoriations and crusting 4. Itraconazole (Sporanox) is contraindicated if given with a. Sildenafil (Revatio, Viagra) b. Propranolol (Inderal) c. Simvastatin (Zocor) d. Warfarin (Coumadin, Jantoven)

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CLASSIFIEDS

NP WANTED

NURSING FACULTY POSITIONS The University of Maryland School of Nursing (UMSON) is currently seeking full-time faculty members for tenured, tenure-track, and non-tenure track positions in the following areas: • Community/Public Health Nursing

• Pediatric Nurse Practitioner

• Adult-Gerontology Nurse Practitioner

• Family Nurse Practitioner

• Psychiatric Mental Health Nurse Practitioner

• Nurse Anesthesia

• Acute Care Nurse Practitioner (focus on Trauma/Critical Care/Emergency) UMSON enrolls more than 1,700 students in its baccalaureate, master’s, and doctoral programs and is ranked 11th among all schools of nursing in the nation. UMSON is part of the University of Maryland graduate professional campus that also includes the schools of medicine, dentistry, social work, pharmacy, and law, and is one of the fastest growing biomedical research centers in the nation. The unique composition of the campus enables health professionals to address clinical care, public policy, and social issues through multidisciplinary research, scholarship, and community action. Its location in the Baltimore-Washington, D.C.-Annapolis triangle maximizes opportunities for collaboration with governmental agencies, health care institutions, and life science industries. Responsibilities: Nursing faculty teach in UMSON’s undergraduate and graduate programs, advise and mentor students, participate in faculty governance and service, and maintain a vigorous program of scholarship. Qualifications: Qualified applicants must hold a master’s degree in nursing or a related field relevant to the position, an earned doctorate in nursing or a related field, and current license or eligibility to practice nursing in Maryland. Evidence of scholarly achievement, including publications and professional presentations, a proven track record in peer-reviewed and externally funded research, and prior academic experience is preferred. Applications: Interested candidates should submit a letter of interest, résumé, and names of three professional references to: Faculty Search Committee • University of Maryland School of Nursing • C/O Lois Reisig 655 West Lombard Street, Room 502 • Baltimore, MD 21201 For additional information, please visit our website: http://nursing.umaryland.edu/hr. The University of Maryland is an Equal Opportunity/Affirmative Action/ADA Employer.

PA/NP WANTED

PA WANTED

Physician Assistant Program

North Country Emergency Medical Consultant’s PC is recruiting a Physician Assistant or Nurse Practitioner to join our current group of 9 physicians, 5 physician assistants and 2 nurse practitioners. NC-EMC, P.C. contracts with Samaritan Medical Center to staff the ED which has an annual volume of 53,000. The PAs work closely with the MDs and staff the ED in both the Urgent Care and Rapid Clinical Evaluation area. SMC recently opened a new ED 11/10 which has in-ED radiology, CT scan, ED Ultrasound and point of care testing. The compensation package includes $120,000.00 salary, plus benefits for approximately 144 hours/month. A RVU-based productivity bonus is awarded quarterly. Upstate New York is an outdoor enthusiast’s paradise with 4-season recreation in the world famous Thousand Islands, Lake Ontario region and the Adirondack Mountains. Montreal, Toronto, Finger Lakes region and NYC are a short drive away. Syracuse International Airport is within a one hour drive. If this opportunity interests you AND you have a minimum of 3 years Emergency Medicine/Urgent Care experience, please send your CV and cover letter to: Dr. Maja Lundborg-Gray President, North Country Emergency Medical Consultants, P.C. Emergency Department 830 Washington Street Watertown, New York 13601 Fax: 315-785-4314 Email: MLGRAY@shsny.com (preferred route)

DeSales University is a Catholic liberal arts institution in eastern Pennsylvania with a total student enrollment of 3,300. The nationally recognized PA Program demonstrates a 100% pass rate on the PANCE since 2002 and has won the AAPA National Challenge Bowl five times. The University is completing a new $27 million building, with state-of-the-art facilities. EOE

Didactic Faculty

DeSales University seeks two full-time instructors for its Physician Assistant Program. These are 12-month, full-time, tenure-track positions mainly responsible for teaching in the first year of the program but also include student advising and recruitment responsibilities. Applicants should enjoy a team-teaching concept and a dynamic, student-centered environment. One day per week is given for continued clinical practice. The ideal candidate will possess at least a Master’s degree in a relevant field. Prior teaching experience is preferred. Physician Assistants should be NCCPA certified and licensed in Pennsylvania. Physicians should be board certified and licensed in Pennsylvania. Rank and salary will be commensurate with experience.

Clinical Coordinator

DeSales University seeks a Clinical Coordinator for its Physician Assistant Program. This 12-month, full-time, nontenure-track position is responsible for obtaining and maintaining clinical training sites for students and visiting and evaluating students and their preceptors during their clinical rotations within the greater Lehigh Valley. One day per week is given for continued clinical practice. Clinical experience as a certified physician assistant required; master’s degree and successful teaching experience preferred. Salary and rank will be commensurate with experience. All positions begin prior to the fall semester 2013. For each position, please send letter of application, curriculum vitae, three letters of recommendation, and photocopies of educational transcripts to: Father Peter Leonard, OSFS, Dean of Graduate Education, DeSales University, 2755 Station Ave., Center Valley, PA 18034-9568 or to peter.leonard@desales.edu. Review of applications begins immediately and continues until the positions are filled.

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CLASSIFIEDS

NP WANTED

MEDICAL EDUCATION

Desert Horizons Psych NP position Phoenix, Arizona We are looking for a Psychiatric Nurse Practitioner to join our team at the District Medical Group Desert Horizons Clinic. The clinic provides outpatient behavioral health services in the East Valley and is seeking a full-time nurse practitioner to join our staff of adult and child and adolescent psychiatrists and master’s level social workers. The position would include employment with District Medical Group Inc. (DMG), a multispecialty group with over 300 clinical providers. The position involves providing evaluation and primarily medication management services to a population of adolescents and adults, most of whom have private insurance coverage. Qualified candidates must have an Arizona NP license with specialization in Psychiatry. Strong interpersonal skills and previous clinical experience are preferred. DMG offers an outstanding work environment and competitive compensation and benefits package, including 4 weeks of PTO (personal time off), one week of continuing education time, CME allowance, pension plan and employer paid malpractice insurance. For consideration, forward your CV to: practice@dmgaz.org

EOE

PA WANTED

Madigan Healthcare System (Tacoma, Washington)

Find Qualified Physician Assistants and Nurse Practitioners

is seeking a full-time civilian General Surgery Certified Physicians Assistant to join a busy Army General Surgery Department which serves as an ACGME teaching program in an academic teaching hospital. Candidates must be motivated and have a broad range of clinical experience, preferably in General Surgery and a willingness to learn. Candidates will work in a clinic setting with both staff and residents. Madigan Army Medical Center is a 243-bed teaching medical center. It supports a primary care population of greater than 100,000. The surrounding greater Puget Sound area offers excellent schools. Proximity to the Cascades and Puget Sound assures year round recreational opportunities. Competitive salary and benefits package. Recruitment incentive based on experience. To submit CV for this position online, go to: https://careers-civilianmedicaljobs.icims.com/jobs/2716/ physician-assistant-%2528general-surgery%2529/job For more information, call Medical Provider Recruiter at: 253-968-4994 or e-mail: MAMCCPD@amedd.army.mil

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COMMENTARY Sharon Fruh, PhD, RN, FNP-BC, an associate professor at the University of South Alabama College of Nursing in Mobile, does research in family meals in health-disparity populations.

Do family meals make a difference? Nurse practitioners (NPs) and physician assistants (PAs) spend a great deal of clinical time implementing health-promotion and disease-prevention strategies with individuals across the life span. Frequent gatherings around the family table can help achieve these goals: People who participate in frequent family meals are more likely to get healthy and stay healthy. Dinnertime with the family has declined drastically since the 1960s. The family meal has been replaced by eating alone, “grazing” (eating smaller meals throughout the day rather than a few big meals at set times), and eating while watching television, working on the computer, or driving.

Youths are not the only ones who benefit from family meals; parents also derive satisfaction from this ritual.

Research has identified that frequent family meals often yield the following benefits for the children and adolescents in the family: • Language development and academic success (better school grades)1 • Healthy food selections (less soda, more fruits and vegetables)2 • Demonstration of positive values (commitment to learning, social competencies, and positive sense of identity)3 • Avoidance of high-risk behaviors in teens (lower incidence of substance abuse, sexual activity, depression/suicide, antisocial behaviors, violence, school problems, binge eating/ purging, and excessive weight loss).3 Many parents believe that youths do not enjoy eating meals with their families. However, one study showed that 79% of teens researched did enjoy this ritual.4 Youths are not the only ones who benefit from family meals; parents do as well. According to research, when parents’ employment interfered with family mealtime, they reported a greater sense of dissatisfaction with their jobs and careers.5 These parents also reported fewer feelings of success at work when they missed dinnertime with their families. Conversely, parents who enjoyed consistent family mealtimes indicated greater job satisfaction and reported a closer relationship with their children and spouses.5

The protective benefits of consistent family meals for single-parent families are similar to those seen in two-parent households. The importance of encouraging this ritual in singleparent families should not be overlooked. NPs and PAs are in a position to assess familymeal frequency and educate patients on the numerous benefits of healthful, consistent family meals. Communicating to patients the value of this practice may inspire the return of dinner to the family table. Family meals do make a difference for the entire family! ■ References 1. Snow CE, Beals DE. Mealtime talk that supports literacy development. New Dir Child Adolesc Dev. 2006;111:51-66. 2. Neumark-Sztainer D, Hannan PJ, Story M, et al. Family meal patterns: associations with sociodemographic characteristics and improved dietary intake among adolescents. J Am Diet Assoc. 2003;103:317-322. 3. Fulkerson JA, Story M, Mellin A, et al. Family dinner meal frequency and adolescent development: relationships with developmental assets and high-risk behaviors. J Adolesc Health. 2006;39:337-345. 4. Zollo P. Wise Up to Teens: Insights into Marketing and Advertising to Teenagers. 2nd ed. Ithaca, N.Y.: New Strategist Publication; 1999. 5. Jacob JI, Allen S, Hill EJ, et al. Work interference with dinnertime as a mediator and moderator between work hours and work and family outcomes. Fam Consum Sci Res J. 2008;36:310-327.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2012 73