September 2012 Clinical Advisor

THE CLINICAL ADVISOR • SEPTEMBER 2012

A F O RU M F O R P H YS I C I A N A S S I S TA N T S

NEWSLINE

■ Providers with hepatitis B ■ Beat pediatric egg allergy ■ Sleep affects vaccination ADVISOR FORUM

■ Prediabetes interventions ■ Treating scrotal dermatitis ■ Strep during pregnancy

✶ FREE CME COURSES! ■ CME Feature

NEONATAL CCHD SCREENING PAGE 34

■ Dermatology Clinic

ISOLATED AREAS OF DARKENED SKIN PAGE 59

VOLUME 15, NUMBER 9

■ Dermatologic Look-Alikes

ASYMPTOMATIC THIGH LESION PAGE 69 Expanded job listings! www.ClinicalAdvisor.com/Jobs

| S E P T E M B E R 2 012 | www.ClinicalAdvisor.com

VITAMIN D DEFICIENCY

BEYOND BONE Low vitamin D has been linked to such immune disorders as rheumatoid arthritis (shown).

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

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2 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

LEVEL

8

CONTENTS SEPTEMBER 2012

NEWS AND COMMENT 14

80

59

■ After a trip to the Caribbean, a man notices darkening skin on his arms.

Newsline ■ Address vascular risk factors to avoid long-term-care dependence ■ Providers with HBV can keep practicing ■ And more

■ Hyperpigmented papules on a young woman’s torso progressively worsen.

34

64

Alternative Meds Update Stinging nettle has been studied as a treatment for BPH.

69

CME/CE Dermatologic Look-Alikes Can you differentiate between these cases of asymptomatic skin lesions?

74

CME/CE Posttest

76

Evidence-Based Medicine

Commentary Hep B alone does not disqualify clinicians 16

FEATURES 20

CME/CE Dermatology Clinic

Vitamin D deficiency: beyond bone health Immunity, calcium absorption, and homeostasis of various organs are all affected by levels of vitamin D. CME/CE Detection of hypoxemia: visual observation vs. pulse oximetry The first of a three-part series designed to improve detection of critical congenital heart disease in newborns.

ADVISOR FORUM 44

Consultations ■ Interventions for prediabetes ■ Treatment of scrotal dermatitis ■ Group B strep during pregnancy

Isoloated areas of skin darkening 59

DEPARTMENTS 45 50

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

51

Legal Advisor One clinician learned the hard way that any breach of HIPAA privacy is grounds for dismissal.

53

Clinical Challenge A woman presents with night sweats, dizziness, fatigue, and abdominal pain.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

Stinging nettle is used to treat joint pain 64

Like us on Facebook facebook.com/TheClinicalAdvisor

Clinical Pearls ■ Try GERD medication for pediatric molluscum ■ Examining the prostate of an obese man ■ And more

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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

© 2012 Pfizer Inc.

All rights reserved.

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)

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)* ≥60 150 300 450 600

Dose Regimen BID or TID

30–60

75

150

225

300

BID or TID

15–30

25–50

75

100–150

150

QD or BID

<15

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

QD

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.

© 2012 Pfizer Inc.

All rights reserved.

September 2012

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ClinicalAdvisor.com/web-only Web Exclusives ClinicalAdvisor.com/WebExclusives Balance, strength training reduces falls among elderly A lifestyle-integrated approach is effective in reducing the rate of falls in older, high-risk people living at home, according to a recent study.

CDC revises guidelines for gonorrhea treatment Updated guidelines no longer recommended such oral cephalosporins as cefixime (Suprax) as first-line therapy.

Competitive food laws tied to lower teen obesity.

Controversial state laws regulating the sale of junk food and sugary drinks in school lead to less weight gained.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Sharon M. O’Brien, MPAS, PA-C Could a sleep disorder cause migraines?

Consider obstructive sleep apnea as a possible cause of ongoing headaches, especially on waking.

Julee Waldrop, DNP, PNP, FNP Trust pediatric lipid screening guidelines Promoting behavioral changes during childhood is much cheaper than treating adults.

Robyn Carlisle, MSN, CNP, WHNP Providing health care for lesbian and bisexual women Don’t overlook the unique health needs of this underserved population.

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coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported. 10.2 Recommended Treatment: General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed.

Zolpidem’s sedative-hypnotic effect was shown to be reduced by flumazenil and therefore flumazenil may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable. As with management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage. 14.2 Special Safety Studies: Driving Study: A randomized, double-blind, placebo-controlled, active-control, single-center, four-period, crossover study in 40 healthy subjects was conducted to evaluate the effects of middle-of-the-night administration of Intermezzo on next-morning driving performance. The four randomized treatments included Intermezzo 3.5 mg four hours before driving, Intermezzo 3.5 mg three hours before driving, placebo, and a positive control (an unapproved sedative-hypnotic) given nine hours before driving. The primary outcome measure was the change in the standard deviation of lateral position (SDLP), a measure of driving impairment. The results were analyzed using a symmetry analysis, which determined the proportion of subjects whose change from their own SDLP in the placebo condition was statistically significantly above a threshold thought to reflect clinically meaningful driving impairment. When driving began 3 hours after taking Intermezzo, testing had to be terminated for one subject (a 23-year old woman) due to somnolence. Overall, the symmetry analysis showed a statistically significant impairing effect at 3 hours. When driving began 4 hours after taking Intermezzo, statistically significant impairment was not found, but numerically Intermezzo was worse than placebo. Zolpidem

“We don’t want to be a burden to you, sweetheart, but who else are we going to be a burden to?”

blood levels were not measured in the driving study, and the study was not designed to correlate specific blood level with degree of impairment. However, the estimated blood level of zolpidem in patients whose SDLP worsened according to the symmetry analysis is considered to present a risk for driving impairment. In some women, the 3.5 mg dose of Intermezzo results in zolpidem blood levels that remain at or sometimes considerably above this level 4 or more hours after dosing.

Therefore, the recommended dose for women is 1.75 mg. A small negative effect on SDLP may remain in some patients 4 hours after the 1.75 mg dose in women, and after the 3.5 mg dose in men, such that a potential negative effect on driving cannot be completely excluded. Rebound effects: In studies performed with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime, there was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg oral zolpidem tartrate. Memory impairment in controlled studies: Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration at bedtime of 5 mg to 10 mg oral zolpidem tartrate. However, in one study involving zolpidem tartrate doses of 10 mg and 20 mg, there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post-dose), i.e., these subjects experienced anterograde amnesia. There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of oral zolpidem tartrate, predominantly at doses above 10 mg.

Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product.

Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 ©2012, Purdue Pharma L.P. Revised 02/2012 302880-0C-A

“And so, kids, if you don’t find this awesome new game under the tree you’ve really got to ask yourselves what you’re doing there.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 13

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common. Studies of abuse potential in former drug abusers found that the effects of single doses of 40 mg of oral zolpidem tartrate were similar, but not identical, to diazepam 20 mg, while 10 mg of oral zolpidem tartrate was difficult to distinguish from placebo. Because persons with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving Intermezzo.

9.3 Dependence: Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative-hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative-hypnotic withdrawal were reported during U.S. clinical trials with other oral zolpidem formulations following placebo substitution occurring within 48 hours following the last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less.

However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence, and withdrawal resulting from use of oral zolpidem tartrate have been received. 10 OVERDOSAGE: 10.1 Signs and Symptoms: In post-marketing experience of overdose with oral zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to

Newsline

ECG screening not advised for low-risk adults page 16

S EMP O T ENMTBHE R2 0212 0 12

To halt egg allergy, try oral immunotherapy page 18

Can more sleep protect against infection? page 18

© PHOTO RESEARCHERS, INC. / HORATIO SORMANI

Address vascular risk factors to avoid LTC

Dementia and stroke are the primary causes of LTC dependence.

lead to substantial achievements,” remarked Bickel. “Our results are only one example of how health risks can be reduced through uncomplicated, routine treatment of risk factors in the framework of a real-world setting.”

Cocoa consumption may be yet another strategy for the prevention of stroke and dementia, according to the findings of two separate studies. A team led by Giovambattista Desideri, MD, reported in the journal Hypertension that eating cocoa flavanols daily may improve mild cognitive impairment. A systematic review for The Cochrane Library by Dr. Karin Ried and fellow investigators indicated that in short-term trials, persons who were given dark chocolate or cocoa powder every day had a slight drop in BP compared with a control group.

Obesity among Headline adults in here with arthritis Obesity rates Text in here are 54% higher among adults with Sourcearthritis here compared to those without the condition.

Source: Hootman JM, Pan L, Helmick CG, Hannan C. Statespecific trends in obesity prevalence among adults with arthritis. MMWR 2011;60:509-513.

2003 40

Obesity Prevalence (%)

A SUCCESSFUL primary-care program designed to prevent stroke and dementia supports the feasibility and effectiveness of such an initiative, reducing a patient’s risk of developing longterm-care (LTC) dependence.

Stroke and dementia are the major causes of LTC dependence in old age, wrote Horst Bickel, PhD, and associates in Journal of the American Heart Association.

Their Intervention Project on Cerebrovascular Disease and Dementia in the District of Ebersberg (INVADE) trial compared a multidomain prevention program for stroke and dementia with usual medical care in reducing the need for LTC in Germany.

A total of 3,908 members of a health plan, aged 55 to 102 years (mean age 67.7 years), were the recipients of relatively simple interventions for improving vascular health. For

example, they were encouraged to be more physically active, eat more healthfully, quit smoking, and reduce their blood pressure and cholesterol. Compared with 13,301 patients in a neighboring area who received usual care without the focus on stroke and dementia prevention, significantly fewer new cases of LTC dependence arose in the intervention district than expected during the 5 years after completion of the recruitment phase of the study.

The incidence of LTC dependence was reduced by 10% among women and by 9.6% among men.

Mortality decreased as well.

In a statement, Bickel expressed confidence that the results could occur in the United States and other western populations that suffer from similar sedentary-lifestylerelated illnesses. “At the population level, even simple measures can

2009

35 30 25 20 15 10 5 0

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

Arthritis

No Arthritis

Newsline THE CDC has upheld its 1991 recommendation that hepatitis B virus (HBV) infection alone should not disqualify health-care workers from the practice or study of surgery, dentistry, medicine, or allied health fields.

“For most chronically HBVinfected providers and students who conform to current standards for infection control, HBV infection status alone does not require any curtailing of their practices or supervised learning experiences,” the updated recommendations stated (MMWR. 2012;61[RR03]:1-12).

The document does make the following changes to the 1991 version: (1) no prenotification of patients as to a health-care provider’s or student’s HBV status; (2) use of HBV DNA serum levels

rather than hepatitis B e-antigen status to monitor infectivity; and (3) for those health-care professionals requiring oversight, specific suggestions for composition of expert review panels and threshold value of serum HBV DNA considered safe for practice (<1,000 IU/mL).

In other hepatitis developments, silymarin—an extract of milk thistle used by many people to combat liver ailments—has been deemed an ineffective treatment for chronic hepatitis C virus (HCV) infection in a study of 154 persons who had previously been treated unsuccessfully with conventional interferonbased therapy. After 24 weeks of therapy with silymarin 420 mg or 720 mg t.i.d., or placebo, only two participants (3.8%) in each treatment group achieved normal

© PHOTO RESEARCHERS, INC. / JAMES CAVALLINI

Providers with HBV can keep practicing

The hep B virus (pink) is transmitted through bodily fluids.

serum alanine aminotransferase (ALT) levels or a reduction of at least 50% from baseline ALT levels. No significant differences were seen in the decline of serum ALT activity, HCV RNA levels, or quality-of-life measures across the three groups ( JAMA. 2012;308:274-282).

THE U.S. Preventive Services Task Force (USPSTF) continues to recommend against screening with ECG asymptomatic adults at low risk of a coronary heart disease (CHD) event.

In 2004, the USPSTF found a lack of evidence that ECG screening in asymptomatic, low-risk adults improves health outcomes.

Recently, USPSTF members Virginia A. Moyer, MD, MPH, and colleagues reviewed new published research and again found that ECG screening was unwarranted for such adults (Ann Intern Med. 2012;157).

Screening low-risk adults could lead to unnecessary procedures.

The USPSTF ultimately concluded that screening asymptomatic, low-risk adults was highly unlikely to result in changes in risk stratification that would eventually reduce CHD events. In addition, such testing could lead to unnecessary invasive procedures, overtreatment, and other harms.

Clinicians may want to incorporate another measure into their risk assessment for heart disease: erectile dysfunction (ED). Martin Miner, MD, and colleagues reported online ahead of print in American Heart Journal that practitioners should inquire about ED

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

symptoms in all men older than age 30 years with cardiovascular disease (CVD) risk factors, as identification of ED—particularly in men younger than age 60 years and in those with diabetes— represents an important first step toward the detection and reduction of CVD risk.

Miner was also a member of the Princeton Consensus (Expert Panel) Conference, which yielded the recommendation that matters of sexual function should be incorporated into CVD risk assessment for all men (Mayo Clin Proc. 2012;87:766-778).

© THINKSTOCK

Task force still says “no” to ECG screening

Newsline

GIVING SMALL but increasing doses of egg-white powder to youths with egg allergy may eventually help such children and adolescents consume eggs with minimal or no allergic reactions.

In a study, 55 children aged 5 to 11 years, with egg allergy received oral immunotherapy or placebo.

After the initial dose-escalation, build-up, and maintenance phases, the children were given an oral food challenge with eggwhite powder at 10 months and 22 months. Those who passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for four to six weeks, and then were given another oral food challenge with egg-white powder and a cooked egg. Children who passed that challenge were placed on an egg-containing diet and were evaluated again at 30 months and 36 months for sustained unresponsiveness to egg products.

At 10 months, 55% of the oralimmunotherapy recipients (but none of the placebo users) passed the oral food challenge and were considered desensitized. After 22 months, 75% of the immunotherapy group members were desensitized. At 24 months, 11 of the 40 oral-immunotherapy patients (28%) passed the oral food challenge, and all 11 were consuming egg products at 30 and 36 months (N Engl J Med. 2012;367:233-243).

Weight at diabetes diagnosis ADULTS WHO were normal weight at the time they were diagnosed with type 2 diabetes had a higher risk of death than did their overweight or obese counterparts, new research has revealed. As explained in the JAMA report (2012;308:581-590), type 2 diabetes in normal-weight adults is an understudied representation of the metabolically obese, normalweight phenotype that has become increasingly common over time.

“Many times [clinicians] don’t expect that normal-weight people have diabetes when it is quite possible that they do and could be at high risk of moratlity, particularly if they are older adults or members of a minority group,” explained first author Mercedes R. Carnethon, PhD, in a statement.

Investigators analyzed data from five cohort studies involving 2,625 participants with incident diabetes. The proportion of those who were normal weight (BMI 18.5 to 24.99) at the time of incident diabetes ranged from

The rates of mortality were higher among those at normal weight.

9% to 21% in the studies, but was 12% overall.

During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 deaths were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher among normal-weight participants than among overweight/ obese participants. After adjustments were made for demographic characteristics as well as for BP, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08, 1.52, and 2.32, respectively.

Older adults and nonwhite participants were more likely to develop normal-weight diabetes.

Previous research suggests that normal-weight persons with diabetes have a different genetic profile than do overweight/obese persons diagnosed with the disease.

Lack of sleep can weaken vaccination power In a recent study, the standard three-dose hepatitis B vaccination was administered to 125 healthy adults aged 40 to 60 years.

Sleep duration, sleep efficiency, and sleep quality of the participants were measured.

The researchers also obtained viral-specific antibody titers prior to the second and third vaccinations to assess primary and secondary antibody responses. In addition, clinical protection status was assessed six months after the final immunization.

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

Shorter sleep duration was associated with a lower secondary antibody response independent of age, sex, BMI, and response to the initial immunization. Shorter sleep duration also predicted a decreased likelihood of being clinically protected from hepatitis B at the end of the vaccination series (Sleep. 2012;35:1063-1069). Persons who slept fewer than six hours on average per night were 11.5 times more likely to be unprotected by the vaccine. ■

© THINKSTOCK

Help kids beat egg allergy

FEATURE: VERONICA BRADY, MSN, FNP-BC, BC-ADM, CDE

Vitamin D deficiency: beyond bone health Immunity, calcium absorption, and homeostasis of various organs are but a few of the physiologic processes affected by levels of vitamin D.

© PHOTO RESEARCHERS, INC. / BSIP

O

Low vitamin D has been linked to rheumatoid arthritis (shown) and other immune disorders.

20 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

ver the past several years, there has been much talk about vitamin D deficiency, with the debate centering around optimal levels of vitamin D; who should be screened; and, after screening, how to treat. In the past, vitamin D deficiency was associated with persons who had inadequate exposure to sunlight or who lacked access to sufficient amounts of foods containing calcium, resulting in rickets. Over the past decade, information in the literature suggests that vitamin D deficiency may be more prevalent than first suspected and that the adverse health effects of low vitamin D levels may be far-reaching.

Vitamin D has been implicated in a variety of health-related disorders. Although the primary indication for vitamin D is maintenance of bone health, vitamin D also factors into a number of physiologic processes, such as immunity, calcium absorption, and homeostasis of various organs.

Adults whose low vitamin D levels remain unresolved may experience muscle weakness, osteoporosis, osteomalacia, and increased risk of falls. Decreased vitamin D intake and lower levels of serum vitamin D have been associated with some autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, type 1 diabetes, systemic lupus erythematosus, and psoriasis. In addition, low serum vitamin D levels have been linked to increased risk of hypertension, MI, and death due to cardiovascular disease (CVD).¹ Table 1 presents a list of diseases in which vitamin D has been implicated.2 According to the Institute of Medicine

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VITAMIN D DEFICIENCY

Vitamin D promotes absorption of calcium in the intestine and maintains adequate serum phosphate and calcium concentration.

(IOM), however, the evidence related to these diseases has been inconsistent and further research is needed. While the investigative work continues, any adverse effects of vitamin D deficiency can be avoided if persons at risk are identified, screened, and treated appropriately in a timely fashion.

Background

Vitamin D was discovered in 1922 during the quest to cure rickets. Originally classified as a vitamin, vitamin D is actually a prohormone in the endocrine system of the skin.

Vitamin D comprises a group of fat-soluble sterol compounds that includes ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D2 can be obtained from UV irradiation of the yeast sterol ergosterol. It is found naturally in sun-exposed mushrooms and may be ingested from plant or fish sources. Vitamin D3 is synthesized by the skin from cholesterol under the influence of UV light and is present in oil-rich fish, such as mackerel and salmon.3 In the liver, vitamin D is hydroxylated to 25-hydroxyvitamin D (25[OH] D), or calcidiol. In the kidney, calcidiol is hydroxylated to 1,25-dihydroxyvitamin D (1,25[OH]2D), or calcitriol. In turn, calcitriol increases intestinal absorption of calcium, enhances bone resorption, and decreases renal calcium and phosphate excretion.

The function of vitamin D is to promote absorption of calcium in the intestine and to maintain adequate serum phosphate and calcium concentration to ensure normal bone mineralization. Without vitamin D, only 10%-15% of dietary calcium and only 60% of phosphorus is absorbed.

When the level of vitamin D is sufficient, these amounts increase to 30%-40% for calcium and 80% for phosphorus.

Vitamin D is also needed for bone growth and remodeling AT A GLANCE ●

Without vitamin D, only 10%-15% of dietary calcium and only 60% of phosphorus is absorbed.

●

Vitamin D deficiency has been defined as a serum 25-hydroxyvitamin D (25[OH]D) level of <20 ng/mL and insufficiency is defined as a serum 25(OH)D level of 21-29 ng/mL.

●

The primary cause of vitamin D deficiency is lack of exposure to sunlight.

●

Treatment of vitamin D deficiency or insufficiency (low D) is usually achieved either through sunlight exposure or vitamin D supplements.

TABLE 1. Conditions sensitive to vitamin D Cancer Childhood infections, allergies, and asthma Cardiovascular disease Immune disorders • Fibromyalgia • Rheumatoid arthritis • Systemic lupus erythematosus • Type 1 diabetes Morbid obesity Neurologic conditions • Alzheimer disease • Dementia • Multiple sclerosis Type 2 diabetes/metabolic syndrome Adapted from Rao DS. Clinical practitioner perspective. In: Burnstein KL, Ehrmann D, eds.

Vitamin D: beyond bone: other benefits. Endocrine News. 2010;35:18-23. Available at www.endo-society.org/endo_news/tri_point/2010/upload/FINAL-Vitamin-D-Tri-Point.pdf.

Accessed on August 15, 2012.

by osteoblasts and osteoclasts. The vitamin D content of various foods is presented in Table 2.

Definition and prevalence

The diagnostic test used to assess for vitamin D deficiency is a serum 25(OH)D determination. Deficiency has been defined as a serum 25(OH)D level of <20 ng/mL and insufficiency is defined as a serum 25(OH)D level of 21-29 ng/ mL. According to recent estimates reported by The Endocrine Society, 20%-100% of U.S., Canadian, and European elderly men and women have vitamin D deficiency, 50% of Hispanic and black adolescents in Boston are deficient, 48% of white preadolescent girls in Maine have vitamin D levels <20 ng/ mL, and 42% of black females aged 15-49 years have levels of <15 ng/mL by the end of winter.3 Other levels of vitamin D and the associated health implications are shown in Table 3.

The primary cause of vitamin D deficiency is lack of exposure to sunlight, with exposure defined as sun shining on the arms and legs for five to 30 minutes between the hours of 10 am and 3 pm twice a week. Keep in mind that application of sunscreen with a sun protective factor (SPF) of 30 decreases the synthesis of vitamin D by 95%. Other causes of vitamin D deficiency include obesity (BMI >30), fat malabsorption syndromes, nephrotic syndrome, hyperparathyroidism, some lymphomas, and HIV/AIDS. Continues on page 24

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 23

VITAMIN D DEFICIENCY

Decreased risk of fracture and prevention of falls in older adults are among the primary benefits of adequate amounts of vitamin D. TABLE 2. Selected food sources of vitamin D Food

IUs per serving

Percent DV*

Cheese, Swiss, 1 oz

6

2

Cod liver oil, 1 tablespoon

1,360

340

Egg, 1 large (vitamin D is found in yolk)

41

10

Liver, beef, cooked, 3 oz

42

11

Margarine, fortified, 1 tablespoon

60

15

Milk, nonfat, reduced fat, and whole, vitamin Dfortified, 1 cup

115-124

29-31

Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies)

137

34

Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV)

40

10

Salmon (sockeye), cooked, 3 oz

447

112

Sardines, canned in oil, drained, two sardines

46

12

Swordfish, cooked, 3 oz

566

142

Tuna fish, canned in water, drained, 3 oz

154

39

Yogurt, fortified with 20% of the DV for vitamin D, 6 oz (more heavily fortified yogurts provide more of the DV)

80

20

DV=daily value; IUs=international units. *DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient content among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children aged 4 yaers and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Adapted from Office of Dietary Supplements. Vitamin D. Available at ods.od.nih.gov /factsheets/VitaminD-HealthProfessional/. Accessed August 15, 2012.

Among the primary benefits of adequate amounts of vitamin D are decreased risk of fracture and prevention of falls in older adults. According to research from Canada, inadequate levels of vitamin D (levels <20 ng/mL) have been linked to increased risks (30%-50%) of colon, breast, and prostate cancer.4 Guidelines for evaluation of vitamin D deficiency

In 2009, the Agency for Healthcare Research and Quality (AHRQ) published guidelines on the evaluation and treatment of vitamin D deficiency,5 and in 2011, The Endocrine Society provided its own recommendations that also included prevention of vitamin D deficiency.3 Both organizations provided comprehensive guidelines on which patients to screen.

However, a side-by-side comparison of these recommendations

(Table 4) reveals some distinct differences. Also included in Table 4 are this authorâ&#x20AC;&#x2122;s recommendations of which of the patients seen in general practice should be screened. The AHRQ included in its recommendations the assessments that comprise an appropriate physical examination. These include general appearance, height and weight, vital signs, overall skin evaluation, skin color, and assessment of bone pain by pressing on the area over the sternum or shin.

In addition to a serum 25(OH)D level, other laboratory studies that should be obtained to assess general bone health include a comprehensive metabolic panel, liver function tests, and thyroid-stimulating hormone, calcium phosphorus, protein, intact parathyroid hormone, albumin, alkaline phosphatase, creatinine, total testosterone, serum C-telopeptide, urinary N-telopeptide, and serum osteocalcin determinations.

Treating vitamin D deficiency

Treatment of vitamin D deficiency or insufficiency (low D) is usually achieved either through sunlight exposure or vitamin D supplements. Sunlight exposure requirements vary based on skin pigmentation. For example, a white infant clothed in a diaper can achieve adequate amounts of sunlight exposure in 30 minutes compared with a black person, who would require nearly three times this amount of exposure to obtain the same benefits.6 Such exposure will provide an estimated 1,000 IU of vitamin D3, an amount that is likely to be inadequate for those with darker skin as well as the elderly because of decreased dermal conversion.

Available vitamin D supplements include ergocalciferol and cholecalciferol. Ergocalciferol, which is available by prescription, is supplied as 50,000 IU and usually is dosed weekly or monthly, depending on the degree of deficiency.

Cholecalciferol is available OTC in doses ranging from 400-5,000 IU and usually is taken as a daily supplement.

Recommendations from the IOM and The Endocrine Society guidelines indicate that the daily vitamin D intake for adults aged 18-50 years should be 600 IU, with an upper limit of 4,000 IU per day.7 The recommended amount for persons who are at high risk (those with dark skin and the elderly) and lack adequate sun exposure is 800-1,000 IU daily.

Once vitamin D deficiency or insufficiency has been determined, treatment with the appropriate amount of vitamin D is necessary. For those who are deficient, the recommendation is for initial treatment with 50,000 IU of ergocalciferol or cholecalciferol weekly for six to eight weeks, then 800-1,000

24 THE CLINICAL ADVISOR â&#x20AC;˘ SEPTEMBER 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

TABLE 3.Various levels of vitamin D and their health-related implications

POLL POSITION n=490

How often do you measure 25(OH)D levels in your practice?

4.9%

5.9%

16.1% 73.1%

At every patient visit: Semi-regularly: Seldom: Never:

For more polls, visit www.ClinicalAdvisor/polls

IU of cholecalciferol daily or IM cholecalciferol (300,000 IU) once or twice a year. In cases of insufficiency, treatment with 800-1,000 IU of cholecalciferol daily should improve vitamin D levels in about three months. The IOM provides recommendations for daily calcium and vitamin D intakes during various life stages (Table 5).

Among the available supplements, calcium citrate is the most easily absorbed and best tolerated by patients with low levels of stomach acid. Recommendations also limit the amount of calcium taken at one time to no more than 500 mg in order to enhance absorption. Therefore, patients who require 1,000 mg of calcium per day should take it in divided doses. Sustained-release calcium is available; this product allows for once-daily dosing.

Cautions and intoxication

Although intoxication with vitamin D is rarely seen, it is a possibility. Intoxication usually occurs at levels >150 ng/mL. According to the National Institutes of Health, levels consistently greater than 200 ng/mL are considered toxic. The intoxication syndrome comprises hypercalciuria, hypercalcemia, renal stones, renal calcifications, renal failure, and death. Nonspecific symptoms of intoxication include

PEER PERSPECTIVES

25-hydroxyvitamin D level (ng/mL)

Health implications

(nmol/L)

<20

<50

Deficiency

21-29

50-80

Insufficiency

30-100

80-250

Sufficiency

54-90

135-225

Normal in sunny countries

>100

>250

Excess

>150

>325

Intoxication

Sources: Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.

J Clin Endocrinol Metab. 2011;96:1911-1930 and University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program. Recommendations for the diagnosis and management of vitamin D deficiency in adults. Available at guideline.gov/content. aspx?id=14868. Accessed August 15, 2012.

anorexia, weight loss, polyuria, arrhythmias, and hypercalcemia—resulting in damage to the cardiac blood vessels and kidneys. The use of calcium and vitamin D supplements by postmenopausal women has been associated with a 17% increased risk of kidney stones over seven years.8 Exercise caution when initiating ergocalciferol in patients with hypophosphatemia, malabsorption syndromes, CVD, renal stones, or impaired renal function. The use of ergocalciferol is contraindicated in persons with hypercalcemia, hypersensitivity to ergocalciferol, its components, or class; renal osteodystrophy; or hypervitaminosis D. Summary

Maintenance of adequate vitamin D levels appears to be beneficial to patients across the life span. While obtaining a 25(OH)D level at each office visit is currently not the standard of care, exploration of the health benefits of adequate levels of vitamin D may result in a change in recommended care in the very near future. If there is a family history of vitamin D deficiency or if the patient falls into one of the risk categories indicated in Table 3, he or she may well benefit from being screened. Although no guidelines state clearly how often vitamin D level determinations should be repeated, our

“I rarely check vitamin D levels because almost everyone is deficient. Balance the cost of testing with the very low cost of supplements and the extremely low risk of toxicity from so-called megadosing. The USPSTF and IOM recommendations are based on flawed research methodologies and muddled in politics.”

Mark Behar, PA-C, Milwaukee (via ClinicalAdvisor.com)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 25

VITAMIN D DEFICIENCY

TABLE 4. Comparison of vitamin D screening recommendations3,5 Risk factor

AHRQ

Endocrine Society

General practice

Cancer

+

Cardiovascular disease

+

Chronic kidney disease

+

+

Chronic steroid use

+

+

Darker skin Depression Diabetes

Elderly

TABLE 5. IOM recommended daily dietary allowances for calcium and vitamin D intake

+

+

+ (African American) + + (T2DM, metabolic syndrome) +

+

Calcium (mg)

Vitamin D (IU)

1-3 y (M &F)

700

600

4-8 y (M & F)

1,000

600

9-13 y (M & F)

1,300

600

14-18 y (M & F)

1,300

600

19-30 y (M & F)

1,000

600

31-50 y (M & F)

1,000

600

51-70 y (M )

1,000

600

51-70 y (F)

1,200

600

>71 y

1,200

800

Key: F=female; IOM=Institute of Medicine; M=male.

(with history of falls or nontraumatic fracture)

Fatigue

+

+

Granuloma-forming disorders: TB, sarcoidosis

+

Hepatic failure

+

Hyperparathyroidism

Life stage

Source: Adapted from Institute of Medicine Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011. Available at www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx.

Accessed August 15, 2012.

Ms. Brady is a nurse practitioner in the Department of Endocrine Neoplasia and Hormonal Disorders at the University of Texas, MD Anderson Cancer Center in Houston.

References

+

1. Khan QJ, Fabian CJ. How I treat vitamin D deficiency. J Oncol Pract. 2010;6:97-

Limited dietary intake of vitamin D

+

+

Limited sun exposure

+

+

2. Rao DS. Clinical practitioner perspective. In: Burnstein KL, Ehrmann D,

Malabsorptive diseases

+

+

eds. Vitamin D: beyond bone: other benefi ts. Endocrine News. 2010;35:18-

101. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2835491/.

Medications: anticonvulsants, antifungals, AIDS medications

+

23. Available at www.endo-society.org/endo_news/tri_point/2010/

+

upload/FINAL-Vitamin-D-Tri-Point.pdf.

Muscle pain

+

Obesity

+

+

+

Osteoporosis

+

+

+

Pregnant or lactating women Rheumatoid arthritis Rickets, osteomalacia

+

+ +

3. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911-1930.

4. Epplin J, Thomas SA. Vitamin D: it does a body good. Ann Long Term Care: Clin Care and Aging. 2010;18:39-45. Available at

+ +

Key : + = recommended; AHRQ = Agency for Healthcare Research and Quality; T2DM = type 2 diabetes mellitus.

www.annalsoflongtermcare.com/content/vitamin-d-it-does-body-good.

5. Agency for Healthcare Research and Quality. Recommendations for the diagnosis and management of vitamin D deficiency in adults. 2009.

Available at guideline.gov/content.aspx?id=14868.

6. Pazirandeh S, Burns DL, Lipman, TO, et al. Overview of vitamin D.

practice at MD Anderson Cancer Center is to monitor every three to six months until sufficient levels are obtained and then at least yearly thereafter. Once serum vitamin D levels are satisfactory, a maintenance dose of vitamin D should be taken daily (or weekly). Along with adequate intake of vitamin D and calcium, patients should be encouraged to perform weight-bearing exercises and stop smoking.

Preventing falls is key among the elderly population, and moderation in alcohol intake should be discussed. ■

Available at www.uptodate.com/contents/overview-of-vitamin-d.

7. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-58.

Available at jcem.endojournals.org/content/96/1/53.long.

8. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.

All electronic documents accessed August 15, 2012.

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

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“Could my client be innocent?

Probably not. My point is it’s interesting to think about.”

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“I’m rather fortunate. I have no parents, so Medicare is no problem, and I have no children, so the environment is no problem.”

CME CE

PROGRAM OUTLINE SEPTEMBER 2012

0.5 CREDITS

Page 34 FEATURE Detection of hypoxemia: visual observation versus pulse oximetry Gerard R. Martin, MD, Alex R. Kemper, MD, MPH, MS, and Elizabeth A. Bradshaw, MSN, RN, CPN Gerard R. Martin, MD, Alex R. Kemper, MD, MPH, MS, and Elizabeth A. Bradshaw, MSN, RN, CPN have no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Identify the specific critical congenital heart disease (CCHD) lesions that require immediate assessment in newborns.

• Evaluate the clinical-trials data and public-policy initiatives that support the use of pulse oximetry as a screening tool for CCHD in newborns.

• Employ recent guidance initiatives and clinical-trials data when considering the timing of CCHD in newborns.

0.5 CREDITS

Page 59 DERMATOLOGY CLINIC Isolated areas of darkening skin Amandeep Sandhu and Julia R. Nunley, MD Amandeep Sandhu and Julia R. Nunley, MD have no relationships to disclose relating to the content of this article.

Dirty-appearing truncal eruption Erin L. Reese, MD Erin L. Reese, MD, has no relationships to disclose relating to the content of this article.

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

Page 69 DERMATOLOGIC LOOK-ALIKES Asymptomatic skin lesions Joe Monroe, PA-C Joe Monroe, PA-C has no relationships to disclose relating to the content of this article.

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

Page 74 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 July 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.

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

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

CME CE

■ EDUCATIONAL OBJECTIVES : After completing the activity, the participant should be better able to: • Identify the specific critical congenital heart disease (CCHD) lesions that require immediate assessment in newborns.

• Evaluate the clinical-trials data and public-policy initiatives that support the use of pulse oximetry as a screening tool for CCHD in newborns.

• Employ recent guidance initiatives and clinical-trials data when considering the timing of pulse-oximetry screening for CCHD in newborns.

■ COMPLETE THE POSTTEST: Page 43

FEATURED COURSE

■ ADDITIONAL CME/CE CREDIT: Pages 59, 69 Turn to page 33 for additional information on this month’s CME/CE courses.

This continuing medical education/continuing education (CME/CE) activity, Taking the Pulse of Neonatal Screening for Critical Congenital Heart Disease, is the first in a 3-part series directed to nurse practitioners and physician assistants designed to take the learner from a comprehensive understanding of critical congenital heart disease (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: September 2012 Expiration Date: September 2013 Estimated time to complete the educational activity: 30 mins 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 Kemper, MD, has no financial relationships to disclose.

Elizabeth A. Bradshaw, MSN, RN, CPN, has no financial relationship to disclose.

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Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period September 2012 through September 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 (September 2012); and 4) complete the evaluation form online.

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34 THE CLINICAL ADVISOR • SEPTEMBER 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

Detection of hypoxemia: visual observation versus pulse oximetry

© DREAMSTIME

O

Neonatal CCHD screening

utcomes for infants with congenital heart disease (CHD) have improved dramatically in recent decades, largely as a result of improvements in medical and surgical treatment. Early diagnosis is essential to providing treatment before clinical deterioration. This is especially true for critical congenital heart disease (CCHD), a group of heterogeneous disorders in which surgical or catheter interventional therapy within the first year of life is mandatory to achieve survival. Together, these defects affect approximately 1.2 infants per 1,000 live births in the United States each year. Clinical signs can be subtle, and as a result, CCHD is easily missed during a standard newborn physical examination.

Indeed, the diagnosis of CCHD is missed in one in three affected newborns, leading to delayed treatment and contributing to preventable morbidity and mortality. To address this clinical gap, universal newborn screening is now recommended to increase the early detection of CCHD. This three-article educational activity, Taking the Pulse of Neonatal Screening for Critical Congenital Heart Disease, is designed to provide guidance on screening for CCHD to improve detection in newborns across a range of care settings. Here, the first article provides an overview of the burden of CCHD and introduces the role of pulse oximetry as a simple, safe, and effective screening tool that complements the standard newborn physical examination to enhance the detection of CCHD. Continues on page 36

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Definition and types of CCHD

CHD is the most common congenital disorder in newborns and one of the leading causes of perinatal and infant mortality, accounting for 24% of infant deaths due to congenital malformations.1 Each year, approximately 1.35 million infants are born with CHD worldwide, although the incidence varies by region.2 In North America, CHD affects 8.2 per 1,000 live births, representing a major public health burden.2 For approximately one in four infants born with cardiac malformations, the defect is potentially life-threatening without prompt intervention. CCHD is defi ned as any congenital cardiac defect that will require surgery or catheterbased treatment during the first year of life. The term CCHD describes seven heterogeneous conditions that collectively affect approximately 1.2 per 1,000 babies born each year in the United States.1 Together, these malformations have also been described as critical congenital cyanotic heart defects, given the likelihood that they will present with significant hypoxemia.3 These conditions include:

• Hypoplastic left heart syndrome (HLHS): a malformation in which the left side of the heart is underdeveloped, resulting in reduced cardiac output and the inability of the left heart to support systemic circulation.3 • Pulmonary atresia with intact septum: a malformation characterized by atresia at the pulmonary valve or blockage in the pulmonary artery itself, causing cyanosis due to the mixing of oxygenated and deoxygenated blood from decreased pulmonary blood flow.3 • Tetralogy of Fallot (TOF): a defect consisting of four related lesions: ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy.

The magnitude of pulmonary blood flow obstruction determines the onset and severity of symptoms, with a greater obstruction associated with more severe illness.3 • Total anomalous pulmonary venous return (TAPVR): a malformation characterized by the absence of any connection between the pulmonary veins and left atrium; instead, the pulmonary veins empty into the right atrium

TABLE 1.Types and natural history of critical congenital heart disease Hypoxemia

Ductaldependent

HLHS

All

All

Up to 7 in 10,000 live births

Immediately, or within first two months of life

Universally fatal without surgery

Pulmonary atresia with intact septum

All

All

1% of all congenital cardiac defects

Immediately

When the ductus closes, the newborn becomes severely ill, leading to death if not urgently treated

Most

Uncommon

3 in 10,000 live births

Neonatal period

Onset and severity of symptoms depend on amount of pulmonary blood flow obstruction

TAPVR

All

None

1%-3% of all congenital cardiac defects

Immediately, or within first two months of life

Survival unlikely if the obstruction is left untreated

TGA

All

Uncommon

Up to 3 in 10,000 live births

Immediately

Onset and severity of symptoms depend on anatomic and functional variants; with inadequate blood flow, the newborn will die

Tricuspid atresia

All

Some

1%-3% of all congenital cardiac defects

Immediately, or within first month of life

Cyanotic newborns with a ductal-dependent defect are critically ill

Truncus arteriosus

All

None

2%-4% of all congenital cardiac defects

Within the first two months of life

Fewer than 25% will survive past the first year of life without surgical intervention

Cardiac defect

TOF

Prevalence

Age at symptom onset

Natural history

CCHD = critical congenital heart disease; HLHS = hypoplastic left heart syndrome; TOF = tetralogy of Fallot; TAPVR = total anomalous pulmonary venous return; TGA = transposition of the great arteries.

Source: Knapp AA, et al. Maternal and Child Health Bureau, U.S. Department of Health and Human Services. 2010.

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

or systemic veins, resulting in a mix of oxygenated and unoxygenated blood entering the systemic circulation.3 • Transposition of the great arteries (TGA): a family of malformations characterized by two discordant circulatory tracks, whereby unoxygenated blood is circulated to the body via the aorta, and oxygenated blood is recirculated between the lungs and the pulmonary artery.

• Tricuspid atresia: a defect where the tricuspid valve fails to develop, leading to a range of symptoms including cyanosis, dyspnea, tachypnea, and metabolic acidosis.

Tricuspid atresia commonly occurs with other cardiac defects that also contribute to cyanosis.3 • Truncus arteriosus: a malformation characterized by the presence of a single great artery that arises from both ventricles and thereby supplies both oxygenated and unoxygenated blood to the pulmonary, coronary, and systemic circulations.3 Table 1 summarizes the epidemiology, clinical features, and natural history of each subtype of CCHD. Many defects are ductal-dependent, meaning that the diagnosis may be delayed in cases when the ductus arteriosus closes after the newborn is discharged from the hospital nursery. The common finding of hypoxemia, however, has important implications for CCHD screening.

Missed and delayed diagnoses of CCHD

For decades, standard clinical practice has called for examining the cardiovascular system as part of the routine newborn examination. Despite this practice, however, one in three infants with a potentially life-threatening form of CHD is discharged from the hospital nursery undiagnosed.4 Clinical evaluation with prenatal ultrasound or newborn physical examination alone can easily miss CCHD, particularly in infants with subtle clinical signs.5 For instance, half of all newborns with CCHD—particularly those with ductaldependent defects—have no distinctive murmur.6 In many cases, symptoms of CCHD do not present until after hospital discharge, contributing to high rates of morbidity and mortality for newborns with CCHD.7 Missed diagnoses prevent newborns with potentially lifethreatening cardiovascular malformations from receiving successful treatments now available with advances in pediatric cardiology and cardiac surgery. Furthermore, although options for surgical correction may be the same regardless of whether the diagnosis is made early or late, the effects on treatment outcomes are substantial.6 Delaying treatment until newborns with CCHD are critically ill is associated with increased

surgical mortality, prolonged hospital stay, and higher incidence of such serious adverse effects as neurologic dysfunction, including learning difficulties and delays in cognitive development.6 The goal of screening is to detect CCHD prior to clinical deterioration in affected newborns.

Despite efforts to increase the recognition of CCHD, timely diagnosis remains an elusive goal. Missed and delayed diagnoses of CCHD occur in anywhere from one in 3,500 to one in 25,000 live births, depending on the type of defect.4,8-10 Chang and colleagues evaluated trends in missed diagnoses of CCHD in a population-based study of California statewide death registry data collected between 1989 and 2004.11 Although the detection of CCHD improved between 1989 and 1999, the total annual number of infants with missed or late diagnoses of CCHD was unchanged between 2000 and 2004. Overall, up to 30 infants died each year in California due to missed or late diagnoses of CCHD. The median age at death was 13.5 days, underscoring the importance of early diagnosis.11 The consequences of missed diagnoses have also been observed in real-world practice.

In a retrospective analysis of newborns younger than age 30 days admitted to the Children’s Hospital of Philadelphia with CCHD, 6.7% had a significant physiologic compromise, including metabolic acidosis, seizure, cardiac arrest, or renal or hepatic injury, due to a missed diagnosis.12 The persistence of missed CCHD diagnoses highlights system-based deficiencies in diagnostic protocols for newborns. For instance, major changes to cardiopulmonary physiology occur during the first few days of life, making diagnosis difficult during this period. Moreover, the trend toward earlier hospital discharge—and the associated shift of newborn care to other health-care settings—adds to the challenge of timely diagnosis. Indeed, the setting where CCHD is first recognized correlates with clinical outcomes, with earlier diagnosis a strong predictor of lower morbidity and mortality.13 Detection of hypoxemia: visual observation vs. pulse oximetry

Visual observation. Determining whether an infant is pink or blue involves examining the face, trunk, and mucous membranes to detect the presence of central cyanosis.

However, several factors other than oxygen saturation can influence the infant’s color. Patient factors such as skin thickness and color, perfusion, and hemoglobin concentration can influence color, while environmental factors such as ambient light conditions can influence color perception.14 Therefore, a major limitation of the newborn physical

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examination is the inability of the human eye to detect important degrees of cyanosis.15 The gap between normal oxygen saturation and visible cyanosis has been described as the “cyanotic blind spot” (Figure 1).16 The ability to detect mild cyanosis by visual examination and the reliability of visual perceptions across different observers are poor even among neonatal intensive-care personnel.

One recent study showed substantial variations in the clinical assessment of infant color.14 In the study, 27 physicians and nurses were asked to observe video recordings of 20 infants taken immediately after delivery. The clinicians were asked to indicate whether each infant was pink at the start of the video, became pink during the recording, or had never been pink. Only one infant (5%) was perceived to be pink by all clinicians. For the remaining 19 infants, clinicians varied widely in their opinions of newborn color. Between 4% and 81% believed that the remaining infants never became pink.

Even when clinicians agreed that infants turned pink, the SpO2 (arterial oxyhemoglobin saturation as measured noninvasively by pulse oximetry) at which individual infants were perceived to become pink varied from 10% to 100%.

Furthermore, the false-positive for hypoxemia was high, with 17% of infants rated as “never pink” despite maximum SpO2 levels ≥95%. Given the extent of disagreement among observers regarding the color of infants observed under identical conditions (i.e., via video recording), the study authors concluded that real-world visual assessment of newborn color is unreliable. Moreover, the lack of correlation between perceived color and SpO2 suggests that visual assessment is an unreliable method for evaluating oxygenation.14 Pulse oximetry. Pulse oximetry is a noninvasive and painless test that measures the percentage of hemoglobin in blood Hemoglobin of 17.5 g/dL 83% Abnormal Saturation Visible Cyanosis

95% Abnormal Saturation No Visible Cyanosis

Normal

78% 95% Hemoglobin of 13.5 g/dL Hemoglobin values reflect the 50th percentile (17.5 g/dL) and 5th percentile (13.5 g/dL) for newborns.

Source: Hokanson JS. Congen Cardiol Today. 2011;9:1-6.

Reprinted with permission from Congenital Cardiology Today (www.CongenitalCardiologyToday.com). Copyrighted Congenital Cardiology Today. All rights reserved.

FIGURE 1. The cyanotic blind spot.

that is saturated with oxygen. Pulse oximetry has been evaluated as a screening tool for CCHD based on the rationale that most defects involve a degree of hypoxemia that may not necessarily produce visible cyanosis.17 Pulse oximetry can reliably detect mild hypoxemia, a feature of many subtypes of CCHD that is difficult to recognize by physical examination.14 As an adjunct to the standard newborn examination, therefore, pulse oximetry can identify cases of CCHD that escape routine clinical detection.

In several clinical trials, pulse oximetry has been shown to be a simple, safe, feasible, and cost-effective screening tool that adds value to the routine physical evaluation of newborns.18-20 In 2012, Thangaratinam and colleagues presented findings from a meta-analysis of studies that assessed the performance of screening for CCHD using pulse oximetry in a total of 229,421 asymptomatic newborns.17 In this study, pulse oximetry was highly specific (99.9%) and moderately sensitive (76.5%) for the detection of CCHD, meeting standard thresholds for universal screening.

The overall false-positive rate was 0.14%, but fell to 0.05%, without any compromise in sensitivity, when pulse oximetry was performed after 24 hours from birth. Although the goal of screening is to detect CCHD, other life-threatening disorders of noncardiac origin, including group B streptococcal pneumonia and pulmonary hypertension, may be detected.

Although the rationale and evidence supporting the use of pulse oximetry as a screening tool are firmly established, the implementation of CCHD screening involves practical issues that remain under evaluation. For instance, the falsepositive rate and positive predictive values are dependent on both the timing of the oximetry and whether or not a repeat measurement of abnormal values had been performed in the at-risk patient. In most studies, a postductal saturation between 94% and 96% has been used as the cutoff point for “normal.”21 Selecting the threshold for a positive pulseoximetry monitoring result is challenging, because it must trade off the harm of missing CCHD against the harm of false-positive screen results.22 Screening performed either primarily after 24 hours or repeated after 24 hours will provide the lowest false-positive rate and the highest positive predictive value.5,9 Earlier screening can lead to false-positive results because of the transition from fetal to neonatal circulation and stabilization of systemic oxygen saturation levels, and later screening can miss an opportunity for intervention before closing of the ductus arteriosus.22 Therefore, most publications recommend the use of CCHD screening at or after 24 hours of life.17,23

38 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

CCHD screening and the ‘‘diagnostic gap’’

Riede and colleagues recently described the “diagnostic gap” in CCHD, where cardiac defects are not recognized despite standard assessment with prenatal ultrasound and newborn physical examination.5 In a prospective multicenter study, the investigators examined the potential role of pulse oximetry to close the diagnostic gap in real-world clinical practice.5 Among 48,348 newborns, 90 cases of CCHD were ultimately diagnosed. Neonatal screening and clinical observation during the first 24 hours of life, however, detected only 80% of these cases, leaving a diagnostic gap of 20%.

All newborns also underwent screening at the age of 24 to 72 hours of life. Any newborn with an SpO2 of ≤95% measured on the lower extremities and confirmed after one hour underwent complete clinical examination and echocardiography. Adding pulse oximetry to the screening protocol closed the CCHD diagnostic gap to 4.4% (Figure 2).5 Several other trials have also demonstrated improved detection rates when pulse oximetry is added to existing diagnostic mechanisms.9,24 Studies in Sweden and the United Kingdom (UK) found that performing a typical physical examination alone for CCHD led to almost 10 times more false-positive results compared with using CCHD screening protocols.9,25 Overall, CCHD screening after 24 hours of life improves early in-hospital detection of CCHD and may reduce the number missed and diagnosed after discharge.26 Even with evidence of improved detection, however, investigators emphasize the importance of using pulse oximetry as an adjunct to the standard newborn physical examination.22,27,28

time included “too many false-positives” with pulse oximetry (26%), the technology is “prone to noise and artifact” (21%), and screening is “very operator-dependent” (30%). More recently, however, new protocols and recommendations have been published to reduce false-positive rates and address other technologic barriers to pulse-oximetry screening (see “Current screening recommendations”).23 Current screening recommendations

Universal screening for CCHD is rapidly becoming the standard of care for infants born in the United States as a result of efforts by the U.S. Department of Health and Human Services (HHS) Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) and other national groups. A brief history of the road to universal screening for CCHD is helpful for putting next steps into context.

Road to universal screening

The current HHS, American Academy of Pediatrics (AAP), and the American Heart Association (AHA) endorsement of universal screening for CCHD caps off years of work by leaders in pediatric cardiology and other fields.

100% 90% 80% 70%

Current status of CCHD screening

Despite growing evidence supporting the implementation of CCHD screening, uptake has been a slow process. In a 2011 survey of hospitals across the UK, only 7% routinely used CCHD screening to supplement the standard newborn physical examination.29 Moreover, there was wide variability among screening protocols, with different screening schedules, different SpO2 values used to trigger further investigation, and different follow-up procedures. These findings reinforce the importance of standardized guidelines for screening procedures, including saturation measurements and follow-up investigations.

Resistance to CCHD screening has also been observed among clinicians in the United States. In a 2009 survey of 363 pediatric cardiologists, 42% reported that current practice is inadequate for detecting significant CHD, yet only 55% supported the mandated use of CCHD screening for all newborns.30 Concerns among the survey respondents at that

60%

diagnostic gap

50%

POS

40%

clinical

30%

prenatal

20% 10% 0%

Prenatal = prenatal ultrasound; Clinical = clinical observation or physical examination within the first 24 hours of life and prior to POS; POS = pulse-oximetry screening between 24 and 72 hours of life.

Source: Riede FT, et al. Eur J Pediatr. 2010;169:975-981.

Copyright Eur J Pediatr.

FIGURE 2. CCHD screening reduces the diagnostic gap.

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• 2009: The AHA and the AAP published a joint scientific statement describing the compelling reasons for utilizing pulse oximetry as part of the newborn clinical evaluation for CCHD.31 Based on the evidence at the time, however, the AHA/AAP statement stopped short of recommending universal screening. Instead, the AHA/AAP called for additional data on key issues that required further clarification, including the following: — Variability in arterial SpO2 during the first 24 hours following birth — Variable definitions of abnormal oxygen saturation (i.e., <92% vs. ≤95%) — Influence of altitude on test performance — Position of the oximetry probe (i.e., upper- or lowerextremity positioning) — Potential implementation at the population level.

• 2010: The SACHDNC recommended adding CCHD screening to the recommended uniform screening panel.22 At the time, however, the HHS Secretary was not ready to adopt this recommendation pending an implementation plan from HHS agencies.32 • 2011: A work group convened to establish a standardized protocol for CCHD screening, including initial screening and follow-up. A white paper outlining the work-group recommendations has been endorsed by the AAP, the AHA, the American College of Cardiology Foundation (ACCF), and other advocacy organizations, including the March of Dimes. 22 These recommendations are TABLE 2. Key recommendations for pulse-oximetry screening • Screening is targeted toward healthy newborn infants.

• Screening should not occur until 24 hours of life, or as late as possible if early discharge is planned.

• Oxygen saturation readings should be obtained 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.

— Repeated measurements are recommended when the initial screening result is positive.

— Any infant with oxygen saturation <90% should receive immediate evaluation.

— Thresholds for positive findings may need adjustment in high-altitude areas.

• For infants with positive screening results, CCHD needs to be excluded with a diagnostic echocardiogram. Infectious and pulmonary causes of hypoxemia should also be excluded.

Source: Kemper AR, et al. Pediatrics. 2011;128:e1259-e1267.

summarized in Table 2. Also in 2011, HHS Secretary Kathleen Sebelius endorsed the SACHDNC recommendation to add CCHD to the uniform screening panel for newborns.32 • 2012: The AAP published a policy statement supporting the HHS endorsement of universal screening for CCHD.23 The AAP also provided guidance for implementing screening into clinical practice.23 Next steps for screening

Although the HHS Secretary has recommended that screening for CCHD be added to the recommended uniform screening panel for newborns, it will be the responsibility of individual states to determine implementation of their own screening programs. This may be accomplished by legislation, regulation, or adoption as a standard of practice.23 In 2011, New Jersey became the first state to mandate universal screening of infants born in birthing facilities.33 Successful implementation of the CCHD screening recommendations will depend on standardized screening criteria within hospitals and the public health system’s commitment to support surveillance. Implementation will also require the integrated participation of the full spectrum of health-care professionals, from pediatric cardiologists and hospital staff to primary-care providers and families.7 While the infrastructure is being developed, community hospitals will be on the front lines of successfully implementing pulse oximetry with a high degree of accuracy.7 An essential component of that strategy also entails the coordination of care between hospitals and primarycare providers.22 Several medical centers across the United States have begun implementing CCHD screening programs, based on screening recommendations from the AAP, the AHA, the ACCF, and other organizations.22 For instance, Children’s National Medical Center in Washington, D.C., has developed the Congenital Heart Disease Screening Program (CHDSP).

The CHDSP provides a toolkit for health-care providers and families, including a pulse-oximetry screening protocol (Figure 3).34 The toolkit is available at www.childrensnational .org/PulseOx/. (Accessed August 15, 2012.)

Conclusions

CCHD screening using pulse oximetry is a simple, noninvasive, evidence-based tool that enhances the early identification of newborns with CCHD. On the heels of recent endorsements from the HHS Secretary, the AAP, the AHA, the ACCF, and other societies, pulse-oximetry

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

Pulse Ox on Right Hand (RH) and One Foot After 24 Hours of Age

Pulse Ox on RH and One Foot After 24 Hours of Age

Pulse Ox <95% (both RH & Foot) and Difference of >3% Between RH and Foot

FAIL

PASS

Repeat Pulse Ox in 1 Hour Normal Newborn Care FAIL Repeat Pulse Ox in 1 Hour FAIL Clinical Assessment

RH Application Site

Foot Application Site

Source: Children’s National Medical Center CHD Screening Program. www.childrensnational.org/PulseOx/.

FIGURE 3. Children’s National Medical Center CHD screening protocol for well babies. 34

screening is poised to change the standard of care in newborn nurseries. Successful roll-out will depend on standardized screening criteria within hospitals and other care settings as well as commitment from state public health systems to support surveillance. Across the continuum of care for CCHD— from the neonatal intensive care unit and in-hospital management to discharge and follow-up care—health-care providers can participate in the implementation of pulseoximetry screening protocols in their institutions. ■

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2. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and metaanalysis. J Am Coll Cardiol. 2011;58:2241-2247.

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Coming up in the next issue

life-threatening neonatal cardiovascular malformations. Arch Dis Child Fetal

Screening for CCHD is now included in the recommended uniform screening panel for infants born in the United States, and individual states are developing programs to implement this new standard of care. The next article in the Taking the Pulse of Neonatal Screening for Critical Congential Heart Disease series will provide a detailed summary of recommendations for CCHD screening and describe strategies for adopting screening programs across a range of health-care settings. In particular, the article will focus on the role of the primary care provider as a key member of the CCHD care team and coordinator of the medical home for newborns with CCHD.

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

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study with evaluation of acceptability and cost-effectiveness. Health Technol Assess. 2012;16:v-xiii, 1-184.

All electronic documents accessed August 15, 2012.

20. Roberts TE, Barton PM, Auguste PE, et al. Pulse oximetry as a screening test for congenital heart defects in newborn infants: a cost-effectiveness analysis. Arch Dis Child. 2012;97:221-226.

21. Levesque BM, Pollack P, Griffin BE, et al. Pulse oximetry: what’s normal in the newborn nursery? Pediatr Pulmonol. 2000;30:406-412.

22. Kemper AR, Mahle WT, Martin GR, et al. Strategies for implementing screening for critical congenital heart disease. Pediatrics.

2011;128:e1259-e1267.

23. 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.

24. Knowles R, Griebsch I, Dezateux C, et al. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

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Health Technol Assess. 2005;9:1-152, iii-iv.

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

CME CE

POSTTEST Expiration date: September 2013

Credit Disignation: 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 or ClinicalAdvisor.com/CMEFeatureSeptember2012.

CREDITS: 0.5

| Detection of hypoxemia: visual observation versus pulse oximetry

1. Congenital heart disease accounts for approximately what percentage of deaths due to congenital malformation? a. 15% c. 25% b. 35% d. 45% 2. According to Wren and colleagues, what should you consider regarding the routine examination and detection of congenital heart defects? a. The physical examination identifies at least 90% of infants with congenital heart defects. b. The physical examination identifies at least 70% of infants with congenital heart defects. c. Nearly all newborns with congenital heart defects are identified during the first week of life. d. One-third of infants with a potentially life-threatening heart defect are discharged from the hospital undiagnosed.

3. The onset and severity of symptoms for tetralogy of Fallot is determined by: a. Obstruction of the right ventricular outflow tract b. Magnitude of pulmonary blood flow obstruction c. Degree of right ventricular hypertrophy d. Override of the ventricular septum by the aortic root

4. What should you consider regarding the current systematic review by Thangaratinam and colleagues regarding the use of pulse oximetry to evaluate this newborn for congenital heart defects? a. An abnormal pulse-oximetry value is highly predictive of a congenital heart defect. b. A normal pulse-oximetry value is highly predictive of the absence of a congenital heart defect. c. Pulse oximetry is only reliable in evaluating for congenital heart defects during the first 24 hours of life. d. Pulse oximetry is only effective in evaluating for coarctation of the aorta and aortic valve stenosis.

5. Screening for critical congenital heart disease performed during what time frame will provide the lowest false-positive rate? a. Before 12 hours of life b. Between 12 and 24 hours c. After 24 hours of life d. Age of the newborn does not affect the false-positive rate

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/CMEFeatureSept2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 43

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 SEPTEMBER 2012

Consultations Interventions for prediabetes. . . . . . . .44 Treatment of scrotal dermatitis . . . . . .45 Group B strep treatment during pregnancy. . . . . . . . . . . . . . .45

Clinical Pearls Try GERD medication for pediatric molluscum . . . . . . . . . . . .45 Examining the prostate of an obese man . . . . . . . . . . . . . . . . .45 Improve eustachian tube dysfunction with nasal spray . . . . . . . . . . . . . . . .46 And more . . . . . . . . . . . . . . . . . . . . . . . 46

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.

Folic acid correction . . . . . . . . . . . . .46

CONSULTATIONS INTERVENTIONS FOR PREDIABETES What is the correct diagnosis for a patient with the following two-hour oral glucose tolerance test results: fasting 100 mg/dL, one-hour 232 mg/dL, and two-hour 115 mg/dL. Hemoglobin (Hb) A1c was 6.1%. I diagnosed dysmetabolic syndrome and added metformin [Fortamet, Glucophage, Glumetza, Riomet]. A physician colleague disagreed and said the patient unquestionably has type 2 diabetes. My diagnosis was not based on the American Diabetes Association [ADA] guidelines, but I was under the impression that I do not have to go by ADA guidelines all the time.—CHRYSTYNE OLIVIERI, FNP-BC, Manhasset, N.Y. This patient has impaired fasting glucose (IFG), or prediabetes, according to the ADA Clinical Practice Recommendations (Diabetes Care. 2012;35 Suppl 1:S64-S71; available at care.diabetesjournals. org/content/35/Supplement_1/S64.full, accessed August 15, 2012).

IFG is defined as a fasting glucose of 100-126 mg/dL. Impaired glucose tolerance (as well as prediabetes) is a two-hour glucose of >200 mg/dL. In putting this patient’s clinical picture together, the HbA1c is also consistent with prediabetes according to the ADA (HbA1c of 5.7%-6.4%). The one-hour glucose level is not considered in the formal diagnostic criteria for type 2 diabetes. Based on the above information, I would not diagnose the patient with metabolic syndrome, as the patient must have at least three of the five metabolic

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

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

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

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

44 THE CLINICAL ADVISOR • SEPTEMBER 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.

syndrome criteria to meet this diagnosis (BP >130/85 mmHg, HDL <50mg/dL in women or <40 mg/dL in men, triglycerides >150 mg/dL, waist circumference >35 in for women and >40 in for men, and fasting glucose 100-125mg/dL).

Your intervention was appropriate and agrees with the ADA recommendations that suggest starting metformin on a patient with prediabetes younger than age 60 years. The ADA guidelines also recommend lifestyle therapy for individuals with prediabetes.—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, Family Nurse Practitioner Program, Duke University School of Nursing, Durham, N.C. (167-1)

TREATMENT OF SCROTAL DERMATITIS What treatment do you recommend for scrotal dermatitis?— JAYAKAR THOMAS, MD, PhD, Chennai, India Scrotal dermatitis may be idiopathic, secondary to a contact etiology (allergic or irritant), the result of scrotal involvement of a systemic dermatosis (e.g., lichen planus or psoriasis), caused by an infection (dermatophyte or candida) or infestation (scabies or lice), or—less likely—an unusual sequela of an underlying neoplastic process (e.g., squamous cell carcinoma or extramammary Paget disease). Symptomatic treatment could begin with a topical low- to mid-potency corticosteroid cream or ointment. If a fungal etiology is suspected, a topical or systemic antimycotic agent could be added. Consider a biopsy if the dermatitis persists or recurs.—Philip R. Cohen, MD (167-2)

GROUP B STREP TREATMENT DURING PREGNANCY A woman 35 to 37 weeks’ pregnant with positive group B streptococcus (GBS) vaginal infection is allergic to penicillin and clindamycin [Cleocin]. What alternative treatment

regimen would have the least adverse effect on the fetus?— YUSHARN WANG, FNP, Honolulu Chemoprophylaxis in the intrapartum period for GBS-positive women decreases morbidity and mortality in the neonatal population.

Standard treatment of GBS-positive women is either penicillin or ampicillin. If a woman is allergic to penicillin (clarify with her if it is a true anaphylactic reaction) check for sensitivities at the time the GBS culture is obtained and treat according to results. Treatment options include cefazolin [Ancef] 2 g IV initial dose then 1 g every eight hours (for patients not at high risk of anaphylaxis), clindamycin 900 mg IV every eight hours, erythromycin 500 mg IV every six hours, or vancomycin [Vancocin] 1 g every 12 hours. All of these antibiotics are Pregnancy Category B, with the exception of vancomycin, which is Pregnancy Category C. None of these antibiotics has been shown to have any adverse effects on the fetus.—Mary Newberry, CNM, MSN (167-3)

CLINICAL PEARLS TRY GERD MEDICATION FOR PEDIATRIC MOLLUSCUM To treat extensive molluscum in children, try cimetidine [Tagamet] 30-40 mg/kg/day divided into two to three daily doses. I have found this to be successful in as little as four to six weeks.—BECKY SCHMITT, PA-C, Allegan, Mich. (167-4)

EXAMINING THE PROSTATE OF AN OBESE MAN Perform digital rectal exams (DREs) on obese individuals can be a challenge. Excess fat around the gluteal region may

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.

teaches at the University of North Carolina School of Nursing in Chapel Hill and practices pediatrics at UNC Hospitals.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 45

Advisor Forum make it extremely difficult to adequately perform this exam with the client simply bending over. One way to overcome this challenge is to have the patient lie on the exam table in the supine position. Have him move his buttocks to the edge of the exam table with his feet placed in the footrest usually reserved for female gynecologic exams. The practitioner can perform the DRE with the index finger turned upward (i.e., toward the umbilicus). The posterior surface of the patient’s prostate should be palpable from this position.—OMAR ABDUL-MALIK, DHEd, MPAS, PA, Washington, D.C. (167-5)

FILE AWAY ANXIETY OVER TRIMMING INFANT FINGERNAILS Many parents are anxious about cutting their infant’s fingernails. A simple solution is to use an emery board on a regular basis to keep the nails shorter and smoother.—PAT CHICHON, RN, MSN, NP, Lambertville, N.J. (167-7)

“I need to see another ten or eleven debates before I make up my mind.”

“Please, Al. You know the backstroke scares the children.”

YOUR COMMENTS FOLIC ACID CORRECTION I found the article “Mixing herbal and prescription meds,” (July 2012) very informative. The author recommended that folic acid be taken prior to and during pregnancy, which is unquestionably true. However, the article referred to folic acid as vitamin B6, which is incorrect. Folic acid is vitamin B9 and pyridoxine is vitamin B6.—NANCY HILL, WHNPBC, New York City You are correct. I apologize for missing this error in the proofreading process.—Lorraine W. Bock, MSN, CRNP, CEN (167-8) ■

“Next, an example of the very same procedure when done correctly.”

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

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

IMPROVE EUSTACHIAN TUBE DYSFUNCTION WITH NASAL SPRAY For children aged 6 years and older with eustachian tube dysfunction, apply a 12-hour nasal decongestant spray and have the child immediately assume a supine position to allow the medication to drip back to the eustachian tube opening (typically directly posterior to the nares). If there is significant mucosal inflammation, follow with a nasal steroid using the same technique. The decongestant enhances the penetration of the steroid while simultaneously reducing the (already low) rate of systemic absorption, increasing the local effect.—THOMAS URSCHEL, RPAC, Clarendon, N.Y. (167-6)

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.

Large oozing plaque on the scalp of an elderly man An 80-year-old man presented complaining of a very large oozing plaque on his scalp that had been slowly growing for more than a year. He claimed that it was not painful but was worried that it was ringworm.

WHAT IS YOUR DIAGNOSIS?

• • • •

Prurigo nodularis Actinic keratosis Squamous cell carcinoma Atopic dermatitis

● See the full case at ClinicalAdvisor.com/DermDx0912A

Abrupt skin eruption following brain surgery A teenaged patient develops a rash on his face, chest, and lateral upper arms following a craniotomy performed to remove a high-grade anaplastic astrocytoma that had invaded the brain stem.

WHAT IS YOUR DIAGNOSIS?

• • • •

Red man syndrome Steroid acne Cutaneous candidiasis Impetigo

● See the full case at ClinicalAdvisor.com/DermDx0912B

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.

Lumps on the heel when standing

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

White streak on the inner leg

LEGAL ADVISOR CASE

Do HIPAA rules apply to family?

BY ANN W. LATNER, JD

Ms. P was a nurse working in the cardiology department of a large hospital. Part of her job was to access patient medical records to review lab values and other diagnostic tests ordered by physicians and writing progress notes in patients’ charts.

When Ms. P was hired, she was given a lecture from human resources about the importance of patient confidentiality. Ms. P was required to sign an agreement stating that she would protect patient confidentiality by only seeking or obtaining information regarding a patient, which was required in order to perform her duties. Later, when the Health Insurance Portability and Accountability Act (HIPAA) went into effect, Ms. P was required to go to another humanresources seminar and sign a revised confidentiality agreement. This agreement stated that she would not access or view information other than what was required to do her job and that she would immediately ask her supervisor for clarification if she had any questions about whether information was required for her job. Finally, the agreement contained a section stating that

© THINKSTOCK

One nurse found out the hard way that any breach of privacy is grounds for dismissal.

The revised agreement stated that she would not view information other than what was required for her to do her job.

Ms. P acknowledged that violation of the facility’s confidentiality policy could result in disciplinary action up to and including termination.

Ms. P understood the importance of patient confidentiality and would never look in the records of patients that weren’t hers—with two exceptions. Ms. P’s mother and sister both had serious chronic conditions that frequently resulted in hospital visits over the years.

Ms. P’s mother had Parkinson disease, was taking numerous medications, and was prone to falls. Ms. P’s older sister, who lived with her, had Down syndrome. Ms. P would periodically look up her mother’s and sister’s health records on the hospital computer to get information or to access their treatment plans. She didn’t see anything wrong with this—after all, it was her own family.

Continues on page 52

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 51

LEGAL ADVISOR One of her colleagues, however, had noticed Ms. P looking at the records on more than one occasion, and anonymously reported her. The hospital’s HIPAA compliance officer began an investigation, which revealed that Ms. P had accessed her mother’s charts on 44 separate occasions and her sister’s charts on 28 occasions. When the human-resources director confronted her with the results of the investigation, Ms. P admitted that she had accessed the records, but that they were the records of her family members and therefore she didn’t see anything wrong with it.

HIPAA violations are taken very seriously, especially if the provider was given training about patient privacy.

“Did you need to access information from their medical records in order to fulfi ll your duties as a clinical affi liate in the cardiology department?” asked the director of human resources.

“I did not,” replied Ms. P. “They were not cardiology patients.”

Ms. P was terminated from her employment that day.

Angered by the loss of her job, Ms. P sought the advice of an attorney to determine whether she could sue the hospital for wrongful termination. The attorney was skeptical.

“HIPAA violations are taken very seriously,” he said. “Did they give you training about patient privacy?”

Ms. P admitted that she’d had training.

“Were you asked to sign anything after the training?” inquired the attorney.

“Well, yes,” said Ms. P. “I did sign a confidentiality agreement, and the hospital does have a policy that you could lose your job for violating it. But this was my mother and sister!

They don’t mind that I looked at their records!”

“That’s irrelevant,” said the attorney. “It doesn’t matter if they are family or not. You still didn’t have the right to look at the records. I don’t think we have a leg to stand on, unless…” the attorney trailed off, thinking.

“How old are you?” he suddenly asked Ms. P. When she told him, he smiled. “I think we may have an angle in this suit. We can try suing the hospital for age discrimination. We can claim that the privacy violation was merely a pretext to get rid of you—a higher paid, experienced nurse—and replace you with a less expensive junior person.”

The attorney fi led the papers against the hospital. The hospital’s attorney promptly fi led a motion to dismiss. The court, after reviewing all the facts, dismissed Ms. P’s case.

Legal background

People who are over 40 years of age can allege age discrimination if it appears that the employer is using another excuse to fi re an older employee and replace him or her with someone younger and cheaper. In this case, however, the hospital had a clear policy, in writing, which Ms. P was familiar with and had signed. In addition, the hospital had a history of terminating employees for HIPAA violations, and more than half of those who were fired were younger than age 40 years at the time. In fact, several of the younger employees were terminated specifically for accessing the medical charts of family members. If an employer has a policy on the books that is being enforced uniformly across all age groups, then a cause of action alleging age discrimination will fail—as it did here.

Protecting yourself

The HIPAA Privacy Rule provides federal protections regarding the accessing of personal health information. At the same time, the Privacy Rule is balanced, so that it permits the disclosure of personal health information when such data are needed for patient care and other important purposes.

Ms. P had no valid reason to be looking at medical records of patients who were not hers.

HIPAA is taken very seriously, and numerous jobs have been lost based on violations of the rule. A hospital or medical practice cannot afford to have violations, as the federal government strictly enforces HIPAA. It is essential to remember that the privacy of a patient—whether it is someone you know or not—is of paramount importance. Also, pay attention to the policies of your employer. Had Ms. P considered the training she’d had, or the agreement she had signed, she might have realized the dire consequences of looking at unauthorized medical records. Always err on the side of caution. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

WHAT DO YOU THINK? Did the jury make the right decision in this case?

Add your comments to this article — or any article — by going to www.clinicaladvisor.com.

52 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

Clinical Challenge Presyncope coupled with an enlarged spleen suggests infection MICHELE D. TINGE, MPAS, PA-C

A 69-year-old woman presents with night sweats, dizziness, fatigue, and chronic pain in the upper abdomen.

Mrs. C is a 69-year-old white woman who has enjoyed good health over the years. Other than a diagnosis of osteoporosis, she has no medical history. She came to our clinic with vague complaints of approximately a week’s duration. Predominantly, she noted presyncope and lightheadedness, fatigue, and mild upper abdominal pain. Two nights prior to presentation, Mrs. C arose from sleep to urinate when, just before micturition, she felt dizzy and subsequently had to sit down on the bathroom floor. She was shaky and sweaty, but after a few moments the symptoms passed and she went back to bed. When she was seen in the office she still noted lightheadedness upon standing and a generalized sense of malaise.

CASE

1. HISTORY

COURTESY OF MICHELE D. TINGE, PA-C

The patient had not noted any unintentional weight changes, fevers, chills, or sweats. There was no cough or shortness of breath, nor were there any respiratory symptoms. Moreover, she denied chest pain and exertional dyspnea. Mrs. C admitted to occasional palpitations, but they were fleeting, unassociated with any other symptoms, and unchanged over the years. She reported mild nausea, but no vomiting. She stated she had mild, intermittent, sharp pains in her upper abdomen that were not associated with food, and no significant belching or indigestion. She said she had loose bowels since the onset of symptoms, but no frank diarrhea and, importantly, no bloody or dark stools.

There were no urinary changes. Further probing indicated that the patient bruises easily, but she stated that this is not a new finding for her, and she attributed it to taking a daily aspirin.

In addition to taking 81 mg of aspirin per day, Mrs. C was on weekly alendronate (Fosamax), fish oil, a calcium supplement, and a multivitamin.

2. EXAMINATION FIGURE 1. CT scan of the abdomen shows splenomegaly (arrow).

Physical examination showed an afebrile woman appearing younger than her stated age. Her vital

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 53

DPN Burner Digital Ad 8.75 x 11.25- PBP485919-01

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

© 2012 Pfizer Inc.

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

DPN Burner Digital Ad 8.75 x 11.25- PBP485919-01

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

75

150

225

300

BID or TID

15–30

25–50

75

100–150

150

QD or BID

<15

25

25–50

50–75

75

QD

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.

© 2012 Pfizer Inc.

All rights reserved.

September 2012

Clinical Challenge signs were: temperature 98.0°F orally, BP 92/52 mm Hg sitting and 82/50 mm Hg standing, pulse 84 beats per minute and regular, respiratory rate 16 breaths per minute, weight 141 lb. (down 8 lb. from one year prior), and height 64.5 in. Her head and neck exam were unremarkable, as were her ears, nose, and throat. Notably, her mucous membranes were moist. There was symmetric expansion of the chest, and lungs were clear to auscultation and percussion bilaterally. On cardiovascular exam the patient was found in a regular rhythm, with S1 and S2 intact and no audible clicks, murmurs, or rubs.

Mrs. C’s abdomen was normoactive with bowel sounds, tympanic, soft, and mildly tender to deep palpation of the left upper quadrant. On examination, her spleen felt enlarged. However, there were no other masses or organomegaly noted. Mrs. C’s skin was nondiaphoretic and nonicteric, but presented with a few small ecchymoses about the legs, which were nontender. Notably, her conjunctivae were pale, and she had a right medial subconjunctival hemorrhage, which was already in the healing stage. No edema was present.

At this juncture the differential diagnosis for Mrs. C included but was not limited to: anemia, unspecified thrombocytopenia, dehydration, adrenal insufficiency, malignancy, and infectious process.

3. LABORATORY DATA The patient was sent for a complete blood count and comprehensive metabolic profile. The results showed: nonfasting glucose 124 mg/dL; blood urea nitrogen 11.5 mg/dL; creatinine 0.8 mg/dL; sodium 139 mEq/L; potassium 4.6 mEq/L; calcium 8.3 mEq/L (ref range 8.6-10.2); total bilirubin 0.7 mg/dL; alkaline phosphatase 124 units/L (ref range 35-104); alanine aminotranferease 307 units/L (ref range 0-31); aspartate aminotransferase 374 units/L (ref range 0-31); total protein 5.8 g/ dL (ref range 6.4-8.3); albumin 4.3 g/dL (ref range 3.4-4.8).

Mrs. C’s blood count was remarkable in that WBC was 18,000/ ml. The differential was set up manually and further revealed neutrophils at 23 (ref range 39.3-73.7%), and lymphocytes 68 (ref range 18.0-48.3%). Hemoglobin and hematocrit were 12.2% and 36.9%, respectively. There was modest thrombocytopenia. Confusing the issue, the laboratory technicians suspected blastocytes on microscopic evaluation and requested a pathology review. However, the official report from pathology was negative for blastocytes.

Lactate dehydrogenase was later found to be high, at 342 units/L, and a hepatitis panel was negative.

Given the patient’s abdominal pain, she was evaluated sonographically as well. It was normal except for a 2-cm

ovoid soft-tissue nodule anterior to the head of the pancreas.

Thereafter, she was sent for CT scan of the abdomen with contrast showing splenomegaly (Figure 1), which descended nearly to the iliac crest. Adenopathy was found in porta-hepatis and near the pancreas head, and there were some ascites surrounding the rectum.

Now suspect for leukemia or lymphoma, Mrs. C was set up for immediate consult with hematology/oncology. Through the specialist, she underwent further blood testing and bonemarrow biopsy. The bone-marrow aspiration was performed exactly two weeks after first presentation to our office, at the right posterior iliac crest. The hypercellular bone marrow was positive for chronic lymphocytic leukemia.

4. DISCUSSION Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of functionally incompetent lymphocytes. It is the most common leukemia in Western countries.1 There is a direct relationship between its incidence and patient age, and the median age of diagnosis is 70 years.2 The disorder is more common in men than women (ratio 1.7:1), and has a preponderance toward Caucasians over their African and Asian counterparts.3 About a quarter of patients with CLL are asymptomatic and the diagnosis is found incidentally on routine laboratory studies.4 Others may note painless swelling of lymph nodes (most commonly in the cervical, supraclavicular, and axillary regions), unintentional weight loss, fever >100.5°F, drenching night sweats, and extreme fatigue. Spleno- and hepatomegaly are seen on exam in a minority of patients as well.5 The skin is the most commonly involved nonlymphoid organ (leukemia cutis), presenting as an array of macules, papules, blisters, or ulcers.6 Naturally, lymphocytosis is the most prominent lab finding, with numbers reaching more than 100,000 μL possible.

Neutropenia, anemia, and thrombocytopenia, although commonly seen concurrent with CLL, are usually not severe.

The clinical course of the disease is variable, with survival rates ranging from two years to 20 years, with a median survival of approximately 10 years.7 The Rai system breaks down CLL into five stages starting with stage 0, characterized by lymphocytosis only. In stage I there are also enlarged lymph nodes; stage II features enlarged lymph nodes and hepatomegaly or splenomegaly; stage III notes anemia (hemoglobin <11 g/dL); and stage IV, thrombocytopenia (platelets <100,000/µL).8 The median survival from time of diagnosis is 150 months,

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

Clinical Challenge 101 months, 71 months, and 19 months, for stages 0, I, II, and III and IV combined, respectively.5 “Watchful waiting” is acceptable in lieu of treatment in an asymptomatic patient with CLL. Observation usually consists of quarterly laboratory evaluation and clinical examination.

However, if the patient presents in advanced disease, has a high tumor burden, repeated infections, or several of the aforementioned symptoms, then chemotherapeutic agents are initiated.

Early stage I CLL may be subject to localized radiation therapy.9 Chemotherapeutic treatment options include such purine analogs as fludarabine (Fludara) and pentostatin (Nipent), such alkylating agents as chlorambucil (Leukeran) and bendamustine (Treanda), and such monoclonal antibodies as rituximab (Rituxan) and alemtuzumab (Campath).

References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.

2. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by subtype: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105:1684-1692.

3. Hernández JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer. 1995;75:381-394.

4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456.

5. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975; 46:215-234.

5. SUMMARY

6. Agnew KL, Ruchlemer R, Catovsky D, et al. Cutaneous

Mrs. C was classified as CLL stage III/IV. She was given rituximab for three days followed by two days of bendamustine. After two cycles, she is in remission. At the time of publication, she is symptomatically improved. She still has mild leukopenia, but with no increase in lymphocytes. CT scan showed resolution of splenomegaly and lymphadenopathy.

Quarterly observation will continue. ■

150:1129-1135.

findings in chronic lymphocytic anemia. Br J Dermatol. 2004; 7. Boggs DR, Sofferman SA, Wintrobe MM, Cartwright GE. Factors influencing the duration of survival of patients with chronic lymphocytic leukemia. Am J Med. 1966;40:243-254.

8. Epstein AL, Marder RJ, Winter JN, et al. Two new monoclonal antibodies, Lym-1 and Lym-2, reactive with human B-lymphocytes and derived tumors, with immunodiagnostic and immunotherapeutic potential. Cancer Res. 1987;47:830-840.

9. Morrison WH, Hoppe RT, Weiss, LM, et al. Small lymphocytic lymphoma.

J Clin Oncol. 1989;7:598-606.

“You have to learn to relax, even though I’m creeping you out.”

58 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

Ms. Tinge is a physician assistant at Alton Internal Medicine in Alton, Ill.

“Very funny.”

CME CE

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

■ COMPLETE THE POSTTEST: Page 74

■ ADDITIONAL CME/CE: Pages 34, 69

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

CASE #1

Isolated areas of darkening skin AMANDEEP SANDHU AND JULIA R. NUNLEY, MD

A man, aged 28 years, came to the clinic complaining of skin darkening on his arms. Although he reported that this color change might have been present for a long time, his wife commented that it became more noticeable while on their recent honeymoon in the Caribbean. Employed as an informaticist at a local medical center, he was not routinely spending extended lengths of time in the sun. The man had no significant medical history, and the only medication he took was ibuprofen on an as-needed basis following sporadic workouts.

What is your diagnosis? Turn to page 60

CASE #2

Dirty-appearing truncal eruption ERIN L. REESE, MD

Over the course of several months, an otherwise healthy 17-year-old woman developed an asymptomatic and progressively worsening rash over her torso. Topical emollients and antifungal creams provided no improvement in her condition. Physical examination revealed hyperpigmented, thin papules with a faintly verrucous surface coalescing into reticulate plaques over the woman’s central and inframammary chest, flanks, and back. KOH preparation of skin scrapings from the involved areas was negative for yeast or fungal forms.

What is your diagnosis? Turn to page 61 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 59

CME CE

CASE #1

Dermatology Clinic

Pigmentary demarcation lines

Pigmentation is a highly variable and diverse trait in human populations; depending on race, genetics, and environmental factors, there is a broad range of skin colors. Considerable variability is frequently found even within the same race. Furthermore, such areas of the body as the genital region, elbows, and knees tend to be naturally darker than others.

Skin color is determined by the production of melanin in the melanocytes that originate in the neural crest and migrate to the epidermis during the second month of gestational development. Melanocytes produce and package melanin into melanophages, an intracellular organelle.

A phagocytic process distributes these melanophages to the epidermal keratinocytes. Melanin granules provide keratinocytes with color and UV light protection, as they typically surround the nucleus, absorbing and reflecting UV radiation and thereby protecting the nuclear DNA from damage. The size, number, maturity, and arrangement of melanosomes within keratinocytes ultimately determine an individual’s skin color.1 Since all races have the same number of melanocytes, color variations are related to these specific characteristics of the melanosomes.

Although genetically predetermined, skin color can vary depending on sun exposure and various physiologic conditions. Exposure to UVA light alters the oxidized state of existing melanin, causing an immediate darkening. Because this oxidized state is unstable, this darkening fades quickly.

UVB light, however, causes keratinocyte DNA damage, stimulating melanocytes to produce more melanin. Melanin production takes time, so UVB exposure results in a delayed darkening, which lasts longer because it also takes time for this excess melanin to degrade. Physiologic states of excess melanocyte-stimulating hormone can also result in more melanin production; pigmentation may be generalized (as in Addison disease) or localized (as in pregnancy), depending on the condition; hyperpigmentation of the linea nigra, genitalia, areolae, and nipples is common in pregnancy.2 A curious variation in pigmentation that is not fully understood can be seen in many normal individuals.

One sees an abrupt linear transition between more- and less-pigmented skin. These pigmentary demarcation lines

(PDLs) are seen most commonly on the arms, legs, chest, back, and face.2 First described in a case series of Japanese women in 1913,3 PDLs are now considered a normal variant of pigmentation and are commonly seen in people of color. Individuals of African, Indian, and Japanese descent are frequently affected, and women may be more frequently affected than men.4-7 PDLs have a variety of manifestations but most often present as a bilaterally symmetric phenomenon. Typically, PDLs become visible during the first six months of life but may be present at birth or develop during puberty. PDLs can be affected by UV light and other physiologic stimuli of melanin production, such as pregnancy.2 Five common types of PDLs (types A-E) have been described.4 Other patterns ( types F-H) have recently been described on the face in Indian patients.1 Type A is the most common and has also been referred to as Voigt lines or lines of Futcher.

• Type A: Pigmentary change found over the upper anterior portion of arms, extending over the pectoral area • Type B : Appear during pregnancy on posteromedial portion of lower limb and typically regress postpartum • Type C : Vertical hypopigmented midsternal lines, extending from the clavicle to the inferior border of the sternum • Type D : Rare, posteromedial lines appearing along the spine • Type E : Bilateral hypopigmented streaks or bands over the chest in the zone between the mid-third of the clavicle and the periareolar skin • Type F: Hyperpigmented, symmetric, “V” shaped lines between the malar area and the temple • Type G : Hyperpigmented, symmetric “W” shaped lines between the malar prominence and the temple • Type H: Hyperpigmented, linear horizontal bands from the angle of the mouth to the lateral aspects of the chin.

The exact cause of PDLs is unknown. The observation that it occurs in 61% of family members supports the possibility that it is inherited in an autosomal dominant fashion; however, twin association has not yet been reported. The reported association with pregnancy and a higher prevalence in women support a hormonal theory.7 The color pattern of PDLs corresponds neither to Blaschko’s lines nor to a dermatomal pattern.2 Instead, the bilaterally symmetric nature suggests that PDLs follow cutaneous nerve patterns; it is speculated that PDLs exist where cutaneous innervation influences embryonic suture lines.1,5 Some

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

theories postulate that PDLs are an evolutionary remnant (i.e., production of more pigmentation in the dorsal skin allows improved sun protection).5 Disorders that should be considered when evaluating a patient with PDLs include exogenous ochronosis, postinflammatory hyperpigmentation, Riehl melanosis, and erythema dyschromicum perstans. Exogenous ochronosis may occur paradoxically in association with the use of high-dose topical hydroquinone, a bleaching agent, and results from deposition of homogentisic acid in the skin.8 Postinflammatory hyperpigmentation is a consequence of epidermal inflammation triggering excessive melanin. Riehl melanosis, which is similar in presentation to facial PDLs, is attributable to a contact dermatitis from cosmetic use and typically resolves with discontinuation of the inciting agent. Erythema dyschromicum perstans, sometimes referred to as ashy dermatitis, presents as blue-gray macules on the chest, head, and neck and is more frequently seen in Hispanics.

Some patients seek treatment of PDLs because of cosmetic concerns.9 Type B lines are the only category of PDLs that spontaneously regress. Use of sunscreen, avoidance of sunlight, and glycolic acid peels show only negligible change in skin color, which reverts to its previous state within months of stopping treatment.1 Very little data are available for other modes of intervention. A 2005 study reported a 70% reduction of the hyperpigmented area in a single patient treated with a Q-switched alexandrite laser.6 This laser produces photoacoustic and photomechanical destruction of the melanin-laden cells within the dermis; subsequent phagocytosis by melanophages provides melanin removal.

Although potentially promising, no therapeutic options have yet shown consistent efficacy in treating PDLs. The patient in this case required only the reassurance that this was a benign, common, and normal condition.

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

References 1. Somani VK, Razvi F, Sita VV. Pigmentary demarcation lines over the face.

Indian J Dermatol Venereol Leprol. 2004;70:336-341. Available at www.ijdvl. com/text.asp?2004/70/6/336/13473.

2. James WD, Meltzer MS, Guill MA, et al. Pigmentary demarcation lines associated with pregnancy. J Am Acad Dermatol. 1984;11:438-440.

3. Matzumoto S. Uber eine eigentumliche Pigmentverteilung an den Voidtschen Linien (Beitrag zur kenntnis der Voigtschen Grenzen). Arch Dermatol Syph (Berlin). 1913;118:157-164.

4. James WD, Caster JM, Rodman OG. Pigmentary dermarcation lines: a population study. J Am Acad Dermatol. 1987;16:584-590.

5. Mintz S, Velez I. Pigmentary demarcation lines (Futcher lines): an orofacial case. Quintessence Int. 2010;41:873-875.

6. Bukhari IA. Effective treatment of Futcher’s lines with Q-switched alexandrite laser. J Cosmet Dermatol. 2005;4:27-28.

7. Gupta LK, Kuldeep CM, Mittal A, et al. Pigmentary demarcation lines in pregnancy. Indian J Dermatol Venereol Leprol. 2005;71:292-293. Available at www.ijdvl.com/text.asp?2005/71/4/292/16630.

9. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Am J Clin Dermatol.

2001;2:213-217.

9. Kumari R, Laxmisha C, Thappa DM. Pigmentary demarcation lines associated with pregnancy. J Cosmet Dermatol. 2006;5:169-170.

All electronic documents accessed August 15, 2012.

CASE #2

CARP

This patient’s presentation was highly suspicious for confluent and reticulated papillomatosis of Gougerot and Carteaud (CARP). CARP is an uncommon dermatosis of unclear etiology. The initial description of this condition was published in 1927 by the physicians for whom it is named. Since then, others have attempted to further delineate the clinical features and pathogenesis, but the rarity of the condition has limited these studies.1 The first report of clearance with antibiotics was documented in 1965,2 and response to antibiotics is now considered one of the distinguishing features of CARP. CARP is most common in adolescents and young adults.

Women and those with darker skin tend to be more susceptible.

However, CARP has been seen in all ages and races.3 CARP classically presents as slowly progressive, asymptomatic, velvety to slightly verrucous, sessile brown papules coalescing into reticulated thin plaques, most commonly on the trunk, neck, and axillae. Many variations in appearance and distribution have been described, but these are encountered much less frequently.3 CARP is most often misdiagnosed as acanthosis nigricans or tinea versicolor. There is a broad differential diagnosis

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 61

CME CE

Dermatology Clinic

for CARP, but this discussion will focus on these two common dermatoses and how they can be differentiated from CARP. Acanthosis nigricans is a velvety hyperpigmentation of the skin of the neck, axillae, and, less often, trunk. The appearance is not reticulated as in CARP. Acanthosis nigricans is strongly associated with obesity, insulin resistance, and dyslipidemia. There are no well-established systemic assocations in individuals with CARP. Tinea versicolor is a common eruption of the trunk caused by overgrowth of pityrosporum. Tinea versicolor consists of variably hyper- or hypopigmented macules on the trunk that produce a pow-

Although generally unnecessary, skin biopsy is indicated if the presentation is unusual or response to treatment is poor. dery scale on scraping. If you suspect CARP, it is important to exclude a diagnosis of tinea versicolor. A KOH preparation of involved skin will be negative in cases of CARP and will yield yeast and hyphal forms with the “spaghetti and meatballs” morphology in cases of tinea versicolor. Tinea versicolor can be treated effectively with antifungals, while CARP does not respond to this therapy.

The following diagnostic criteria have been proposed for CARP: (1) scaling brown macules and patches, at least part of which appear reticulated and papillomatous; (2) involvement of the upper trunk and neck; (3) fungal staining of scales is negative; (4) no response to antifungal treatment; and (5) excellent response to minocycline (Dynacin, Minocin, Myrac).1 Although generally unnecessary, skin biopsy is indicated if the presentation is unusual or response to treatment is poor.

Biopsy will show papillomatosis, hyperkeratosis, and mild acanthosis of the epidermis, with variable hyperpigmentation of the basilar layer.1,3,4 Acanthosis nigricans has similar histopathologic features, so correlation with clinical findings is important. Special stains for fungus are usually negative.

There are many hypotheses regarding the etiology of CARP. Some propose that this is a disorder of keratinization. In support of this, CARP has been shown to improve with medications (i.e., retinoids, vitamin D analogues) that act to normalize keratinization.3 Others believe Pityrosporum species to be causative, but proving this is difficult, as pityrosporum are part of the normal skin flora. In addition, tinea versicolor is characterized by an excess of pityrosporum and is a clinical mimicker of CARP, so it has been argued that this association may have

been the result of misdiagnosis.3 CARP has also been linked to endocrinopathies, UV light exposure, and even genetic inheritance.3 However, none of these proposed mechanisms explain the response to antibiotics. More recently, a newly described actinomycete was cultured from skin scrapings of an individual with CARP, and this bacterium was shown to be suspectible to antibiotics commonly used to treat CARP. However, it is difficult to prove causality, as it remains unclear whether this organism is simply a contaminant, commensal, or truly pathogenic.2 Additionally, antibiotics may be exerting an anti-inflammatory rather than an antibacterial effect, which is why more studies are needed to determine exactly how and why they work in this condition.

The treatment of choice for CARP is minocycline 100 mg orally b.i.d. for at least four weeks. Several other antibiotics have shown efficacy including doxycycline, clarithromycin (Biaxin), fusidic acid, erythromycin, and azithromycin (Zithromax, Zmax)—all requiring a several-week course of therapy for improvement/clearance.5 Other treatments that are reported to be beneficial are topical retinoids, oral retinoids, topical vitamin D analogues, and even swabbing with 70% alcohol.3,6 There is the possibility of a slight risk of recurrence after treatment; if this occurs, a repeat course of antibiotics is usually effective.

The patient in this case received a two-month course of minocycline with near complete resolution of the rash. ■ Dr. Reese is assistant professor in the Department of Dermatology at Virginia Commonwealth University in Richmond.

References 1. Davis MD, Weenig RH, Camilleri MJ. Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis. A study of 39 patients and a proposal of diagnostic criteria. Br J Dermatol. 2006;154:287-293.

2. Natarajan S, Milne D, Jones AL, et al. Dietzia strain X: a newly described Actinomycete isolated from confluent and reticulated papillomatosis. Br J Dermatol. 2005;153:825-827.

3. Scheinfeld N. Confluent and reticulated papillomatosis : a review of the literature. Am J Clin Dermatol. 2006;7:305-313.

4. Tamraz H, Raffoul M, Kurban M, et al. Confluent and reticulated papillomatosis: clinical and histopathological study of 10 cases from Lebanon.

J Eur Acad Dermatol Venereol. 2011. [Epub ahead of print].

5. Jang HS, Oh CK, Cha JH, et al. Six cases of confluent and reticulated papillomatosis alleviated by various antibiotics. J Am Acad Dermatol.

2001;44:652-655.

6. Berk DR. Confluent and reticulated papillomatosis response to 70% alcohol swabbing. Arch Dermatol. 2011;147:247-248.

62 THE CLINICAL ADVISOR • SEPTEMBER 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.

Stinging nettle

© PHOTO RESEARCHERS, INC. / LAWRENCE LAWRY

With a name like stinging nettle, consumers are not likely to sample this perennial plant. Urtica dioica, a herbaceous flowering plant, is considered the porcupine of the plant world. Its leaves and stems have tiny, needlelike fibers,that act like hypodermic needles, injecting histamine and other chemicals into the skin. The needles pump a mixture of acetylcholine, histamine, serotonin, moroidin, leukotrienes, and formic acid into the epidermis, producing a stinging or burning sensation.1

Background Stinging nettle spreads rapidly by means of an aggressive network of underground rhizomes.2 The plant has long, serrated, soft green leaves and bears green/brown flowers.2 A dense coating of hairy spines on the exterior leaves give the plant its name.The stinging nettle has a long history of medicinal uses. As early as the 10th century, the stinging nettle was used to treat arthritis and other inflammatory conditions.3

Science One of the more studied uses of stinging nettle extract is in the treatment of benign prostatic hyperplasia (BPH). BPH affects more than 90% of men by age 70 years and treatment costs exceed $11 billion annually in the United States.4 Prescription medication for BPH first became available with the introduction of finasteride (Proscar) in 1992.5 The drug’s mechanism of action is based on its ability to inhibit 5 alpha-reductase.This

enzyme reduces dihydrotestosterone concentrations, which, in turn, reduces the size of the prostate gland and improves urinary flow rates. In a head-to-head trial, nearly 500 men with BPH were randomized to treatment with a nettle root extract or finasteride.At the end of a six-month trial, there was no statistically significant difference between the two groups, indicating that stinging nettle was at least as effective as finasteride.6 In a randomized, double-blind, placebo-controlled trial, 246 BPH patients were given 459 mg dry extract of stinging nettle roots or placebo.The men were followed for one year and monitored for both safety and efficacy. Efficacy was determined by patient’s self-rated scores at baseline and at the end of the trial on the International Prostate Symptom Score (IPSS) instrument. At the end of one year, IPSS scores for the stinging-nettle patients had dropped an average of six points, whereas the scores in the placebo arm dropped slightly more than four points.7 In another trial, researchers enrolled more than 600 men with BPH and randomized them to placebo or to nettle extract. Both groups were monitored for 18 months. At the end of six months,

64 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE 81% of the nettle patients reported subjective improvement in symptoms, compared with only 16% of patients in the placebo group.8 In addition, at the end of the trial, post-void residuals dropped more than 50% in the treatment group, compared with no change in the placebo group.8 Stinging nettle also is used for the treatment of osteoarthritis.The mechanism of action for oral use is thought to involve the ability of nettle leaf extracts to reduce or block the formation of tumor necrosis factor-alpha and other inflammatory cytokines.3 When used topically as the actual plant, the needlelike structures produce a stinging sensation that is a counter-irritant and also decreases the activity of substance P, a neuropeptide that enhances the transmission of pain impulses.3 Few randomized, placebo-controlled clinical trials have been conducted using nettle extracts for osteoarthritis, but bench research has verified their chemical activity as anti-inflammatory products.

Researchers in an open-label trial recruited 23 patients with radiographically diagnosed osteoarthritis and administered a topical cream of nettle extract twice daily for two weeks. Using the standardized Western Ontario and MacMaster Universities Osteoarthritis Index, participants’ scores were compared from baseline to post study. A mean reduction of 4.17 points (24%) was noted, indicating improved function and reduction of pain.9

the treatment of osteoarthritis can take the form of a crushed fresh leaf applied to the area for 30 seconds b.i.d. for one week or a compounded cream containing nettle extract, also applied b.i.d.3

Summary Stinging nettle’s mechanism of action is similar to that of other accepted botanical preparations, such as capsaicin.Thus, stinging nettle is a viable alternative for use in mild-to-moderate BPH, osteoarthritis, and other pro-inflammatory ailments. ■ Urtica dioica, or stinging nettle, is used to treat osteoporosis.

References 1. Skidmore-Roth, L. Mosby’s Handbook of Herbs & Supplements, 3rd ed. St. Louis: Mosby, Inc., Elsevier;

Caution should be used when applying, as stinging nettle can interact with certain classes of drugs, including antidiabetics.

2006:762-776.

2. Herbs with similar side effects as stinging nettle.

Quality Health website. Available at www.qualityhealth .com/health-encyclopedia/alternative-medicine/ herbs-similar-side-effects-stinging-nettle.

3. Stinging nettle (Urtica dioica) page. Natural Standard website. Available at www.naturalstandard.com/ databases/stingingnettle.

4. Fenter TC, Naslund MJ, Shah MB, et al. The cost of treating the 10 most prevalent diseases in men 50 years of age or older. Am J Manag Care. 2006;612:S90-S98.

5. Proscar. Daily Med: Current Medication Information website. Available at dailymed.nlm.nih.gov/dailymed /drugInfo.cfm?id=66361.

6. Sökeland, J. Combined sabal and urtica extract com-

Safety, interactions

pared with finasteride in men with benign prostatic hyperplasia: analysis of prostate volume and therapeutic

Stinging nettle has the potential for significant allergic reactions when used topically or taken orally. It has few interactions when used topically, but oral use can cause gastric disturbance.3 If taken in large quantities, stinging nettle has been shown to reduce BP, lower blood glucose levels, and induce urinary tract contractility.3 As such, it can potentially interact with such drugs as antihypertensive and antidiabetic agents.3

outcome. BJU Int. 2000;86:439-442.

7. Schneider T, Rübben H. Stinging nettle root extract (Bazoton-uno) in long-term treatment of benign prostatic syndrome (BPS). Results of a randomized, double-blind, placebo controlled multicenter study after 12 months.

Urologe A. 2004;43:302-306.

8. Safarinejab MR. Urtica dioica for treatment of benign prostatic hyperplasia: A prospective, randomized, double-blind, pacebo-controlled, crossover study. J Herb Pharmacother. 2005;5:1-11.

9. Rayburn K, Fleishbein E, Song J, et al. Stinging nettle cream for osteoarthritis. Altern Ther Health Med.

For oral use in treatment of BPH, equivalents of 300 mg extract taken once or twice daily for up to a year have been used in studies.3 Topical use for 68 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

2009;15:60-61.

All electronic documents accessed on August 15, 2012

© THINKSTOCK

How supplied, dosage

CME CE

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

■ COMPLETE THE POSTTEST: Page 74

■ ADDITIONAL CME/CE: Pages 34, 59

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

Asymptomatic skin lesions JOE MONROE, PA-C

CASE #1

CASE #2

A man, aged 38 years, presented with an asymptomatic, colorless, 3-cm lesion on his thigh. The lesion has been present since birth and has remained unchanged in size and appearance. The man was concerned because a friend had recently been diagnosed with amelanotic melanoma.

The patient was otherwise in good health with no similar lesions elsewhere and no personal or family history of diseases manifesting on the skin. Punch biopsy of the lesion was performed and read as normal with no pathologic changes.

Asymptomatic skin changes began almost one year before this 53-year-old woman sought evaluation in dermatology. Her lesions, located on her upper shoulder, had also grown appreciably, adding to her concern. The woman’s primary-care provider had diagnosed the lesions as a fungal infection, but the oxiconazole (Oxistat) cream she applied to the lesions twice a day had provided no relief. OTC hydrocortisone 0.5% cream was ineffective as well. The patient was in good health otherwise and reported no difficulty swallowing, or breathing.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 69

CME CE

CASE #1

Dermatologic Look-Alikes

Nevus anemicus

A diagnosis of melanoma can have a ripple effect among friends and family, generating concern over a wide range of lesions, even ones present for many years. Fortunately, the appearance and congenital nature of the lesion in this case narrow the differential considerably, making the diagnosis of nevus anemicus (NA) all but certain. First described in 1906, NA has since been investigated thoroughly. The condition appears to represent a localized vascular anomaly in which the defect is an increased sensitivity to catecholamines. For this reason, NA is perhaps best termed a “pharmacologic nevus,” a conclusion also supported by donor-site dominance in autograft exchange transplantation studies.1 In addition to being quite pale, NA macules are predictably cooler than surrounding skin; tend to vary in size and shape; and cannot be turned red by trauma, cold, heat, or even with injection of such vasodilatory agents as bradykinin, serotonin, histamine, acetylcholine, or nicotine.2 However, a sympathetic block or local intradermal injection of the potent alpha-adrenergic blocking agent pilocarpine (Salagen) allows the normal triple response of Lewis, strongly supporting the pharmacologic basis for what is seen with NA.3 NA is unusual but not rare. The condition is usually congenital, often presenting in early childhood with characteristic asymptomatic depigmented macules with irregular margins. The macules can measure up to 10 cm and can involve the presence of satellite lesions as well. Typically an incidental finding on routine physical examination, NA is slightly more common in women but does not appear to have any racial predilection. The lesions can be solitary or multiple, linear or rounded, and are easily overlooked. They can be found on every part of the body, including the lips, but are most commonly seen on the upper trunk.

In certain cultures, especially in India, any loss of pigment in a child is viewed with alarm. This reaction is partly due to concern about possible Hansen disease (one type of which can present in such a manner), and partly because the darker skin of these people makes such lesions stand out so starkly, thus representing a “defect” for the entire world to see, including the parents of a potential spouse in an arranged marriage.

The finding of such a depigmented patch suggests several possible diagnoses, particularly vitiligo. Several useful techniques to separate NA from its lookalikes have evolved. For example, Wood’s lamp examination accentuates vitiligo and other truly depigmenting conditions but makes NA lesions all but disappear. Diascopy (i.e., viewing the lesion through a transparent glass slide or clear plastic convex instrument pressed to the skin) causes NA to merge with surrounding skin, while the margins of a vitiligo lesion remain distinguishable. Unlike vitiligo, biopsy of NA lesions shows a normal amount of melanin and, remarkably, normal vasculature, even under electron microscopy.

Biopsy is seldom necessary for diagnosis.

Nevus depigmentosus (ND) is another type of lesion in the differential for NA, but this condition is often dermatomal, is accentuated with Wood’s lamp examination, and turns red with vigorous stroking. ND is thought to represent a developmental defect of fetal melanocytes. Unlike the depigmented lesions of a type of Hansen disease, none of the other items in the differential for NA demonstrate a loss of sensation in the surface of the lesions.

As mentioned above, NA lesions are unique in their lack of an erythematous response to a linear scratch across the lesion, while surrounding normal skin reacts as expected.

This sets NA lesions apart from such other items in the differential as the depigmented macules seen with tuberous sclerosis, neurofibromatosis, or as one component of phakomatosis pigmentovascularis. A form of Hansen disease can also involve acquired areas of depigmentation, as can a large number of such other conditions as cutaneous T-cell lymphoma, tinea versicolor, nevus depigmentosus, lupus, and sarcoidosis.4,5 NA lesions are devoid of such epidermal change as atrophy, scaling, or other textural defects. This characteristic sets them apart from such other depigmenting conditions as lichen sclerosus et atrophicus and morphea.6 Along with the other methods of differentiation, the lack of surface detail of NA also helps to set it apart from other items in the differential.

Treatment of NA lesions is neither necessary nor possible, except as a means of camouflage or other cover-up. Again, biopsy is seldom necessary since a clinical diagnosis is usually apparent. The diagnosis of NA has no pathologic implication but does occasionally require definitive diagnosis with biopsy and copious patient and/or family reassurance. In this case, the congenital nature of the lesion and its history of stability allowed ready differentiation from amelanotic melanoma,6-8 and no treatment was required.

70 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

CASE #2

Lichen sclerosus et atrophicus

The majority of cases of lichen sclerosus et atrophicus (LS&A) involve the genitals, but as this case illustrates, the condition can occur on nongenital skin as well. A chronic inflammatory condition, LS&A manifests with porcelain-white papules and plaques demonstrating epidermal atrophy. Genital cases outnumber nongenital by 5:1, with the vast preponderance (6:1) of cases appearing in women. Oral involvement has also been described but is thought to be rare.9 LS&A is also seen on the penile glans, where it is termed balanitis xerotica obliterans (BXO). This skin disease presents most often in uncirmcumcised individuals, first as atrophy and whiteness of focal areas of the glans. BXO may then move proximally to result in a phimotic balanitis of the foreskin and, in the extreme, meatal stenosis. Also seen with vaginal LS&A, meatal stenosis is thought to be responsible for cases that present with dysuria.10 LS&A represents infi ltration of the papillary dermis with altered fibroblastic function, leading to fibrosis and ultimately to atrophy of the upper dermis and epidermis.

The more common genital involvement with LS&A is usually symptomatic (in women more so than in men), predominantly with burning and itching. The symptoms frequently progress in severity in women (e.g., bleeding, obliteration of the labia minora, and stenosis of the introitus with resulting dyspareunia). Occasionally, the perivaginal inflammation becomes so severe that it results in the formation of bullae.9 In a fully developed case of LS&A, sharply demarcated hypopigmentation and atrophy outline the perivaginal and perianal areas, sparing the perineum, resulting in an hourglass or figure-eight appearance. This manifestation can be difficult to appreciate unless specifically sought on inspection of the area.10 Early on in extragenital LS&A, white polygonal papules and plaques marked by evenly spaced comedolike plugs correspond to obliterated appendiceal ostia. These plugs disappear over time, giving way to a smooth, porcelainlike, and shiny atrophic surface on which focal telangiectasias and purpura can be seen. The sizes of the lesions vary from multiple tiny guttate papules to confluent lesions involving large areas of the upper trunk.

LS&A is thought to result from autoantibodies to the glycoprotein extracellular matrix protein 1, which may be associated with histological evidence of vasculitis. The role of hypoxia and ischemia in the initial cellular and vascular damage is supported by the relative lack of vascular endothelial growth factor expressed in affected skin.11 Because LS&A and morphea can coexist and have similar histology, some authors posit that they are essentially the same condition.

Reports have long surfaced in Europe of the association of LS&A with Borrelia burgdorferi, but polymerase chain reactionbased studies in this country have failed to corroborate this theory. Although no definite cause is known, several authors have mentioned the possibility of an autoimmune basis.12 Under the microscope, the histologic picture of LS&A shows an interface dermatitis with vacuolar alteration of the keratinocytes early on. With maturation, the epidermis thins, and rete ridges are effaced. At the outset, the upper

The use of powerful topical steroids has proven so successful that it has drastically changed the therapeutic picture. dermis is remarkably edematous, but this is transformed by dense homogenous fibrosis as the lesions mature.

The differential diagnosis for LS&A includes vitiligo, lichen planus, discoid lupus, atrophoderma of Pasini and Pierini, and morphea. When found on the genitals especially, the differential also includes extramammary Paget disease, Bowen disease, and erythroplasia of Queyrat, among others.10 The appearance of the patientâ&#x20AC;&#x2122;s lesion in this case was characteristic enough to allow visual identification, and treatment with clobetasol 0.05% cream every other day was instituted. While this strategy should at least stop the progression of the condition, the asymptomatic nature of extragenital LS&A often obviates treatment.

The use of such powerful topical steroids as clobetasol cream has proven so successful that it has drastically changed the therapeutic picture. Nevertheless, control is still a more likely outcome than is cure. Mild cases in young girls may clear on their own.

BXO is also treated with class 1 or 2 steroid creams or ointments but frequently requires circumcision to control the phimotic process. Pathologic examination of the removed tissue also serves to rule out focal cancerous transformation,

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ SEPTEMBER 2012 71

CME CE

Dermatologic Look-Alikes

which can also be seen in vaginal involvement, where it manifests as focal ulceration.12-14 Referral to urology may be necessary in cases of associated meatal stenosis. In cases of significant introital stenosis, a gynecologic consult is advised. LS&A in young girls can mimic sexual abuse; refer to pediatrics for evaluation if necessary.15 ■ Mr. Monroe is a physician assistant specializing in dermatology at Dawkins Dermatology in Oklahoma City.

References 1. Greaves MW, Birkett D, Johnson C. Nevus anemicus: a unique catecholamine-dependent nevus. Arch Dermatol. 1970;102:172-176.

Available at archderm.jamanetwork.com/article.aspx?articleid=531720.

2. James WD, Berger TG, Elston DM. Dermal and subcutaneous tumors.

In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:582.

3. Ahkami RN, Schwartz RA. Nevus anemicus. Dermatology. 1999;198:327-329.

4. Castori M, Rinaldi R, Angelo C, et al. Phacomatosis cesioflammea with unilateral lipohypoplasia. Am J Med Genet A. 2008;146A:492-495.

5. Mountcastle EA, Diestelmeier MR, Lupton GP. Nevus anemicus. J Am Acad Dermatol. 1986;14:628-632.

6. Alagheband M, Engineer L. Nevus anemicus. Skin and Aging. 1998;11:60.

7. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilation of preexisting vessels. J Am Acad Dermatol. 1997;37:523-549.

8. Medscape Reference. Nevus anemicus. Available at emedicine .medscape.com/article/1084329-overview.

9. Medscape Reference. Lichen sclerosus et atrophicus. Available at 10. James WD, Berger TG, Elston DM. Lichen planus and related condi-

“Of course I want to have kids, Claire— just not all the time.”

tions. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed.

Philadelphia, Pa.: Saunders-Elsevier; 2006:227-229.

11. Chan I, Oyama N, Neill SM, et al. Characterization of IgG autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Clin Exp Dermatol.

2004;29:499-504.

12. De Vito JR, Merogi AJ, Vo T, et al. Role of Borrelia burgdorferi in the pathogenesis of morphea/scleroderma and lichen sclerosus et atrophicus: a PCR study of thirty-five cases. J Cutan Pathol. 1996;23:350-358.

13. Bjekic´ M, Šipetic´ S, Marinkovic´ J. Risk factors for genital lichen sclerosus in men. Br J Dermatol. 2011;164:325-329.

14. Jones RW, Sadler L, Grant S, et al. Clinically identifying women with vulvar lichen sclerosus at increased risk of squamous cell carcinoma: a case-control study. J Reprod Med. 2004;49:808-811.

15. Meffert JJ, Davis BM, Grimwood RE. Lichen sclerosus. J Am Acad Dermatol. 1995;32:393-416.

All electronic documents accessed August 15, 2012.

72 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

emedicine.medscape.com/article/1123316-overview.

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Log on to www.ClinicalAdvisor.com/CartoonContest and write your own caption for this drawing. We’ll pick three finalists, and then you vote for your favorite online. If you win, you get a framed copy of your cartoon.

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POSTTEST

CE

Expiration date: September 2013

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

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

CREDITS: 0.5

Dermatology Clinic

Dermatologic Look-Alikes

page 59

page 69

Case #1: Pigmentary demarcation lines

Case #1: Nevus anemicus

1. What describes the category of pigmentary demarcation lines (PDLs) that spontaneously regress? a. Appears during pregnancy on posteromedial portion of lower limb b. Pigmentary change found over the upper anterior portion of arms c. Vertical hypopigmented midsternal lines extending from the clavicle d. Rare, posteromedial lines appearing along the spine 2. Which treatment has shown consistent efficacy for PDLs? a. Liberal use of sunscreen b. Avoidance of direct sunlight c. Glycolic acid peels d. None of the above Case #2: Confluent and reticulated papillomatosis 3. What is a distinguishing characteristic of confluent and reticulated papillomatosis (CARP)? a. Most commonly found on the extremities b. Fungal staining of scales is negative c. Often associated with obesity and dyslipidemia d. Appears as hyper- or hypopigmented macules on the trunk 4. What is the treatment of choice for CARP? a. Ciprofloxacin (Cipro, Proquin) b. Amoxicillin c. Metronidazole (Flagyl) d. Minocycline (Dynacin, Minocin, Myrac)

1. One characteristic of nevus anemicus (NA) is that it a. Tends to vary in size and shape b. Is generally warmer than surrounding skin c. Presents as a dark-pigmented lesion d. Is most commonly seen on the scalp 2. A biopsy of NA lesions shows a normal amount of melanin, which helps distinguish it from a. Tinea versicolor b. Discoid lupus c. Vitiligo d. Sarcoidosis Case #2: Lichen sclerosus et atrophicus 3. What is the clinical appearance of lichen sclerosus et atrophicus (LS&A)? a. Discoid lesions that are plaquelike in character b. Porcelain-white papules and plaques with epidermal atrophy c. White to reddish-brown lesions covered with dustlike scale d. Small red patches with well-defined raised borders 4. What is the treatment of LS&A to stop its progression? a. High-potency topical steroid cream b. Topical tretinoin c. Systemic corticosteroid d. UVB phototherapy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermSept2012

74 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

CME

POSTTEST Expiration date: September 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 October 2011. 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 59

page 69

Case #1: Pigmentary demarcation lines

Case #1: Nevus anemicus

1. What describes the category of pigmentary demarcation lines (PDLs) that spontaneously regress? a. Appears during pregnancy on posteromedial portion of lower limb b. Pigmentary change found over the upper anterior portion of arms c. Vertical hypopigmented midsternal lines extending from the clavicle d. Rare, posteromedial lines appearing along the spine 2. Which treatment has shown consistent efficacy for PDLs? a. Liberal use of sunscreen b. Avoidance of direct sunlight c. Glycolic acid peels d. None of the above Case #2: Confluent and reticulated papillomatosis 3. What is a distinguishing characteristic of confluent and reticulated papillomatosis (CARP)? a. Most commonly found on the extremities b. Fungal staining of scales is negative c. Often associated with obesity and dyslipidemia d. Appears as hyper- or hypopigmented macules on the trunk 4. What is the treatment of choice for CARP? a. Ciprofloxacin (Cipro, Proquin) b. Amoxicillin c. Metronidazole (Flagyl) d. Minocycline (Dynacin, Minocin, Myrac)

1. One characteristic of nevus anemicus (NA) is that it a. Tends to vary in size and shape b. Is generally warmer than surrounding skin c. Presents as a dark-pigmented lesion d. Is most commonly seen on the scalp 2. A biopsy of NA lesions shows a normal amount of melanin, which helps distinguish it from a. Tinea versicolor b. Discoid lupus c. Vitiligo d. Sarcoidosis Case #2: Lichen sclerosus et atrophicus 3. What is the clinical appearance of lichen sclerosus et atrophicus (LS&A)? a. Discoid lesions that are plaquelike in character b. Porcelain-white papules and plaques with epidermal atrophy c. White to reddish-brown lesions covered with dustlike scale d. Small red patches with well-defined raised borders 4. What is the treatment of LS&A to stop its progression? a. High-potency topical steroid cream b. Topical tretinoin c. Systemic corticosteroid d. UVB phototherapy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermSept2012

74 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

ADDITION OF MYOCARDIAL PERFUSION IMAGING TO STANDARD EXERCISE TESTING FOR INITIAL DIAGNOSIS MAY NOT IMPROVE OUTCOMES FOR WOMEN WITH SUSPECTED CORONARY ARTERY DISEASE Level 2: Mid-level evidence Guidelines from the American Heart Association recommend standard treadmill exercise testing of symptomatic women as an initial evaluation for suspected coronary artery disease (CAD) (Circulation. 2005;111:682-696). Exercise testing in combination with myocardial perfusion imaging (MPI) to diagnose CAD is known to have better sensitivity and specificity than standard exercise testing (Am J Cardiol. 1999;83:660-666).

Despite the absence of data showing a difference in clinical outcomes, some clinicians prefer exercise testing with MPI as the initial test when evaluating women.

A randomized trial, What is the Optimal Method for Ischemic Evaluation in Women (WOMEN), investigated the value of adding MPI to exercise testing for initial diagnosis in 824 symptomatic women (Circulation. 2011;124:1239-1249).

Women with typical or atypical angina (if aged 50 to 60 years) or nonanginal symptoms (if aged 60 years or older) were randomized to standard exercise treadmill test alone vs. exercise treadmill test plus MPI, and were followed for two years. The primary endpoint was incidence of major cardiac adverse events, a composite of cardiovascular mortality and hospitalization for acute coronary syndrome or heart failure.

Results were normal for 64% of initial exercise tests in the exercise-test-alone group and for 91% of MPI tests in the MPI group. Follow-up MPI testing was performed in 18% of the exercise alone

group, while 9% of the MPI group had repeat MPI. In an analysis of 93.7% of the randomized women at two years, there were no significant differences in major cardiac adverse events (1.7% vs. 2.3%) or in hospitalization for chest pain (3% vs. 4%). Additionally, there were no significant differences in the rates of angina-free status at two years (60.4% vs. 64.9%, respectively).

Systematic reviews have found that CRT may reduce mortality and hospitalization in patients with QRS prolongation.

76 THE CLINICAL ADVISOR â&#x20AC;˘ SEPTEMBER 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

BENEFIT OF CARDIAC RESYNCHRONIZATION THERAPY FOR HEART FAILURE MAY BE LIMITED TO PATIENTS WITH SEVERE QRS INTERVAL PROLONGATION Level 2: Mid-level evidence Current guidelines from the American College of Cardiology and the American Heart Association recommend cardiac resynchronization therapy (CRT) for patients with NYHA class III or IV heart failure symptoms who have an ejection fraction <35% and a QRS interval >120 milliseconds, and are in sinus rhythm (ACC/AHA Class I, Level A recommendation, (Circulation.

2009;119:1977-2016). Systematic reviews have found that CRT may reduce mortality and hospitalization in patients with QRS prolongation, in patients with class III-IV symptoms (Health Technol Assess. 2007;11:iii-iv, Ann Intern Med. 2004;141:381-390) and patients with class I-II symptoms (Ann Intern Med. 2011;154:401-412).

Continues on page 79

The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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PA WANTED

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Director – Physician Associate Program Yale School of Medicine is seeking a Director of the Physician Associate Program. The successful candidate will lead a talented faculty to prepare graduates for leadership roles in patient care, education, research and health care administration. Applicants must demonstrate potential for creative leadership locally and nationally, and scholarship in fields related to physician associate practice.

Yale School of Medicine is one of the nation’s premier institutions for patient care, medical training and research. With 28 academic departments and strong institutional support for clinical and basic science research, the school is among the handful of leading recipients of funding from the National Institutes of Health.

Yale University is an affirmative action/equal opportunity employer. Yale values diversity in its faculty, staff, and students and strongly encourages applications from women and members of underrepresented minority groups.

Applicants are requested to forward a letter of interest and CV to: Walter N. Kernan, MD, Professor of Medicine Suite 515, 2 Church Street South, New Haven, CT 06519 walter.kernan@yale.edu

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PHYSICAN ASSISTANT GENERAL SURGERY / MINNESOTA Excellent opportunity exists for a qualified Physician Assistant to work in General Surgery at Sanford Health in Bemidji, MN. The expected schedule is Monday through Friday with 1:8 call. This position involves time in the OR assisting the surgeons. Graduation from an accredited APP program and current certification required. One year experience in clinical practice is preferred but not required.

Live and work in a community that offers exceptional schools, a state university with NCAA Division I hockey and community symphony and orchestra. With over 500 miles of trails and 400 surrounding lakes, this active community was ranked #27 by Outdoor Life Magazine.

Enjoy a fulfilling lifestyle and rewarding career.

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

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

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For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 â&#x20AC;˘ Fax: 727.445.9380 â&#x20AC;˘ E-mail: ca@russelljohns.com

PA WANTED

PA WANTED

Department of Physician Assistant Studies

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

Physician Assistant Program

2 Full-Time Faculty Positions The University of Arkansas for Medical Sciences (UAMS) is seeking motivated and innovative individuals for faculty positions at a developing program.

We are searching for team-oriented faculty members to develop a dynamic and collaborative program. Clinical practice opportunity and tuition assistance for advanced degrees is available.

Minimum qualifications include graduation from an accredited physician assistant program, Masterâ&#x20AC;&#x2122;s degree (Doctoral degree strongly preferred), current NCCPA certification, 2-3 years of clinical experience as a practicing PA, teaching experience in PA education strongly preferred, and eligibility for licensure in the state of Arkansas.

Evaluation of applications will begin immediately and will continue until the position is filled. Please send a curriculum vitae and letter of interest electronically or by mail to: Patricia J. Kelly, PhD, MMSc, PA-C Chair, Dept. of Physician Assistant Studies College of Health Professions University of Arkansas for Medical Sciences 4301 W. Markham St., #772 Little Rock, AR 72205-7199 501-686-7211 (office) kellypatriciaj@uams.edu UAMS is an inclusive Equal Opportunity and Affirmative Action Employer committed to excellence.

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 Masterâ&#x20AC;&#x2122;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; masterâ&#x20AC;&#x2122;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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78 THE CLINICAL ADVISOR â&#x20AC;˘ SEPTEMBER 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

A new systematic review examined data from randomized trials that provided subgroup analyses of patients stratified by severity of QRS prolongation (Arch Intern Med. 2011;171:14541462). QRS intervals 120-149 milliseconds were classified as moderately prolonged and intervals >150 milliseconds as severely prolonged. Analyses included 1,738 patients with class III-IV symptoms (from two trials; 64% with severe prolongation) and 4,228 patients with class I-II symptoms (from three trials; 60% with severe prolongation).

The primary outcome in all trials was a composite of adverse clinical events including mortality and hospitalization.

CRT was associated with reduced risk of adverse clinical events in patients with severely prolonged QRS intervals in the overall analysis (risk ratio [RR] 0.6, 95% CI 0.53-0.67) and in analyses of patients with class III-IV symptoms (RR 0.67, 95% CI 0.57-0.8) and patients with class I-II symptoms (RR 0.47, 95% CI 0.37-0.6). In patients with only moderately prolonged QRS intervals, there were no significant differences in risk overall or in either symptom subgroup.

ULIPRISTAL ACETATE CONTROLS UTERINE BLEEDING AND REDUCES DISCOMFORT IN WOMEN WITH SYMPTOMATIC FIBROIDS Level 1: Likely reliable evidence Uterine fibroids can cause pain and heavy bleeding and are a common indication for hysterectomy, but little evidence exists to guide fibroid management (AHRQ Research Report, March 2011). The gonadotropin-releasing hormone agonist leuprolide acetate has been shown to reduce uterine volume and fibroid size prior to surgery (Cochrane Database Syst Rev. 2001;2:CD000547), but it may also increase the incidence of hot flushes and reduce bone mineral density. Two recent trials, PEARL I and PEARL II, evaluated the efficacy of ulipristal acetate (Ella), a selective progesterone receptor modulator, in women planning to have surgery for symptomatic fibroids.

In the PEARL I trial, 242 women (mean age 42 years) with excessive uterine bleeding were randomized to ulipristal acetate (5 mg vs. 10 mg orally once daily) vs. placebo for up to 13 weeks (N Engl J Med. 2012;366:409-420). All women received iron supplementation and were eligible to have fibroid surgery after the end of the treatment period.

Excessive uterine bleeding was defined as a score >100 on the pictorial blood-loss assessment chart (PBAC) (0 to >500 scale with higher score indicating greater bleeding).

At 13 weeks, uterine bleeding was controlled (defined as PBAC score <75) in 91% of women taking ulipristal 5 mg,

© PHOTO RESEARCHERS, INC. / DR. NAJEEB LAYYOUS

Evidence-Based Medicine

Uterine fibroids (shown) can cause menorrhagia, anemia, and infertility.

in 92% taking ulipristal 10 mg, and in 19% taking placebo (p <0.001, NNT 2 for each ulipristal dose vs. placebo).

Amenorrhea rates (PBAC <2) were 73% for ulipristal 5 mg, 82% for ulipristal 10 mg, and 6% for placebo (p <0.001, NNT 2 for each ulipristal dose vs. placebo). Both ulipristal doses were associated with reduced discomfort (p <0.001).

There were no significant differences in surgical rates or in adverse events. The most common adverse events reported in the ulipristal groups were headache and breast pain.

The PEARL II trial compared the same two daily doses of oral ulipristal for 13 weeks vs. three monthly intramuscular injections of leuprolide acetate 3.75 mg in 301 women (mean age 40 years) with symptomatic fibroids (N Engl J Med. 2012;366:409-420). Women received supplemental iron at the discretion of the treating clinician and were eligible for surgery after treatment. Rates of controlled uterine bleeding were non-significantly higher for ulipristal: 90% for ulipristal 5 mg, 94% for ulipristal 10 mg, and 86% for leuprolide (not significant) in an intention-to-treat analysis. The 10-mg ulipristal dose was associated with significantly greater bleeding control vs. leuprolide in a per-protocol analysis (p=0.03, NNT 12). Incidence of hot flushes was significantly lower in both ulipristal groups (11% for ulipristal 5 mg, 10% for ulipristal 10 mg, 40% for leuprolide, p<0.001, NNT 4 for each ulipristal dose vs. leuprolide). There were no significant differences in pain reduction, surgical rates, or severe adverse events. Leuprolide was associated with significantly greater reduction in uterine volume.

Neither trial was designed to address differences in surgical rates or in surgical outcomes after treatment. Ulipristal is currently available only in a 30-mg tablet. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • SEPTEMBER 2012 79

COMMENTARY Jeanne S. Sluk, BSN, RN, is a nurse practitioner student at Carlow University in Pittsburgh, Pa.

Help kids who are bullied or bullies Bullying can begin as early as kindergarten, and it can affect all children regardless of race, gender, and socioeconomic status. According to a November 2010 article by Bob Roehr, about 25% of high-school students have reported being bullied, 13% of those students have considered suicide, and 8% of those who considered suicide admitted to attempting suicide (www.pasap.org/protected/ articleView.aspx?iid=5G0AP0&dasi=3PYI, accessed August 15, 2012).

Jessica Henderson Daniel, PhD, a psychologist at Boston Children’s Hospital, notes the multiple types of bullying (www.childrenshospital.org/views/august06/what_makes_a_bully_p.html, accessed

Counsel parents to have the child practice how to look a bully in the eye, stand tall, walk away, and speak in a firm voice.

August 15, 2012): Physical bullying occurs when one individual gains power over another through kicking, punching, hitting, or other physical attacks. In relational bullying, gossip or rumors may be spread about the targeted person, or the person may be excluded from social situations. Peer sexual harassment is characterized by unwanted and/or inappropriate sexual touching and/or language that creates a hostile and unsafe environment for the victim.

In stereotyping, bullying takes place because of the victim’s race, ethnicity, religion, disability, sexual orientation, or gender identity. Finally, cyber-bullying is delivered through email, text messages, or such social networks as Facebook or Twitter.

The American Academy of Pediatrics (AAP) offers some ideas that health-care providers can share with the parents or guardians of children who are being bullied (www.healthychildren .org/English/safety-prevention/at-play/pages/ Bullying-Its-Not-Ok.aspx, accessed August 15, 2012): • Ask the child: “How are things at school?

“Does anyone get picked on or bullied?”

• Listen to the child’s fears and concerns.

• Teach the child how to respond to the bullies.

Have the child practice how to look a bully in the eye, stand tall, walk away, and speak in a firm voice. Teach him or her to make such statements as, “I don’t like what you are doing,”

80 THE CLINICAL ADVISOR • SEPTEMBER 2012 • www.ClinicalAdvisor.com

and “Please do not talk to me like that.” Also teach the child how to ask for help.

• Encourage the child to make friends.

Children who are loners are more likely to get bullied.

• Support activities that interest the child, such as sports, scouting, or music groups.

• Notify school officials of any bullying problems and work with them to fi nd solutions.

• Help children’s self-esteem by letting them know that they are valued and cared for.

Health-care providers also can evaluate and educate the bullies themselves. Parents or guardians can help change their child’s bullying behavior by taking steps recommended by the AAP: • Set firm and consistent limits on the child’s aggressive behaviors. Make sure that the child knows bullying is not acceptable.

• Be a positive role model for the child.

• Show the child that he or she can reach a desired goal without teasing, threatening, or hurting someone.

• Use effective, nonphysical discipline with the child, such as loss of privileges.

• Help the child understand how bullying hurts other children.

• Develop practical solutions with others.

Work with school officials, teachers, and the parents of the bullied child to find positive ways to stop the bullying. ■

Laugh your way to a $100 prize Enter The Clinical Advisor’s Cartoon Contest Every month The Clinical Advisor surveys its readers to determine which articles they find most relevant — and which cartoons give them the biggest chuckle. We use the feedback to keep our readership high, which in turn keeps ad exposures high. All you have to do is browse through The Clinical Advisor and guess which two cartoons readers will like the most. Is there a more fun way to make $100?

The two cartoons clinicians will rate the funniest in the September issue of The Clinical Advisor are: (Indicate first choice with a “1” and second choice with a “2”)

1st prize

_____

page 13, left

_____ page 46, bottom

If you guess the top two cartoons, you will receive a $100 American Express gift cheque.

_____

page 13, right

_____ page 54, left

_____

page 32, left

_____ page 54, right

_____

page 32, right

_____ page 72, top

_____

page 46, top

_____ page 72, middle

_____

page 46, middle

_____ page 72, bottom

2nd prize If you guess only the top-ranked cartoon, you will receive a $40 American Express gift cheque.

Name (please print)

3rd prize If you guess only the second-ranked cartoon, you will receive a $25 American Express gift cheque.

Company

Address

Signature Limited to persons in the advertising and pharmaceutical industries.

One entry per person per issue. Please detach and send no later than October 15, 2012.

Index to Advertisers AMERICAN LIFELINE INC Florajen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C4

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NOVO NORDISK NovoLog Journal . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Victoza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 PFIZER Lyrica DPN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Lyrica FM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Children’s Advil . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

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