October 2012 Clinical Advisor

THE CLINICAL ADVISOR • OCTOBER 2012

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

NEWSLINE

■ Seizure med for cough ■ Prescribing for the elderly ■ Walnuts and male fertility ADVISOR FORUM

■ Causes of high creatine ■ Schizophrenia in pregnancy ■ TSH and bone density LEGAL ADVISOR

Incorrect triage causes a critical delay in the ED

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■ CE Feature: Part 2 of

NEONATAL CCHD SCREENING PAGE 28

VOLUME 15, NUMBER 10

■ Dermatologic Look-Alikes

WHITE PATCH ON THE TONGUE PAGE 67 ■ Special Feature

Osteoarthritis and Rheumatoid Arthritis 2012

| O C TO B E R 2 012 | www.ClinicalAdvisor.com

WHAT TO DO WITH A POSITIVE

HEPATITIS C TEST Cirrhosis (shown) is one potential consequence of chronic hepatits C.

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

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 3

CONTENTS OCTOBER 2012

NEWS AND COMMENT 10

74

57

16

28

■ An intensely itchy rash spread from a woman’s back to her upper chest.

Newsline ■ Seizure drug relieves chronic cough ■ Antibiotics may lead to weight problems ■ And more

■ A man undergoing radiation treatment

developed painful facial vesiculopustules.

62

Alternative Meds Update The hormone DHEA is taken for its supposed anti-aging properties.

67

CME/CE Dermatologic Look-Alikes Can you differentiate between these white plaques in the oral cavity?

73

CME/CE Posttest

Commentary

FEATURES

CME/CE Dermatology Clinic

Gabapentin improves chronic cough 10

What to do with a positive hepatitis C test If the virus cannot be eradicated, aim to slow progression, lower risk of liver cancer, and improve quality of life.

ADVISOR FORUM

CME/CE CCHD screening guidelines: Implementation of standardized protocols The second of a three-part series designed to improve detection of critical congenital heart disease in newborns.

42

Consultations ■ Causes of elevated creatine ■ Treating psychiatric illness

during pregnancy ■ Thyroid hormone and bone density ■ Osteoporosis in a patient taking

Small red spots spread from back to chest 57

anti-seizure medication

DEPARTMENTS 44 38

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

48

Legal Advisor A woman in the ED with chest pain is placed in the wrong triage category.

52

Clinical Challenge Headache, photophobia, nausea, and an unsteady gait develop after a checkup.

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While there are many diabetes complications,

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

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “ If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.

For full guideline, visit www.aan.com/guidelines.

Level A=Established as effective, based on at least 2 Class I studies.

Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria.

AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia.

PBP485919-01

© 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

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LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

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

Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)*

Dose Regimen

≥60

150

300

450

600

BID or TID

30–60

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

Newsline O C T O B E R 2 0 12

Add walnuts to improve sperm vitality page 14

Daily aspirin lowers overall cancer mortality page 14

Antibiotics in infancy may lead to high BMI later page 12

© THINKSTOCK

Seizure drug relieves chronic cough

GABAPENTIN now appears to also be an effective treatment for refractory chronic cough.

Similarities between central reflex sensitization in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might help such cough, explained Nicole M. Ryan, PhD, and colleagues in a Lancet report published online ahead of print. To establish the efficacy of the drug for this use, the team randomized 32 clinic outpatients in Australia to gabapentin and an additional 30 to placebo.

Gabapent i n sig n i f ica nt ly improved cough-specific quality of life, cough severity, and cough frequency compared with placebo.

After eight weeks of treatment, 74% of patients in the gabapentin group reported an improvement in Leicester Cough Questionnaire score >1.3 (the smallest change in score considered to be clinically

Gabapentin reduced cough severity and frequency.

meaningful), compared with 46% of the patients on placebo.

Another drug has also been found to have a potential role in cough relief, in this case for people with idiopathic pulmonary fibrosis (IPF): the anti-inflammatory agent thalidomide (Thalomid).

Used as a treatment for morning sickness and as a sleep aid in the 1950s, thalidomide was taken off the market in 1961 after it was shown to cause severe birth defects. Today, the agent is prescribed with strict controls to treat multiple myeloma, kidney cancer, and other diseases, but had not been tested in the context of lung disease until the recent work of a team led by Maureen R. Horton, MD. Constant cough is a hallmark of IPF, the risk of which increases with age.

In the small study, 20 men and women with IPF (all aged 50

years and older; mean age 67 years) took either low-dose thalidomide pills or a placebo for three months, and then switched to the opposite arm for another three months after a two-week washout period. Coughing frequency decreased by approximately 63% during thalidomide therapy, and the ability to perform daily activities improved by about 20%. These improvements were noticed within two weeks of beginning thalidomide treatment.

Coughs returned when treatment was discontinued.

Constipation, dizziness, malaise, and other side effects were reported by 74% of the study participants during thalidomide treatment, and by 22% during placebo treatment.

Horton and associates described their findings in Annals of Internal Medicine.

Top 10 chronic conditions in residential-care facilities According to the CDC, almost 60% of persons living in residential-care facilities have hypertension.

Source: National Survey of Residential Care Facilities, 2010.

60 50 40

Hypertension

Osteoporosis

Dementias

Diabetes

Heart disease

COPD

Depression

Cancer

Arthritis

Stroke

30 20 10 0

57%

42%

10 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

34%

28%

27%

21%

17%

15%

11%

11%

Newsline ADMINISTERING antibiotics to infants younger than age 6 months may predispose them to becoming overweight at some point in childhood.

In a population-based study of 11,532 children born in the United Kingdom, during 1991 and 1992, being exposed to antibiotics before reaching age 6 months was associated with consistent increases in BMI from age 10 months to age 38 months.

However, antibiotic use only appeared to have this effect in very young babies; exposures later in infancy (6–14 months) showed no association with BMI, but children who received antibiotics at 15 to 23 months of age had somewhat greater BMI for their age and gender by age 7 years.

“Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and defi ne lifecourse implications for body mass and cardiovascular risks,” wrote Leonardo Trasande, MD, MPP, and coauthors in their report for International Journal of Obesity, published online ahead of print.

Similar findings were recorded when young mice were given subtherapeutic antibiotic therapy (STAT) (Nature. 2012;488:621626). In this form of treatment, antibiotics are administered to increase weight gain in cattle, swine, sheep, chickens, turkeys, and other farm animals.

After approximately six weeks of treatment, mice undergoing

© THINKSTOCK

Antibiotics may lead to weight problems

Exposure to antibiotics in infancy led to increased BMI.

STAT had gained about 10% to 15% more fat mass than had mice that did not receive any antibiotics. In addition, bone density was significantly increased in STAT mice early in development, and some hormones related to metabolism were affected by the exposure to antibiotics.

ADDING THE common carotid intima-media thickness (CIMT) to the Framingham Risk Score can slightly improve 10-year risk prediction of fi rst heart attack or stroke, but this improvement is unlikely to be of clinical importance.

Evidence that the common CIMT measurement improves the prediction of absolute cardiovascular risk has been inconsistent. To determine whether the measurement can, in fact, bolster 10-year risk prediction of first-time MI or stroke above that of the Framingham Risk

Improvement is unlikely to be of clinical importance.

Score, researchers conducted a meta-analysis of 14 populationbased cohorts, involving data on 45,828 individuals.

The analysis revealed that 4,007 first-time MIs or strokes occurred during a median follow-up of 11 years. The Framingham Risk Score was applied to create a model of absolute 10-year risk of such occurrences. When common CIMT addition was added to the score, the net reclassification improvement was small. In those at intermediate risk, the net reclassification improvement was 3.6% in all persons, with no differences

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

between men and women (JAMA. 2012;308:796-803).

In a separate study published in the same issue of JAMA, however, coronary artery calcium, anklebrachial index, high-sensitivity C-reactive protein, and family history were all found to be independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors (2012;308:788-795). Coronary artery calcium was found to provide superior discrimination and risk reclassification compared with other risk markers.

© PHOTO RESEARCHERS, INC. / BSIP

Carotid thickness adds little to risk prediction

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Statements have not been evaluated by the Food and Drug Administration.

This product is not medicinal and is not intended to diagnose, treat, cure or prevent any disease.

©2012 American Lifeline, Inc. All rights reserved. 0812

Newsline RECENT USE of daily aspirin was associated with slightly lower cancer mortality, but this reduction may be more modest than that observed for long-term aspirin use, say researchers.

An examination of the relationship between daily aspirin use and overall cancer mortality among 100,139 men and women with no history of the disease demonstrated that between 1997 and 2008, 5,138 participants died of cancer. Compared with no use, daily aspirin use at baseline was linked with slightly lower cancer mortality, regardless of duration of daily use.

The estimated reduced risk of cancer mortality among individuals taking daily aspirin compared with persons who did not take daily aspirin was 16%.

This outcome was much lower than the 37% reduction in cancer mortality observed during a five-year follow-up period in a recent analysis. Nevertheless, acknowledged the investigators,

Daily aspirin use reduced cancer mortality by about 16%.

“Even a relatively modest benefit with respect to overall cancer mortality could still meaningfully influence the balances of risk and benefits of prophylactic aspirin use” ( J Natl Cancer Inst.

2012;104:1208-1217).

Another study, published online ahead of print in Journal of Clinical Oncology, indicated differences in aspirin’s impact on a specific form of cancer. In that research, Kevin S. Choe, MD, and colleagues found the risk of prostate cancer–specific mortality to be significantly lower among 2,175 men who were receiving anticoagulants (warfarin [Coumadin, Jantoven], clopidogrel [Plavix], enoxaparin [Lovenox], and/or aspirin) than among 3,780 men who were not. The study participants had all undergone radical prostatectomy or radiotherapy for localized adenocarcinoma of the prostate. The risks of disease recurrence and bone metastasis were also significantly lower among the anticoagulant users.

Walnuts improve semen quality Adding walnuts to a Western-style diet improved sperm vitality, motility, and morphology in a recent study. Walnuts are a rich source of dietary polyunsaturated fatty acids (PUFAs), which are important in sperm maturation and membrane function.

As Wendie A. Robbins and colleagues described in Biology of Reproduction, they recruited 117 healthy men, aged 21 to 35 years, to test whether 75 g/day of wholeshelled walnuts would benefit semen quality

in men who routinely consumed a Westernstyle diet. By the end of the 12-week study, the 59 men who had been randomly assigned to add walnuts to their usual diet had a significant improvement in sperm vitality, motility, and morphology. The other 58 men, who continued their usual diet but avoided tree nuts, exhibited no such changes.

Various PUFAs also increased significantly in the blood serum of the walnut-eaters but not in that of the other men.

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

A PPROX I M ATELY ON E in five prescriptions to elderly persons in primary care is inappropriate, a systematic review of studies has found.

Inappropriate medication prescribing can refer to prescriptions that introduce a significant risk of an adverse drug-related event when there is evidence for an equally or more effective alternative agent, or can refer to underprescribing, misprescribing, or overprescribing of a given medication. All 19 studies selected for review measured inappropriate medication prescription for elderly patients (aged 65 years and older) in the primary-care setting. Seven of the studies were conducted in the United States.

The meta-analysis uncovered a median rate of inappropriate medication prescriptions of 20.5%.

Propoxyphene (Darvon, PP-Cap) had the largest median rate of inappropriate prescriptions at 4.52%, followed by doxazosin (Cardura) at 3.96%, diphenhydramine at 3.3%, and amitriptyline (Elavil, Endep, Vanatrip) at 3.2%.

Diphenhydramine and amitriptyline were the most common inappropriately prescribed medications with high-risk adverse events, whereas propoxyphene and doxazosin were found to be the most commonly prescribed medications with lowrisk adverse events (PLoS One. 2012;7:e43617). ■

© THINKSTOCK

Aspirin reduces cancer deaths Improper prescribing in elderly

FEATURE: LYNN RAPSILBER, MSN, ANP-BC, APRN

What to do with a positive hep C test If the treatment goal of viral eradication cannot be met, strive to slow disease progression, lower risk of liver cancer, and improve quality of life.

© PROF. P.M. MOTTA / UNIV. “LA SAPIENZA”, ROME / PRI

Phagocytes (yellow), associated with tissue damage, appear in the cells of a liver affected by cirrhosis.

A

ccording to the CDC, there are approximately 180 million hepatitis C antibody-positive individuals worldwide, 4.1 million of whom reside in the United States.

With 3 million to 4 million new cases diagnosed per year, hepatitis C is among the fastest growing illnesses. There are more than 7 million carriers of the hepatitis C virus (HCV) and 2.7 million chronically infected individuals.

Approximately 12,000 people die from hepatitis C every year. The highest prevalence of the disease is among those aged 30 to 54 years.

Hepatitis C is often not recognized until asymptomatic persons are identified as HCV-positive.

Blood testing, first made available in 1992, is the only way to determine that an individual has hepatitis C. The treatment goal is viral eradication. If eradication cannot be accomplished, clinicians must slow disease progression, improve histology, decrease the risk of hepatocelluar carcinoma, and improve quality of life.

What is hepatitis C and who is at risk?

Hepatitis C (Flaviviridae hepacivirus) is a small, enveloped, single-stranded RNA virus. This virus mutates rapidly, so changes in the envelope proteins may help it invade the immune system. HCV does not incorporate itself into the host DNA, resulting in the ability to cure the infection indefinitely.

Acute hepatitis C refers to the first six months after infection. Between 60% and 70% of individuals infected with HCV develop no symptoms during this acute phase. In the minority of 16 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

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HEPATITIS C

All persons should be screened for behaviors that place them at risk for hepatitis C infection as part of comprehensive health screening. patients, acute-phase symptoms may be mild and nonspecific.

Approximately 55% to 85% of persons with acute hepatitis C will remain infected. Signs and symptoms of acute hepatitis C infection include fatigue, fever, dark urine, clay-colored stools, abdominal pain, loss of appetite, nausea, vomiting, joint pain, and jaundice.

Hepatitis C can also be chronic and cause chronic liver disease that ranges from mild to severe, including cirrhosis and liver cancer. Liver disease associated with chronic hepatitis C is usually insidious and progresses slowly, without any signs or symptoms for several decades.

HCV can be transmitted through: • Transfusions and organ transplants received before 1992 • IV drug use • Intranasal cocaine use • Sharing personal items with an infected person (e.g., razors, shavers, and toothbrushes) • Tattooing and body piercing • High-risk sexual activity • Clotting factors received before 1987 • Occupational exposures (health-care professionals) • Mother-to-infant contact (rare, but still considered a risk).

Testing and screening

The American Association for the Study of Liver Diseases (AASLD) recommends that all persons be screened for behaviors that place them at risk for hepatitis C infection as part of comprehensive health screening. However, universal testing is not required at this time.

The groups most strongly recommended for testing include: • Recent and current injection-drug users (even if they have only used once) • HIV-infected individuals • Hemodialysis recipients • Hemophilia patients who received clotting factor concentrates before 1987 • Patients with unexplained elevated liver abnormalities • Recipients of organ transplant or transplantation before July 1992 • Children born to women infected with hepatitis C • Health-care workers who have had a needle exposure • Current sexual partners of individuals with hepatitis C • Persons who have used illicit noninjected drugs (e.g., intranasal cocaine).

The CDC has updated its guidelines for testing individuals born between 1945 and 1965. This group accounts for 73% of HCV mortality, and 35% of these undiagnosed “baby boomers” have already progressed to advanced stages of liver disease. A one-time test for HCV is recommended without prior ascertainment of risk.

HCV antibody testing is sensitive and inexpensive. AntiHCV screening assays include the enzyme immunoassay (EIA) or the enhanced chemiluminescence immunoassay (CIA).

Positive results are reportable and should be confirmed with a repeat test. The recombinant immunoblot assay (RIBA), a more specific serologic anti-HCV assay, is no longer used.

Once the antibody test is positive, HCV-polymerase chain reaction (PCR) RNA test measures how much HCV is in the bloodstream.

In addition to the viral load measurement or the PCR RNA testing, genotyping should be performed. Of the six genotypes, genotypes 1, 2, and 3 are the most common.

Consequences of hepatitis C

Some of the consequences of chronic hepatitis C include hepatic fibrosis, cirrhosis, hepatocellular carcinoma, endstage liver disease requiring transplantation, and various extrahepatic manifestations.

Hepatitis C causes inflammation of the tissue. This results in fibrosis, which in turn leads to scarring. The scarring affects liver function, and cirrhosis develops, eventually leading to liver failure and ultimately transplant. About 30% of those with hepatitis C will experience liver scarring leading to potential cirrhosis. Hepatocellular carcinoma occurs in about 3% of the population infected with hepatitis C. This incidence has increased over the past two decades and is identified through imaging studies or the presence of jaundice and in elevated alpha-fetoprotein levels in the blood. Surgical resection or ablative procedures increase the chance for cure.

Extrahepatic manifestations of hepatitis C include: • Hematologic (anemia, and lymphoma) • Dermatologic (lichen planus and vasculitis) • Renal (glomerulonephritis and nephritic syndrome) • Endocrine (hypothyroidism and diabetes) • Neuropsychiatric disease • Ocular (corneal ulcer and uveitis) • Vascular (polyarteritis nodosa and necrotizing vasculitis) • Neuromuscular (arthralgias and arthritis) • Autoimmune (CREST syndrome).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 19

HEPATITIS C

If a patient is considering treatment and is unsure whether or not to proceed, a biopsy can document what liver damage has occurred.

Transmission

Avoiding transmission is one of the best ways to contain the spread of HCV infection. Advise individuals with hepatitis C to: avoid sharing toothbrushes, razors, other shaving equipment, and nail files and clippers; avoid getting tattoos and piercings; do not donate blood, tissue, or semen; cover wounds to prevent contaminating others; discontinue illicit drug use; do not share needles. Because of the low sexual transmission rate, barrier protection is not needed in monogamous relationships; otherwise, safe-sex practices are warranted.

Alcohol and hepatitis C

The effects of alcohol on hepatitis C are well documented.

Alcohol consumption of greater than 50 g per day clearly increases the progression of hepatitis C fibrosis. Even daily consumption of less than 50 g appears to increase hepatitis C PCR RNA viral load levels.

Treatment eligibility

The AASLD recommends that all persons with chronic hepatitis C be considered candidates for treatment. Review all risks and benefits with the patient. Treatment is based on histology, symptoms, probability of viral eradication, and progression of disease—not just the alanine aminotransferase levels. Treatment is contraindicated in patients with: • Major uncontrolled depression • Solid organ transplant (e.g., kidney, heart, or lung) • Autoimmune hepatitis and other autoimmune conditions that could be worsened by treatment • Undiagnosed and untreated thyroid disease • Pregnancy unwillingness to comply with contraception • Severe hypertension, congestive heart failure, coronary artery disease, diabetes, or chronic obstructive pulmonary disease that is not well controlled • Hypersensitivity to any of the treatment medications, i.e., peginterferon alfa-2a (Pegasys) and alfa-2b (PEG-Intron), ribavirin (Copegus, Rebetol, RibaTab, Ribasphere), telaprevir (Incivek), Boceprevir (Victrelis).

proceed, a biopsy can document what liver damage has occurred and determine the grade of inflammation and the stage of liver fibrosis. Dental work must be completed prior to treatment. Vaccination for hepatitis A and B should be initiated and should not delay the start of treatment.

Predictors of treatment response include age (younger individuals have greater likelihood of response), sex (both males and females have the same rate of treatment response), race (blacks respond less favorably to treatment than do whites), and weight (higher BMI, insulin resistance, and fatty liver can hinder the ability to process medications that can help treatment response). Severe depression and anxiety and continued drug and alcohol use will impact the effectivenes of the medications. HIV-positive individuals who are coinfected with hepatitis C respond less favorably to treatment.

Treatment response

Treatment response for hepatitis C is measured by viral response. Rapid viral responders have no measurable virus at four weeks. Early viral responders have a >2 log drop at four weeks and no measureable virus at 12 weeks. Slow viral responders are not negative at week 12 but turn negative at week 24. Null responders have <2 log drop in viral load.

Sustained viral response is characterized by no measurable virus six months after treatment and is considered a cure.

Genotype used to be a factor in treatment response, but with the development of the new PIs, genotype 1 responses are equal or comparable to genotypes 2 and 3. The higher the

10%

2%

n=1,049

8%

80%

Work-up

The initial work-up of hepatitis C should include a complete medical, family, and social history; depression scale; and laboratory testing (Table 1). With the advent of the protease inhibitors (PIs), liver biopsy is not required. However, if a patient is considering treatment and is unsure whether to

Which risk factor is most likely to raise your suspicion for HCV infection?

POLL POSITION

Tattoos and piercings High-risk sexual activity IV drug use Cocaine use

For more polls, visit www.ClinicalAdvisor/polls

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

HEPATITIS C

TABLE 1. Initial hepatitis C workup Alpha fetoprotein blood test

Hepatitis B total antibody test

Antinuclear antibody test

Hepatitis B surface antigen test

Chemistry panel

HIV test

Complete blood count

Iron studies

Complete history

Partial thromboplastin time

Depression scale

Prothrombin time

Hepatitis A total antibody test

Thyroid studies

viral load the greater the virus to be killed, which can impede response. Adherence to treatment is favorable when there is a good patient/provider relationship; when adequate support systems are in place; when the patient is compliant with follow-up instructions, appointments, and lab draws; when the patient believes that treatment will be beneficial; when treatment is complete; and when the patient receives a thorough explanation of the costs associated with treatment.

Treatment recommendations

The current treatment recommendations for hepatitis C are based on genotype. Individuals with genotype 2 HCV receive peginterferon and ribavirin. Peginterferon helps fight the virus in two ways: (1) It helps healthy cells defend themselves against the virus; and (2) it strengthens the immune response, which helps the T and B cells fight off the virus. Peginterferon (alfa-2a and alfa-2b) is administered as subcutaneous weekly injections. Side effects of treatment include flulike symptoms, fatigue, headache, arthralgias and myalgias, fever, and chills. Other potential symptoms include anemia, diarrhea, nausea, worsening depression, mood instability, injection-site reaction, weight change, alopecia, increased susceptibility to infections, and insomnia.

Ribavirin is an antiviral that interferes with RNA metabolism and slows the growth of HCV when used together with peginterferon. Ribavirin is administered orally b.i.d. Side effects include nausea; hemolytic anemia; MI with anemia; and such pulmonary symptoms as dyspnea, infi ltrates, and pneumonitis. Ribavirin is teratogenic and can cause birth defects or death of an unborn child. Female patients and

PEER PERSPECTIVES

female partners of individuals being treated with ribavirin should not become pregnant during treatment or for six months after treatment has stopped.

Protease inhibitors

PIs give new hope to individuals infected with genotype 1 HCV. Eligibility includes those who are treatment-naïve, partial responders, relapsers, and null responders. PIs are given in conjunction with peginterferon and ribavirin. The response rates are quite phenomenal: 80% in treatment-naïve individuals; 75%-85% in relapsers; 50% in partial responders; and even 30% in null responders. There are two PIs available at this time.

Boceprevir. This medication is given orally 800 mg (four 200-mg tablets) t.i.d., every eight hours with food. Treatment is initiated with a four-week lead-in period of peginterferon and ribavirin alone; the triple therapy with boceprevir begins at week 5. Duration of therapy for treatment-naïve individuals depends on response. If a negative HCV PCR RNA is achieved at week 8 and week 12, treatments can cease at 28 weeks. Response-guided treatment (RGT) continues depending on whether the patient is below 100 IUs of viral load measurement at specific intervals. A treatment-naïve patient detected at eight weeks and negative at 12 and 24 weeks will complete boceprevir at week 36 but continue the peginterferon and ribavirin for a total of 48 weeks.

Previous partial responders and relapsers get the four-week lead in of peginterferon and ribavirin, followed by triple therapy for at least 36 weeks if negative viral-load measurements are found at weeks 8, 12, 24, and 36. A patient who had measureable viral load at week 8 but was below 100 IU/mL would continue treatment for a total of 36 weeks and then dual therapy with peginterferon and ribavirin for 48 weeks. Null responders and all cirrhotic patients get a four-week lead-in, followed by triple therapy with boceprivir, peginterferon, and ribavirin for a total of 44 weeks.

Any time the viral-load measurement is above 100 IU/mL, the treatment is discontinued.

Telaprevir. This medication is given orally 750 mg (two 375-mg tablets) t.i.d. every eight hours with a high-fat, 20-g

“In addition to anemia and lymphoma, thrombocytopenia should also be included in the hematologic effects of hepatitis C. Over the past 20 years, hepatitis C is the leading cause of isolated thrombocytopenia in my hematologic practice.”

Luther Glenn, MD, Rancho Mirage, Calif. (via ClinicalAdvisor.com)

24 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

HEPATITIS C

snack. RGT for telaprevir includes starting with triple therapy.

Therapy for treatment-naïve and previous relapsers includes all three medications up front (telaprevir, peginterferon, and ribavirin) for a period of 12 weeks. Depending on response, the treatment can end as early as 24 weeks or may continue for up to 36 weeks. Patients with cirrhosis may benefit from a full 48-week course. For a previous partial responder or null responder, prescribe triple therapy (telaprevir, peginterferon, and ribavirin) for 12 weeks, followed by 36 weeks of peginterferon and ribavirin alone. If viral load is nondetected at week 4 and week 12, discontinue the telaprevir and continue the peginterferon and ribavirin for a total response-week duration of 24 weeks. If the viral load is detectable but below 1,000 IU/mL at week 4 and week 12, continue the treatment to week 12, then order an additional 36 weeks of dual therapy with peginterferon and ribavirin for a total treatment duration of 48 weeks. If at any time the viral load measurement goes above 1,000 IU/mL, at week 4 or week 12, or detectable at week 24, the therapy is discontinued.

Managing side effects

Educate patients on the importance of adequate hydration and maximizing nutrition and energy-conservation strategies.

If possible, clinicians should work with patient’s employer to see about decreasing 12-hour shifts to eight hours to maximize energy conservation. It is imperative that patients undergoing treatment for hepatitis C be able to continue to work, as this provides a distraction from the side effects of the medication. Counseling, patient support groups, and/or referral for professional help should also be considered.

Advise patients to use moisturizer to prevent rashes and dry skin. Alopecia can be minimized through less-frequent hair manipulation. Antiemetics for nausea, hematologic support for anemia, and premedication with nonsteroidal anti-inflammatory drugs and alternating with acetaminophen for flulike symptoms is recommended.

During treatment monitoring, have the patient visit every other week for side-effect management, counseling, and review of lab data. Viral-load measurements throughout treatment as described by the PI treatment algorithms are recommended and should be adhered to for the futility rules.

Above all, no PI should be stopped once it is started. The chance of developing resistance to these medications rapidly increases with the omission of even one dose. It is essential that all patients take peginterferon and ribavirin with these medications as well, and they are not interchangeable.

Always stop the PI if the viral-load measurement continues to increase.

CLINICAL SLIDESHOW For more information on identifying hepatitis infection, visit ClinicalAdvisor.com/HepatitisSlideshow.

Patient selection for antiviral therapy

Clinicians must spend the time up-front to counsel and teach the patients. Explain that commitment is required for the full duration of treatment. Have patients sign a consent form agreeing to frequent blood testing, office visits, pregnancy prevention, and abstention from alcohol and drug use.

There is significant risk for medication reactions with PIs. Obtain a thorough medication review before starting these drugs. Several medications are contraindicated, including simvastatin (Zocor), St. John’s wort, and sildenafi l (Revatio, Viagra). Other medications require cautious use, including amlodipine (Norvasc), clarithromycin (Biaxin), methadone (Dolophine, Methadose), and zolpidem (Ambien, Edluar, Intermezzo, Zolpimist). See the Victrelis and Incivek pagackage inserts for a complete list of potential drug interactions.

The clinician’s role with any of the treatments described here is to support the patient through the process, foster a partnership in this unique opportunity to cure, and provide congratulations on the successes along the way. ■ Ms. Rapsilber is a nurse practitioner with Litchfi eld County Gastroenterology in Torrington, Conn.

Read on ■

Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and

treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.

■

Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and

treatment of hepatitis C. Hepatology. 2004;39:1147-1171.

■

Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of

genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology.

2011;54:1433-1444.

■

Victrelis (boceprevir) [package insert]. Merck & Co., Inc.; 2011. Available

at www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

■

Incivek (telaprevir) [package insert]. Vertex Pharmaceuticals; 2011.

Available at pi.vrtx.com/files/uspi_telaprevir.pdf.

All electronic documents accessed September 15, 2012.

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

CME CE

PROGRAM OUTLINE OCTOBER 2012

0.5 CREDITS

Page 28 FEATURE CCHD screening guidelines: Implementation of standardized protocols 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: • Analyze American Academy of Pediatrics, American Heart Association, and U.S. Department of Health and Human Services criteria for critical congenital heart disease (CCHD) screening of newborns • Assess recent clinical-trials data when considering pulse-oximetry screening for CCHD in newborns • Evaluate the role of the primary-care provider in employing pulse-oximetry screening for CCHD in newborns.

0.5 CREDITS

Page 57 DERMATOLOGY CLINIC Extremely pruritic rash on the back and chest Esther Stern, NP-C Esther Stern has no relationships to disclose relating to the content of this article.

Facial pustules after radiation treatment Adam Rees, MD Adam Rees, 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 67 DERMATOLOGIC LOOK-ALIKES White plaques in the oral cavity Kerri Robbins, MD and Damjan Jutric Kerri Robins, MD, and Damjan Jutric have no relationships to disclose relating to the content of this article.

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

Page 37, 73 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 October 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 • OCTOBER 2012 27

CME CE FEATURED COURSE

■ EDUCATIONAL OBJECTIVES : After completing the activity, the participant should be better able to: • Analyze American Academy of Pediatrics, American Heart Association, and US Department of Health and Human Services criteria for CCHD screening of newborns • Assess recent clinical trials data when considering pulse-oximetry screening for CCHD in newborns • Evaluate the role of the primary care provider in employing pulse-oximetry screening for CCHD in newborns ■ COMPLETE THE POSTTEST: Page 37 ■ ADDITIONAL CME/CE CREDIT: Pages 57, 67 Turn to page 27 for additional information on this month’s CME/CE courses.

This continuing medical education/continuing education (CME/CE) activity, CCHD Screening Guidelines: Implementation of Standardized Protocols, is the second in a three-part series directed to physicians, nurse practitioners and physician assistants. The exercise is 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: October 2012 Expiration Date: October 2013 Estimated time to complete the educational activity: 30 minutes This activity is supported by an educational grant from Covidien and jointly sponsored by Medical Education Resources (MER), Nurse Practitioner Associates for Continuing Education (NPACE), and Haymarket Medical Education (HME).

Target Audience: This activity has been designed to meet the educational needs of physicians, nurse practitioners (NPs), and physician assistants (PAs) in family practice, pediatrics, obstetrics, women’s health, neonatology, and cardiology specialties.

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

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

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

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

Disclosure Policy—NPACE It is the policy of Nurse Practitioner Associates for Continuing Education to ensure balance, independence, objectivity, and scientific rigor in all of its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that the participants may evaluate the objectivity of the presentations. In addition, any discussion of off-label, experimental, or investigational use of drugs or devices will be disclosed by faculty.

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty Reporting Financial Relationship Gerard R. Martin, MD, has no financial relationships to disclose.

Alex R. Kemper, MD, MPH, MS, has no financial relationships to disclose.

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

Name of Content Managers Reporting Financial Relationship Joe Kopcha, Marina Galanakis, Nick Zittell, Susan Basilico, and Anne Jacobson, of HME, have no financial relationships to disclose. Victoria C. Smith, MD, of Medical Education Resources has no financial relationships to disclose.

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

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

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

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

Jointly Sponsored by

Supported by an educational grant from:

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

TAKING THE PULSE OF NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE

CCHD screening guidelines: implementation of standardized protocols

© CORBIS ® IMAGES

C

Pulse oximetry is best used as an adjunct to the newborn physical exam.

ongenital heart disease (CHD) is a potentially devastating diagnosis that accounts for 24% of infant deaths due to congenital malformations.1 Early diagnosis and follow-up are essential first steps in preventing infant morbidity and mortality associated with cardiac defects. Timely care is particularly important for critical CHD (CCHD), a heterogenous group of disorders affecting 1.2 infants per 1,000 live births in the United States in which surgical or catheterbased therapy within the fi rst year of life is mandatory for survival. Despite the urgency of diagnosis, however, CCHD is missed in one in three affected newborns, increasing the risk of unrecognized hypoxemia, clinical deterioration, and life-threatening complications.

This second article of the educational activity, CCHD Screening Guidelines, is designed to provide guidance on the use of screening for CCHD using pulse oximetry to improve early detection in newborns across a range of care settings. The first article discussed the burden of CCHD and introduced the role of pulse oximetry as a simple, safe, and effective screening tool that improves the detection of CCHD when added to physical examination. Here, the second article in the series provides an in-depth examination of current guideline recommendations for universal CCHD screening with pulse oximetry, including strategies for implementing screening recommendations and establishing a medical home for infants who are found to have CCHD.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 29

CME CE

NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE

Rationale for CCHD screening using pulse oximetry

Several subtypes of CCHD lesions are ductal-dependent (Table 1). As a result, the affected neonate may not be symptomatic during the birth hospitalization because the ductus arteriosus has not closed prior to discharge. Closure of a patent ductus arteriosus can precipitate rapid clinical deterioration with potentially life-threatening consequences (i.e., severe metabolic acidosis, seizures, cardiogenic shock, cardiac arrest, or end-organ injury).2 In parts of the United States, hospital stays of 12 to 24 hours for uncomplicated vaginal births, and 48 to 72 hours for uncomplicated caesarean births, had become standard by the mid-1990s.3 One reason why CCHD may be missed in newborns, but certainly not the only reason, focuses on possible adverse outcomes of early discharge. Such concerns led the U.S. Congress to pass legislation in 1996 mandating that private insurers cover postnatal stays of at least 48 hours after a vaginal birth and 96 hours after a caesarean section.

However, four years later, the majority of newborn term infants were still being discharged “early.”4,5 Therefore, the newborn physical examination can miss CCHD, particularly in infants with subtle clinical signs.6 Half of all newborns with CCHD, particularly those with ductal-dependent defects, have no distinctive murmur.7 In many cases, symptoms of CCHD do not present until after hospital discharge.8 Indeed, one in three infants with a potentially life-threatening cardiac defect is discharged from the hospital nursery undiagnosed.9 Current estimates indicate that the diagnosis of CCHD is missed or delayed in 1 in 3,500 to 1 in 25,000 live births, depending on the type of defect.6,9-11 Diagnostic delays can prevent newborns with cardiac defects from receiving timely treatment, which in turn increases the risk of

complications and poor outcomes.7 Postponing treatment until newborns with CCHD are critically ill increases surgical mortality, prolongs hospital stays, and increases the risk of such serious adverse effects as neurological dysfunction.7 The goal of screening for CCHD using pulse oximetry is to increase the rate of detection prior to clinical deterioration in affected newborns.

Hypoxemia is a common feature of CCHD that results from the mixing of systemic and venous circulations or other circulatory defects (Table 1).8 Approximately 4 g to 5 g of deoxygenated hemoglobin is needed to produce visible hypoxemia, independent of the hemoglobin concentration.7 For the typical newborn with a hemoglobin concentration of 17.5 g/dL, cyanosis will become visible only when arterial oxygen saturation falls below 83%.12 For those with low hemoglobin concentration (eg, 13.5 g/dL), oxygen saturation must be <78% to produce visible cyanosis.12 Given these parameters, mild hypoxemia is often missed with visual assessment alone. Such factors as skin thickness, skin color, and perfusion can influence color, while such environmental factors as ambient light conditions can influence color perception.13 Indeed, a major limitation of the newborn physical examination is the inability for the human eye to detect important degrees of cyanosis.12 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%. The gap between normal oxygen saturation and visible cyanosis, approximately 95% to 80%, has been described as the cyanotic blind spot.14 Following delivery, newborns transition from fetal to neonatal circulation. During this time there is fluctuation in oxygen saturation levels. Oxygen saturation levels

TABLE 1. CCHD types and clinical characteristics Cardiac defect

Prevalence per 10,000 live births

Hypoxemia

Ductal-dependent

Hypoplastic left heart syndrome

3.3

All

All

Pulmonary atresia with intact septum

0.8

All

All

Tetralogy of Fallot

6.1

Most

Uncommon

Total anomalous pulmonary venous return

1.2

All

None

Transposition of the great arteries

4.0

All

Uncommon

Tricuspid atresia

0.5

All

Some

Truncus arteriosus

1.0

All

None

CCHD = critical congenital heart disease Source: Knapp AA, et al. Maternal and Child Health Bureau, U.S. Department of Health and Human Services. 2010.

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

typically stabilize within 24 hours.8 The median value measured at 24 hours at the lower extremity is 97.3%,15 or slightly lower at higher altitudes.16 Screening with pulse oximetry bridges the diagnostic gap in CCHD, where cardiac defects are not recognized despite prenatal ultrasound and newborn physical examination.17 In a prospective multicenter study of 48,348 newborns, 90 were diagnosed with CCHD. After the first physical examination and clinical observation during the first 24 hours of life, i.e., before pulse-oximetry screening, 80% of all CCHD had been diagnosed, leaving a diagnostic gap of 20%. In this study, all newborns also underwent screening at the age of 24 to 72 hours. 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 standardized screening protocol closed the CCHD diagnostic gap to 4.4%.17 Pulse oximetry is best used as an adjunct to the newborn physical examination, and is not meant to replace standard clinical judgment and physical assessment.18-21 Current screening recommendations BACKGROUND

The U.S. Department of Health and Human Services (HHS) Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) provides guidance to the Secretary of HHS about which conditions should be included in the recommended uniform screening panel (RUSP), and how to implement screening programs and follow-up care. Historically, screening has been limited to dried blood spot analysis to detect various endocrine, hematologic, and metabolic conditions. More recently, newborn hearing screening has been added.20 The current approach to universal CCHD screening reflects the efforts of multiple agencies and collaborative groups, with several important milestones (Table 2). In 2009, the American Academy of Pediatrics (AAP) and the American Heart Association (AHA) published a joint scientific statement describing the compelling reasons for utilizing pulse oximetry as part of the newborn clinical evaluation for CCHD.8 Based on the evidence at the time, however, the AAP/AHA statement stopped short of recommending universal screening. Instead, the AAP/AHA called for additional data on key issues that required further clarification, such as variability in arterial oxygen saturation during the first hours of life, appropriate thresholds for “normal” oxygen saturation, the influence of sensor placement and altitude on test performance, as well as appropriate implementation at the community hospital level.

In 2010, the SACHDNC recommended that CCHD be added to the RUSP, with the goal of identifying newborns with cardiac defects that may cause significant early morbidity and mortality associated with closing of the ductus arteriosus or other adverse physiologic changes.20 In particular, the SACHDNC identified seven types of CCHD lesions associated with hypoxemia (Table 1). The HHS Secretary was not ready to adopt the recommendation for universal CCHD screening at the time, however, pending an implementation plan from HHS agencies.22 CURRENT GUIDELINES

With a growing evidence base to support pulse oximetry as a noninvasive method for detecting CCHD, the momentum for universal screening has gained wide acceptance. A multidisciplinary working group published a white paper outlining their recommendations for screening, which have since been endorsed by the AAP, AHA, American College of Cardiology Foundation (ACCF), and other advocacy organizations.20 Reflecting the expansion of information to support implementation of CCHD screening, HHS Secretary Kathleen Sebelius endorsed the SACHDNC recommendation to add CCHD to the RUSP for newborns in 2011.22 Most recently, the AAP published a policy statement to support the HHS endorsement of universal screening for CCHD and provided guidance for implementing screening in clinical practice.23 TABLE 2. Road to universal CCHD screening Year

Milestones

2009

• Joint scientific statement from the AAP and AHA identifying compelling reasons for newborn CCHD screening, but calling for additional studies before recommending universal POS8

2010

• SACHDNC recommended that CCHD be added to the uniform screening panel20

2011

• Publication of working group guidelines for POS, endorsed by the AAP, AHA, and ACCF20 • Endorsement from HHS Secretary Kathleen Sebelius of the SACHDNC recommendations to add CCHD to the uniform screening panel for newborns22

2012

• AAP policy statement supporting the HHS endorsement of universal CCHD screening23

AAP = American Academy of Pediatrics; ACCF = American College of Cardiology Foundation; AHA = American Heart Association; CCHD = critical congenital heart disease; HHS = U.S. Department of Health and Human Services; POS = pulse-oximetry screening; SACHDNC = Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children.

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SCREENING CRITERIA

Key features of the CCHD screening recommendations are outlined in Table 3, and summarized in greater detail in Figure 1 on page 33.

Who to screen: The CCHD screening guidelines are targeted to newborns in the well-infant nursery.20 This population was chosen for the initial version of the screening guidelines to focus on the risk of missing CCHD among asymptomatic, healthy-looking newborns. Although the work group considered including infants in the neonatal intensive care unit (NICU), this population was ultimately excluded in the screening algorithm. Infants in the NICU have a range of underlying conditions, undergo repeated medical evaluations, already undergo monitoring with pulse oximetry, and have longer lengths of stay that allow for close observation. It should be noted, however, that infants with short stays in the NICU are still eligible for screening (for example, a day or two). Initial screening recommendations do not address screening for infants born at home and other out-of-hospital births, due to the challenges of coordinating follow-up care. Screening for these newborn populations will be addressed in future guidelines.20 When to screen: The timing of newborn screening is important to reduce the risk of false-positive results while maintaining high sensitivity for CCHD. Current guidelines recommend that screening should occur at 24 hours of life TABLE 3. Key recommendations for pulse-oximetry screening • Screen healthy newborn infants.

• Screen at 24-48 hours of life, or as late as possible if earlier discharge is planned.

• Obtain oxygen saturation readings in the right hand and one foot — A reading of ≥95% in either extremity with a ≤3% absolute difference between the upper and lower extremity is considered normal, and no further screening is required.

— Repeat measurements when the initial screening result is positive.

— Refer any infant with oxygen saturation <90% for immediate diagnostic evaluation.

— Adjust thresholds for positive findings in high-altitude areas.

• Findings that require additional screens — Oxygen saturations of 90% to 94% in both extremities — Absolute difference of >3% • Exclude CCHD with a diagnostic echocardiogram in infants with positive screening results and no infectious or pulmonary causes of hypoxemia.

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

or later, or as close to 24 hours of age as possible if early discharge is planned.14 Due to the normal transition from fetal to neonatal circulation and stabilization of systemic oxygen saturation levels that occur in the first hours of life, screening earlier than 24 hours can increase the risk of falsepositive results. By comparison, screening later than the second day of life misses an opportunity to intervene before the ductus arteriosus closes.20 How to screen: Oxygen saturation readings should be obtained for the right hand and either foot (see Figure 1).20 Normal findings are defined as an oxygen saturation of ≥95% in either extremity with a ≤3% absolute difference between the upper and lower extremity. No further screening is required for infants with normal readings. When an initial reading is positive for hypoxemia, however, up to two repeated screens at one-hour intervals are recommended to lower the likelihood of a false-positive result. Any infant with oxygen saturation <90% should receive immediate evaluation.

According to a report from Arkansas Children’s Hospital, 98.5% of newborns will show definitive positive or negative results with the first screen.24 Only 1.46% will require a second repeat screen, and 0.17% will require a third.24 Follow-up evaluation: Any infant with a positive screening result requires a comprehensive evaluation for hypoxemia.20 In the absence of other findings to explain the hypoxemia, such as infectious or pulmonary causes, CCHD must be excluded on the basis of a diagnostic echocardiogram.

This may require transfer to another unit with echocardiogram services within the hospital or birthing center, transfer to another medical center, or telemedicine for remote evaluation. The echocardiogram should not be replaced by other diagnostic tools, such as a chest radiograph or electrocardiogram, as these can be inaccurate for detecting CCHD. Moreover, the echocardiogram should be interpreted by a pediatric cardiologist due to the challenges of diagnosis in some cases. Hospitals and birthing centers should establish institutional protocols to ensure the timely evaluation and follow-up of all newborns with a positive screen for CCHD (see “Role of the medical home,” page 35).

Special considerations: Thresholds for hypoxemia may need to be adjusted when evaluating infants in high-altitude areas. To date, most studies surrounding CCHD screening have been conducted in lower-altitude areas, and these findings have been used to develop standard thresholds for normal oxygen saturation. Oxygen saturation is known to be lower at higher altitudes, however, particularly above 5,000 ft.8 In one study, the mean oxygen saturation at 24 hours of life was 95.4% among infants evaluated at 5,300 ft.16 Individual

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

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

FIGURE 1. The proposed pulse-oximetry monitoring protocol based on results from the right hand (RH) and either foot (F).

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ OCTOBER 2012 33

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NEONATAL SCREENING FOR CRITICAL CONGENITAL HEART DISEASE

states and medical centers can adjust the screening algorithm thresholds, as appropriate, to reflect mean values for healthy newborns in higher altitudes.

Clinical studies of CCHD screening

Several international clinical trials have shown pulse oximetry to be a simple, safe, feasible, and cost-effective screening tool that adds value to the standard newborn physical examination.11,13,19,21,25-29 In a prospective study of 20,055 infants born in the United Kingdom, pulse oximetry showed a sensitivity of 75% for detecting CCHD, with a low false-positive rate of 0.84%.28 Importantly, the screening program identified 12 critical cases that were not suspected despite newborn ultrasound examination.28 In a German trial of 41,445 newborns, pulse oximetry showed a sensitivity and specificity for detecting CCHD of 77.8% and 99.9%, respectively.17 In a Swedish study of 39,821 newborns, adding pulse oximetry to the newborn screening protocol improved the sensitivity for CCHD from 62.5% with physical examination alone to 82.8% with physical examination plus pulse oximetry.11 Most recently, in a meta-analysis published earlier this year, investigators evaluated 13 primary studies surrounding CCHD screening with a total of 229,421 asymptomatic newborns.21 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%, without any compromise in sensitivity when pulse oximetry was performed after 24 hours from birth. Although the goal of screening was to detect CCHD, pulse oximetry also identified other life-threatening disorders of noncardiac origin, including group B streptococcal pneumonia and pulmonary hypertension.

Implementation

In the wake of the HHS Secretary’s recommendation that screening for CCHDs be added to RUSP for newborns, it is the responsibility of individual states to implement screening programs through legislation, regulation, or adoption of standard clinical practice.23 States will need to establish standardized screening protocols, address how screening results will be reported, determine how those not screened in the well-newborn nursery will be screened, regulate reimbursement for screening, and clarify how state health departments will assist in the implementation of screening initiatives. State public-health systems will also play an active role in quality assurance through the collection and analysis of real-time screening data.20 Several states (i.e., Arkansas, Indiana, Maryland, and New Jersey) and individual medical centers across the country have begun CCHD screening programs based on screening recommendations from the AAP, AHA, ACCF, and other

Telemedicine

Patient/family education

Pediatric cardiology

Electronic health records

NICU

Data registries

Medical Home

NICU = neonatal intensive care unit.

FIGURE 2. The medical home for newborns with CCHD

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

Quality measures

organizations.20 Successful implementation of CCHD screening initiatives will depend on the collaboration between state public-health departments and the full spectrum of health-care providers, from pediatric cardiologists and hospital staff to primary-care clinicians and families.30 Implementing the RUSP in current clinical practice requires multidisciplinary collaboration among health-care providers who conduct newborn screening and inpatient follow-up, coordinate outpatient follow-up care, report to state-based public-health systems, and monitor the effectiveness of screening through surveillance programs and data registries.20 Role of the medical home

Establishing a medical home for infants who are found to have cardiac defects is a key feature of CCHD screening (Figure 2 ).20 In general, the term “medical home” describes the clinician or facility that coordinates the care of an individual who has a complex medical condition. The AAP has described the required elements of medical homes for infants and children with special medical needs, including:31 • Continuity of care from infancy through adolescence and young adulthood • Comprehensive care that includes screenings, preventive care, primary and tertiary care, and referral to specialty care as needed • Development of a multidisciplinary care plan that is shared with other providers, agencies, and organizations involved in the care of the patient • Coordination of care among multiple providers, including pediatric medical subspecialists, surgical specialists, and mental health/developmental professionals • Maintenance of a central record or database containing all pertinent medical information, including hospitalizations and specialty care.

In the context of CCHD screening, the AAP, ACCF, and AHA have outlined strategies for establishing a medical home to facilitate timely diagnosis and follow-up care.12,20,23 For instance, the results of all newborn CCHD screenings should be communicated to the infants’ primary-care providers. During the first outpatient visit, the primary-care provider should ensure that all newborns have been screened according to current guidelines and have received appropriate follow-up. Primary-care providers will need to develop strategies to screen newborns who were not screened in the newborn nursery (e.g., for infants born at home).

Coming up in the next issue Evidence-based recommendations are currently available to guide clinicians in the use of screening for CCHD. Supported by the AAP, AHA, ACCF, and SACHDNC, these recommendations represent a new standard of newborn care. The third article in the Taking the Pulse of Neonatal Screening for Critical Congenital Heart Disease series will focus on the implementation of CCHD screening in realworld clinical practice. By examining case studies from states and medical centers that have successfully launched universal screening initiatives, the article will highlight best practices in protocol development and rollout. The article will also address barriers to successful screening, including the sensitivity of the newer-generation devices, strategies to reduce false-positive and false-negative rates, options for patient and provider education, evidence on cost-effectiveness, and what lies ahead for pulse oximetry for CCHD in newborns.

Within the medical home model, the primary care provider also plays a central role in coordinating long-term follow-up care with cardiologists and other specialists for those newborns who are diagnosed with CCHD via newborn screening.20 Health information exchange systems related to CCHD screening can be used to facilitate communication between public health, primary care providers, cardiologists, and other members of the care team.The AAP recommends that health systems develop standards for electronic reporting of screening results to streamline tracking and facilitate the development of quality measures related to CCHD screening.20 Conclusions

CCHD screening using pulse oximetry is safe, simple, noninvasive, and effective in improving the early identification of newborns with CCHD. CCHD screening at 24 to 48 hours of life is now included in the RUSP for infants born in the United States, with clear guidance from the AAP, AHA, ACCF, and other societies to facilitate successful screening. For infants who are found to have cardiac defects, primary-care providers can play a leadership role in coordinating follow-up care via the medical home. Health-care providers can collaborate across the spectrum of newborn care—from the neonatal intensive care unit and well-baby nursery to the postdischarge primary-care setting—to improve early detection rates for CCHD. ■

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

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References

18. Kemper AR, Boyle CA, Aceves J, et al. Long-term follow-up after diagnosis

1. Centers for Disease Control and Prevention. Pulse oximetry

resulting from newborn screening: statement of the US Secretary of Health

screening for critical congenital heart defects. www.cdc.gov/ncbddd

and Human Services’ Advisory Committee on Heritable Disorders and

/pediatricgenetics/documents/CCHD-factsheet.pdf.

Genetic Diseases in Newborns and Children. Genet Med. 2008;10:259-261.

2. Schultz AH, Localio AR, Clark BJ, et al. Epidemiologic features of the

19. Watson MS, Mann MY, Lloyd-Puryear MA, et al; American College of

presentation of critical congenital heart disease: implications for screening.

Medical Genetics Newborn Screening Group. Newborn screening: toward

Pediatrics 2008;121:751-757.

a uniform screening panel and system—executive summary. Pediatrics.

3. Declerq E, Simmes D. The politics of “Drive-through deliveries”: put-

2006;117(5 pt 2):S296-S307.

ting early postpartum discharge on the legislative agenda. Milbank Q.

20. Kemper AR, Mahle WT, Martin GR, et al. Strategies for

1997;75:172-202.

implementing screening for critical congenital heart disease. Pediatrics.

4. Lansky A, Barfield WD, Marchi KS, et al. Early postnatal care among

2011;128:e1259-e1267.

healthy newborns in 19 states: pregnancy risk assessment monitoring sys-

21. Thangaratinam S, Brown K, Zamora J, et al. Pulse oximetry screening for

tem, 2000. Matern Child Health J. 2006;10:277-284.

critical congenital heart defects in asymptomatic newborn babies: a system-

5. Brown S, Small R, Argus B, et al. Early postnatal discharge from hospital

atic review and meta-analysis. Lancet. 2012;379:2459-2464.

for healthy mothers and term infants (review). Cochrane Database Syst Rev.

22. Secretary’s Advisory Committee on Heritable Disorders in Newborns

2009;3:CD002958.

and Children. Recommendations and responses from the HHS Secretary.

6. Ng B, Hokanson J. Missed congenital heart disease in neonates. Congenit

www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/

Heart Dis. 2010;5:292-296.

recommendations/index.html.

7. Hoffman JI. It is time for routine neonatal screening by pulse oximetry.

23. Mahle WT, Martin GR, Beekman RH, et al. Endorsement of Health and

Neonatology. 2011;99:1-9.

Human Services recommendation for pulse oximetry screening for critical

8. Mahle WT, Newburger JW, Matherne GP, et al. Role of pulse oximetry

congenital heart disease. Pediatrics. 2012;129:190-192.

in examining newborns for congenital heart disease: a scientific statement

24. Morrow WR. Statewide implementation of CCHD newborn screening.

from the AHA and AAP. Pediatrics. 2009;124:823-836.

Arkansas Pediatric Forum, 2012.

9. Wren C, Reinhardt Z, Khawaja K. Twenty-year trends in diagnosis of

25. Knowles R, Griebsch I, Dezateux C, et al. Newborn screening for con-

life-threatening neonatal cardiovascular malformations. Arch Dis Child Fetal

genital heart defects: a systematic review and cost-effectiveness analysis.

Neonatal Ed. 2008;93:F33-F35.

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

10. Mellander M, Sunnegardh J. Failure to diagnose critical heart malforma-

26. Meberg A, Andreassen A, Brunvand L, et al. Pulse oximetry screening as

tions in newborns before discharge—an increasing problem? Acta Paediatr.

a complementary strategy to detect critical congenital heart defects. Acta

2006;95:407-413.

Paediatr. 2009;98:682-686.

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

27. Griebsch I, Knowles RL, Brown J, et al. Comparing the clinical and eco-

oximetry screening on the detection of duct dependent congenital heart

nomic effects of clinical examination, pulse oximetry, and echocardiography

disease: a Swedish prospective screening study in 39,821 newborns. BMJ.

in newborn screening for congenital heart defects: a probabilistic cost-

2009;338:a3037. Available at www.bmj.com/content/338/bmj.a3037.

effectiveness model and value of information analysis. Int J Technol Assess

12. Jopling J, Henry E, Wiedmeier SE, et al. Reference ranges for hematocrit

Health Care. 2007;23:192-204.

and blood hemoglobin concentration during the neonatal period: data from

28. Ewer AK, Furmston AT, Middleton LJ, et al. Pulse oximetry as a screen-

a multihospital health care system. Pediatrics. 2009;123:e333-e337.

ing test for congenital heart defects in newborn infants: a test accuracy

13. O’Donnell CP, Kamlin CO, Davis PG, et al. Clinical assessment of infant

study with evaluation of acceptability and cost-effectiveness. Health Technol

colour at delivery. Arch Dis Child Fetal Neonatal Ed. 2007;92:F465-F467.

Assess. 2012;16:v-xiii, 1-184.

14. Hokanson JS. Pulse oximetry screening for unrecognized congenital

29. Roberts TE, Barton PM, Auguste PE, et al. Pulse oximetry as a screening

disease in neonates. Congenital Cardiology Today. 2011;9:1-6.

test for congenital heart defects in newborn infants: a cost-effectiveness

15. Levesque BM, Pollack P, Griffin BE, Nielsen HC. Pulse oximetry: what’s

analysis. Arch Dis Child. 2012;97:221-226.

normal in the newborn nursery? Pediatr Pulmonol. 2000;30:406-412.

30. Cuzzi S, Bradshaw E. The road to universal pulse-oximetry screening:

16. Bakr AF, Habib HS. Normal values of pulse oximetry in newborns at

are we there yet? Pediatrics. 2011;128:e1271-e1272.

high altitude. J Trop Pediatr. 2005;51:170-173.

31. American Academy of Pediatrics. Medical Home Initiatives for Children

17. Riede FT, Worner C, Dahnert I, et al. Effectiveness of neonatal pulse

With Special Needs Project Advisory Committee: The medical home.

oximetry screening for detection of critical congenital heart disease in daily

Pediatrics. 2002;110:184-186.

clinical routine—results from a prospective multicenter study. Eur J Pediatr.

2010;169:975-981.

All electronic documents accessed September 15, 2012.

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

CME CE

POSTTEST Expiration date: October 2013

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

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPACE designates this educational activity for a maximum of 0.5 contact hours of credit.

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

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Posttest must be completed and submitted online. Please go to myCME.com/neonatal or ClinicalAdvisor.com/CMEFEatureOct2012.

CREDITS: 0.5

| CCHD screening guidelines: Implementation of standardized protocols

1. According to the American Academy of Pediatrics (AAP) and the American Heart Association (AHA), screening for critical congenital heart disease (CCHD) should not take place before: a. 12 hours b. 18 hours c. 24 hours d. 48 hours

4. In a Swedish study of 39,821 newborns, adding pulse oximetry to the newborn screening protocol improved the sensitivity for CCHD to: a. 60% b. 70% c. 80% d. 90%

2. In the absence of other findings to explain the hypoxemia, such as infectious or pulmonary causes, CCHD must be excluded on the basis of: a. Chest radiograph b. Electrocardiogram c. Echocardiogram d. Phonocardiogram

5. According to current AAP/AHA and American College of Cardiology Foundation recommendations, the primarycare provider should: a. Screen all newborns for CCHD b. Assist in the interpretation of a diagnostic echocardiogram c. Coordinate long-term follow-up care with the cardiologist and other specialists for newborns diagnosed with CCHD d. All of the above

3. Normal oxygen saturation is defined as a reading of: a. ≥95% in either extremity with a ≤3% absolute difference between the upper and lower extremity b. ≥95% in both extremities with a ≤3% absolute difference between the upper and lower extremity c. ≥90% in either extremity with a ≤2% absolute difference between the upper and lower extremity d. ≥90% in both extremities with a ≤3% absolute difference between the upper and lower extremity

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 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 patients’ 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.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 37

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.

An ulcer developed after a trip to Central America A man presented with an ulcer on his arm that had been present many weeks. The growth started as a small papule, which he ignored until it started expanding into a larger nodule that eventually ulcerated.

WHAT IS YOUR DIAGNOSIS?

• • • •

Leishmaniasis Squamous cell carcinoma Pyoderma gangrenosum Chagas disease

● See the full case at ClinicalAdvisor.com/DermDx1012A

A soft, nontender, rounded papule on the inner lower lip A boy presented with a painless lump in his inner lower lip that had been present for several weeks. No fever or other symptoms were reported. The boy was otherwise well and taking no medications.

WHAT IS YOUR DIAGNOSIS?

• • • •

Congenital epulis Pyogenic granuloma Focal epithelial hyperplasia Mucocele

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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.

Discoloration around the mouth

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

An embarrassing mole

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 O C TO B E R 2 0 1 2

Consultations Causes of elevated creatine . . . . . . . . .42 Treating psychiatric illness during pregnancy. . . . . . . . . . . . . . .43 Thyroid hormone and bone desnity . . . . . . . . . . . . . . . . . .43 Osteoporosis in a patient taking anti-seizure medication . . . . . . . . . .43

Your Comments Scrotal swelling and impotency . . . . . .44

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

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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.

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CONSULTATIONS CAUSES OF ELEVATED CREATINE A patient has had elevated creatine over the past several years. Could this be caused by chemotherapy or BP medication? The patient also twitches, which I thought might be attributable to electrolyte imbalance.—MICHAEL WANG, PA-C, Buffalo, N.Y. Creatine, a naturally occurring amino acid found in meat and fish, is also made in the liver, kidneys, and pancreas. It is stored in muscle and plays a major role in energy production. Creatine is broken down to creatinine, which enters the circulation and is excreted by the kidneys. Elevated creatine may occur with high meat intake, active rheumatoid arthritis, testosterone therapy, and any process that results in destruction of muscle. Elevated creatinine can be an indication of kidney disease or can be attributable to such medications as aminoglycosides, penicillins, ACE inhibitors, nonsteroidal anti-inflammatory drugs, and chemotherapy and biological agents.

It would be best to follow the levels of both creatine and creatinine in consultation with an oncologist.

Twitching (fasciculations) are involuntary movements of small groups of muscle fibers and are often benign. Other common causes include dehydration, caffeine, stress, electrolyte imbalance, drug side effect, renal disease, or degenerative neurologic diseases. Abnormal levels of potassium, calcium, magnesium, or sodium may result in twitching, but the patient typically has other symptoms or signs

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.

42 THE CLINICAL ADVISOR • OCTOBER 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.

indicative of electrolyte imbalance. Further investigation is necessary.— Claire Babcock O’Connell, MPH, PA-C (168-1)

TREATING PSYCHIATRIC ILLNESS DURING PREGNANCY What considerations exist regarding the safety of using aripiprazole (Abilify) during pregnancy? If the medication is withheld and the patient becomes psychotic and injures herself, the fetus, or others, what are the legal ramifications for the clinician? Similarly, what liability exists if the medication is provided and the child is born with neural tube defects?— TIMOTHY COOGAN, PA-C, Carterville, Ill. Aripiprazole, used to treat schizophrenia, bipolar disorder, and refractory depression, is a Pregnancy Risk Factor C drug, as it has been demonstrated to cause developmental toxicity and teratogenic effects in animal models. Newborns who are exposed to antipsychotics in utero during the third trimester may experience withdrawal symptoms (e.g., feeding difficulties, agitation, somnolence, tremor, respiratory depression) as well as extrapyramidal symptoms. Like all Pregnancy Risk Factor C drugs, aripiprazole should be used only if the potential benefit outweighs the potential risks to the fetus.

Treating psychiatric illness in a pregnant woman is a balancing act.

The clinician must maximize the patient’s psychological well-being while minimizing any risks to the health of her child associated with psychotropic medications. Unless a woman has been determined unfit to make decisions for herself, the provider is obligated to discuss the risks and benefits of using a drug like aripiprazole during pregnancy and then let the patient make the final decision. Thorough documentation of this conversation, as well as ongoing monitoring and reassessment, is required to protect against future litigation if the patient were to decompensate while off medication or the newborn were determined to have a health issue caused by exposure to a prescribed medication.

In all cases involving a pregnant woman with a psychiatric illness, a mental-health professional must be involved. Such a patient is vulnerable due to hormonal changes and the profound stressors of becoming a mother.—Mary Newberry, CNM, MSN (168-2)

THYROID HORMONE AND BONE DENSITY Does thyroid hormone replacement therapy affect bone density?

—DONNA M. O’BRIEN, ANP, North Truro, Mass.

Before the advent of anti-thyroid hormone drugs in the 1940s, osteoporosis from hyperthyroidism was very common and potentially severe. Since then, adverse bone changes from over-replacement of thyroid hormone are more the norm. Thyroid hormone excess mostly increases bone resorption from osteoblasts that are not accompanied by increases in bone formation. This effect is more pronounced in postmenopausal women. Clinically, this means that patients with suppressed thyroid-stimulating hormone (TSH) (below normal range) on thyroid hormone therapy are at higher risk for bone loss.

Patients on thyroid hormone after thyroidectomy for thyroid cancer typically maintain a suppressed TSH level to inhibit any recurrence of thyroid cancer; these patients should be monitored more closely for osteoporosis. Likewise, it is important to avoid a suppressed TSH in other individuals on thyroid hormone replacement to avoid this adverse event (Clin Endocrinol [Oxf]. 2004;61:285-298).—Kathy Pereira, DNP, RN, FNP-BC, ADM-BC, assistant professor, coordinator, Family Nurse Practitioner Program, Duke University School of Nursing, Durham, N.C. (168-3)

OSTEOPOROSIS IN A PATIENT TAKING ANTI-SEIZURE MEDICATION Should a patient taking anti-seizure medication have a dual-energy x-ray absorptiometry (DEXA) scan to check

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

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

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

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

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

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

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

Advisor Forum for osteoporosis? If so, at what age should this be started and how often? Should calcium with vitamin D be advised to prevent osteoporosis as well? – DEANE BERG, PA-C, Sioux Falls, S.D. Many anti-seizure medications, especially phenytoin (Di-Phen, Dilantin, Phenytek) and phenobarbital (Solofton), can result in reduction in bone mass, causing a secondary osteoporosis. Cumulative drug load over time has a progressive effect. Possible mechanisms include reduced absorption or utilization of vitamin D, altered parathyroid hormone and calcitonin levels, and reduction of serum estrogen.

There are no current consensus guidelines for screening patients with seizure disorders for bone health. Counseling regarding risk is imperative, and risk related to medications as well as lifestyle factors should be included. Screening vitamin D levels and DEXA scans are two possible screening methods. Vitamin D has been shown to prevent the bone loss and reduce risk for fractures in patients taking anti-seizure medications, similar to those not taking such medications (Epilepsy Behav. 2011;22:94-102). Further research is needed to better understand the interplay of neurology and endocrinology in patients with seizure disorders.—Claire Babcock O’Connell, MPH, PA-C (168-4)

“But how do you know for sure you’ve got power unless you abuse it?”

SCROTAL SWELLING AND IMPOTENCY I often palpate spermatoceles measuring 0.5 cm (“Infections, tumors, and lumps affecting the scrotal content,” August 2012). What level of impotence occurs with each grade of a varicocele? What percentage of epididymitis cases are not infectious but rather are caused by an idiopathic inflammatory process? What credence do you place on cremasteric reflex, as it is almost always absent in cases of testicular torsion?— GERALD VEGA, MPAS, PA-C, Orlando, Fla. Spermatoceles that are <0.5 cm are difficult to palpate. You can feel normal epididymal tissue, which can be confusing. The size of a varicocele does not correlate with the degree of infertility; there is no correlation between spermatocele and erectile dysfunction. I am not aware of specific data regarding infectious vs. noninfectious epididymitis. An indurated epididymis in a patient with no fever or ill feeling is much less likely to be associated with infection. A significant number of men present with scrotal pain that is misdiagnosed as epididymitis. The cremasteric response can be diminished or reduced with scrotal pain from any source. Swelling and a high-riding testicle in the scrotum are more consistent indications for torsion.—Craig Ensign, MPAS, PA-C (168-5) ■

“We don’t offer a health-care plan. Instead, we have Lou persuade you not to get sick.”

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

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

YOUR COMMENTS

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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Osteoarthritis and Rheumatoid Arthritis 2012: Pathophysiology, Diagnosis, and Treatment

KORI A. DEWING, DNP, FNP, ARNP

Rheumatology Nurse Practitioner, Virginia Mason Medical Center, Seattle, WA STEPHEN M. SETTER, PharmD, DVM, CDE, CGP, FASCP

Clinical Geriatric Pharmacy Consultant, GeriMed Consulting, Spokane, WA BARBARA A. SLUSHER, MSW, PA-C

Rheumatology Associates of Houston, a division of NW Diagnostic Clinic, Houston, TX

46 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 46 THIS ARTICLE IS PROVIDED BY THE NURSE PRACTITIONER HEALTHCARE FOUNDATION

S P E C I A L F E AT U R E

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common musculoskeletal conditions affecting individuals across the United States. Distinguished by cartilage degeneration and bony overgrowth, OA affects approximately 13.9% of adults who are ≥25 years of age.1 The incidence of OA rises with age with estimates that OA affects 12.4 million adults ≥65 years of age.1 OA occurs more frequently in women, particularly after reaching 50 years of age; women are also at greater risk for developing OA in the knee or hip.1 RA, unlike OA, is an autoimmune condition characterized by inflammation, usually in bilateral joints, and systemic features, such as fatigue or fever.2 RA is estimated to affect 1.5 million adults.2 RA sufferers are typically younger than those who develop OA, with RA occurring between 20 to 30 years of age, and the incidence peaking at 35 to 50 years of age.2,3 The incidence of RA is higher in women2 with a higher lifetime risk (3.6%) compared to men (1.7%).4 While there is no cure for OA or RA, treatments that slow or halt the progression of RA are available. Unfortunately, the same is not true for OA, where current pharmacologic treatment focuses on symptomatic relief. This article not only highlights the differences in the pathophysiology and diagnostic criteria for OA and RA, but also describes current and potentially new treatment options for these conditions.

Pathophysiology

Although the primary manifestations of OA and RA involve the joints, the underlying pathophysiology of each condition is distinct.

Osteoarthritis and cartilage degeneration Normally, cartilage undergoes a remodeling process, stimulated by joint movement or use.5 In OA, this process is altered by a combination of mechanical, cellular, and biochemical processes, resulting in abnormal reparation of cartilage and an increase in cartilage degradation5 (Figure 1). OA is primarily characterized by progressive cartilage loss, accompanied by an increased thickness of the subchondral plate, osteophytes (new bone at joint margins) and subchondral bone cysts.6 With disease progression, vascular invasion and further calcification of nearby articular cartilage may occur, leading to decreased thickness of articular cartilage and, over time, bone remodeling and enhanced cartilage deterioration.6 The inflammation that occurs typically involves the periarticular tissues and is generally milder in severity compared to RA.5 Osteoarthritis is associated with specific risk factors or causes including age, joint trauma, injury, or obesity.7 Individuals

who are >50 years of age are at a higher risk of developing OA.5 The aging process has an impact on the cartilage extracellular matrix structure and components6 ; it is also associated with declining chondrocyte function and response rate to stimuli.5 Joint injury and trauma, prolonged stress on the joint from sports activities or strenuous occupations, and joint overactivity, can increase an individual’s risk over time.5 Obesity increases the risk of OA, particularly in the weight-bearing joints.1,5 With the growing number of both overweight and obese individuals, the incidence of OA and the number of hip and knee replacements is rising.8-10 Genetics may also contribute to an increased risk.6 Joint damage in rheumatoid arthritis Unlike the pathophysiology of OA, which is largely mechanical, RA is an autoimmune disease. The initial triggers of RA are unclear; hormones, genetics and environmental factors may all play a role.2 Once the initial immune response is triggered, cells of the immune system produce autoantibodies and inflammatory cytokines, creating a cascade of inflammation resulting in the formation of pannus; the pannus invades and destroys cartilage and bone. Additional joint damage and systemic complications ensue, resulting from a complex process of inflammatory mediators being released in the affected joint11 (Figure 1).

Many factors impact the risk of developing RA. The risk of developing RA doubles with a first degree relative who has RA. There is also a hormonal relationship; RA is more common in females, and there are high rates of disease onset associated with pregnancy.2,11,12 The impact of environmental stressors, especially smoking and chemical exposure (e.g., silicate), on genes is thought to drive the processes that induce autoimmune reactions leading up to the inflammation seen

Normal and Arthritic Joints FIGURE 1. Joint impact of osteoarthritis and rheumatoid arthritis

© ADAPTED FROM MEDICINENET, INC.

Introduction

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TABLE 1. Summary of diagnostic criteria for osteoarthritis and rheumatoid arthritis Arthritis

Patient History

Physical Exam

Tests

Osteoarthritis

• C/o palpable bony joint enlargement • Morning stiffness (lasting <30 minutes) • Pain

• Reduced range of motion • Joint malalignment • Crepitus

Radiologic • Presence of osteophytes • Joint space narrowing Laboratory • Clear synovial fluid

Rheumatoid Arthritis

• Pain duration ≥6 weeks • Morning stiffness (lasting >30 minutes) • Systemic symptoms (e.g., fatigue, anorexia)

• Synovitis • Joint involvement, symmetrical • Joint destruction • Extra-articular manifestations

Radiologic • Erosions on X-ray or MRI • Synovitis noted by ultrasound or MRI Serology • ESR or C-reactive protein • Anti-CCP • Rheumatoid factor

Sources: Singh et al.14; Altman et al.15; Aletaha et al.16

in RA.11,12 Research estimates that a history of smoking can increase the relative risk of RA onset more than 2-fold, especially in individuals who are positive for anti-citrullinated protein antibodies (ACPA) or anti-cyclic citrullinated protein antibodies (anti-CCP); smoking is the strongest risk factor associated with RA.2 Assessment of osteoarthritis and rheumatoid arthritis

Diagnosing osteoarthritis The diagnosis of OA is based on patient history as well as the physical exam (Table 1). In advanced disease, radiologic signs of OA include asymmetrical narrowing of the joint space indicating loss of cartilage and/or the presence of osteophytes or bony overgrowth. The lack of radiologic evidence does not, however, rule out the presence of OA.5 Joint aspiration is an invasive procedure and not required for diagnosis. However, if done, synovial fluid analysis may help confirm OA is non-inflammatory, with a white blood cell count <2000/mm 3 ; it may also help rule in or out other conditions, such as gout or inflammatory arthritis.13 Unlike RA, biologic markers are typically absent in OA patients.13 OA symptoms tend to start on one side of the body initially and may include one or more joints.5 The distal joints of the hands are most commonly affected as are the weight-bearing joints (e.g., knees, hips, cervical and lumbar spine).1 Morning stiffness is generally short-lived, usually lasting 30 minutes or less and may also occur with moderate activity5,13; pain is usually relieved by rest.13 Other signs associated with OA typically involve joint tenderness, limited mobility, and local inflammation; systemic symptoms are usually absent.13 Crepitus, a grating sensation between the joints, may also be present in later stages of the disease.13

Diagnosing rheumatoid arthritis To diagnose RA, patient history is important. However, the physical exam, laboratory tests, radiographs, and other assessments (ie, functional status, disease activity) are frequently helpful in confi rming a diagnosis (Table 1). RA usually affects multiple joints, although it may only affect a few sites during its initial presentation.11 Contrary to OA, joint involvement in RA is typically symmetric and commonly affects small distal joints (ie, wrists, proximal interphalangeal joints, metacarpophalangeal joints).11 Affected joints are usually tender, warm, and erythematous, with a “puffy” appearance, due to increased blood flow and synovial infi ltration or synovitis from pannus formation.11 This infl ammation or pannus is generally palpable on physical exam as a “bogginess” or fullness over the joints.

Morning stiffness lasting >30 minutes is also a common sign of RA; the stiffness typically improves with movement.11 Early symptoms of pain and stiffness in the joints, which may be accompanied by systemic features (e.g., anorexia, weakness, low-grade fever, fatigue), are recognized as the prodromal phase.11 Assessment of the patient’s prognosis can impact treatment decisions. The American College of Rheumatology (ACR) recommendations for RA finds a poor prognosis can be inferred by one or more of the following features: functional limitations, presence of extra-articular manifestations (e.g., Felty’s syndrome, rheumatoid nodules, RA vasculitis), positive rheumatoid factor or anti-CCP antibodies; or radiographic evidence of bony erosions.14 Treatment and management strategies

Numerous treatment strategies are available to help improve patient functionality and mobility in both RA and OA.

S P E C I A L F E AT U R E

Treatment for OA is mostly symptomatic whereas treatment for RA can slow down or prevent disease progression and joint destruction.

Nonpharmacologic treatment options Nonpharmacologic therapy plays an important role in the successful treatment of OA and RA.17,18 Exercise, a key component of nonpharmacologic management, helps patients maintain mobility and function.18,19 Both OA and RA guidelines recommend regular aerobic exercise18,19; RA patients, in particular, are urged to participate in strengthening exercises to maintain joint function, while non-weight bearing exercises (e.g., water aerobics) are highly recommended for OA patients.18,19 Weight loss may also be suggested for patients with OA as a means to alleviate stress on weight-bearing joints.17,19-21 Self management, including patient education and cognitive and behavioral therapy, can also help manage OA and RA symptoms and improve both social and self-care capabilities.19,21 OA guidelines recommend surgery in patients with extensively impaired function and pain that is refractory to medication therapy.17 RA guidelines suggest surgery in patients experiencing intolerable pain due to joint destruction.18 Acetaminophen Acetaminophen, an effective option for mild-to-moderate pain, is the preferred first-line agent for the management of OA.19,22 At recommended doses (less than 3000mg/day), acetaminophen is associated with fewer risks than non-steroidal anti-inflammatory drugs (NSAIDs), and can be effective at controlling OA pain.19 Acetaminophen is hypothesized to work through the central nervous system, instead of the periphery, to inhibit prostaglandin synthesis.17 If a patient does not have an adequate response to acetaminophen at an adequate dose and duration, topical or oral NSAIDs should be considered.19 Non-steroidal anti-inflammatory drugs and COX-2 inhibitors NSAIDs work by reducing production of pro-inflammatory and pain-related prostaglandins.17 They inhibit two cyclooxygenase (COX) enzymes: COX-1 is important in the normal regulation of the gastrointestinal (GI) tract; COX-2 is upregulated at sites of inflammation, among other functions, and may be responsible for inflammation.17 Therefore, NSAIDs are effective in treating pain, immobility, and inflammation associated with OA.23 As recommended by the ACR guidelines, initial RA treatment includes the use of NSAIDs (including selective COX-2 inhibitors) or salicylates. These treatment options neither alter RA progression nor protect

against joint damage and therefore, are used along with other medications.18 Adverse events associated with NSAIDs can have varying effects in the GI, cardiovascular, hepatic, and renal systems.23 When managing patients with OA, the risk for adverse events increases with higher doses and longer treatment duration.23 Characteristics that increase the risk of GI adverse events include prolonged NSAID use, history of GI disorders, heavy smoking or alcohol use, and concurrent use of aspirin, warfarin, or clopidogrel.23 With the increased risk of adverse events with advanced age, topical NSAIDs may be preferred in patients who are â&#x2030;Ľ75 years of age, especially for patients with few joints involved.19 RA patients, compared to OA patients, have an increased likelihood of experiencing adverse events, specifically gastroduodenal ulcers, with NSAID treatment.

Patients at the highest risk of serious NSAID-associated ulcers include patients who have a history of ulcers, patients >75 years of age, those taking high dose or multiple NSAIDs, and concomitant corticosteroids or anticoagulant use.

NSAIDs can be combined with a gastro-protectant agent (proton pump inhibitors (PPIs), histamine receptor antagonists (H2RAs), misoprostol) for patients who are at increased risk of GI adverse events.23 Of those mentioned, PPIs may be the most effective overall.24 PPIs have been found to be superior to H2RAs in preventing and healing GI events caused by NSAID use.24 Although misoprostol, a prostaglandin analogue, has been found to be just as effective as PPIs,25 GI adverse events (e.g., cramps, diarrhea) limit its use.24 There are several formulations where the NSAID and the gastro-protectant are available as a combination (e.g., diclofenac sodium + misoprostol, ibuprofen + famotidine, naproxen + lansoprazole, naproxen + esomeprazole).

These formulations may be useful in reducing the risk of GI adverse events and enhancing compliance.

Glucocorticoids If an OA patient fails NSAID therapy, intra-articular corticosteroid injections are another option.19 Corticosteroid injections may provide pain relief over short-term periods (one to four weeks), but there is no evidence that these injections improve function.17 Current ACR guidelines recommend the use of glucocorticoid injections for knee and hip OA if other pharmacologic therapies do not provide sufficient relief. The guidelines do not recommend corticosteroid injections in the treatment of hand OA.19 Low-dose oral glucocorticoids or local glucocorticoid injections are another treatment option for RA. These therapies are effective in relieving active RA symptoms (e.g., morning stiffness, joint pain, fatigue) in combination

S P E C I A L F E AT U R E

DMARDs= disease-modifying antirheumatic drugs TNF = tumor necrosis factor

Hydroxychloroquine Leflunomide Methotrexate Minocycline Sulfasalazine

Non-biologic

DMARDs

Non-TNF

Abatacept Rituximab Tocilizumab

Anti-TNF

Adalimumab Certolizumab pegol Etanercept Golimumab Infliximab

Biologic

Source: Singh et al.14

FIGURE 2. DMARD categorization

with disease-modifying antirheumatic drugs (DMARDs).18 They are frequently used as a short-term rescue medication or as a “bridge” therapy helping to control pain while a new DMARD is started. The lowest glucocorticoid dose (e.g., ≤5mg prednisone daily) should be prescribed, if appropriate. Delayed-release prednisone was approved by the Food and Drug Administration on July 2012 for use in RA patients. This formulation addresses the physiologic biorhythm of symptoms and was developed to help reduce joint symptoms upon awakening; it is intended to be taken at bedtime.26 Despite their efficacy, long-term low-dose oral glucocorticoid use can also cause several adverse events including hypertension, hyperglycemia, cataracts, osteoporosis, weight gain, fluid retention, and immunosuppression. For patients at high risk of osteoporotic fractures, ACR guidelines recommend maintaining adequate calcium and vitamin D intake, and to consider the use of a bone preserving agent.

Glucocorticoid injections may also be used to provide rapid and directed relief during RA flares.18 For flares involving a small number of joints, glucocorticoid injections can provide effective symptom relief without medication regimen changes. No joint should be injected more than three times in one year; therefore, if more injections are required, other treatment options should be considered.18 Alternative to NSAIDs in osteoarthritis Opioids should be reserved as a last option.19 Tramadol may be effective in treating moderate-to-severe pain, however, for

individuals with severe pain who are unable to tolerate or do not respond to tramadol, opioid therapy should be considered.

For patients who are not candidates for surgery, opioid therapy may also be considered.27 Opioid therapy may be effective initially at reducing pain, but it is questionable whether or not the analgesic effect is sustained long-term.23 Duloxetine is conditionally recommended by the ACR guidelines if other therapies are not effective. Hyaluronic acid injections are also recommended for patients who do not respond to pharmacologic and nonpharmacologic OA interventions; its use is limited to specific joints (e.g., knee).19 Disease-modifying antirheumatic drugs for rheumatoid arthritis As a mainstay of RA pharmacotherapy, DMARDs are often utilized in combination with NSAIDs or glucocorticoids to decrease RA progression and maintain joint functionality.18 DMARDs are classified as biologic or non-biologic agents; biologic DMARDs are further categorized as non-tumor necrosis factor (non-TNF) and anti-TNF agents (Figure 2) based on their mechanism of action.14 The goal of using DMARDs in RA patients is to obtain medical remission or low disease activity.14 Ideally, DMARD therapy should be started at disease onset, during early RA. Although therapy selection depends on RA severity, duration of symptoms, desired effects, toxicity, comorbidities, and administration requirements, it is important to know that treatment with DMARDs should be implemented at the onset of RA and can be adjusted at any stage.14 For instance, RA patients may

S P E C I A L F E AT U R E

TABLE 2. Useful resources for patient information

References 1. Centers for Disease Control and Prevention. Osteoarthritis.

Arthritis Foundation www.arthritis.org American College of Rheumatology www.rheumatology.org National Institute of Arthritis and Musculoskeletal and Skin Diseases www.niams.nih.gov/Health_Info/Rheumatic_Disease/default.asp National Institutes of Health http://health.nih.gov/topic/Osteoarthritis http://health.nih.gov/topic/RheumatoidArthritis

www.cdc.gov/arthritis/basics/osteoarthritis.htm.

2. Centers for Disease Control and Prevention. Rheumatoid arthritis. www.cdc.gov/arthritis/basics/rheumatoid.htm.

3. Arthritis Foundation. News from the Arthritis Foundation: Rheumatoid Arthritis Fact Sheet. 2008. www.arthritis.org/media/newsroom/media-kits/ Rheumatoid_Arthritis_Fact_Sheet.pdf.

4. Crowson CS, Matteson EL, Myasoedova E, et al. Arthritis Rheum. 2011 Mar;63:633-639.

5. Hinton R, Moody RL, Davis AW. Am Fam Physician. 2002;65:841-848.

6. Goldring SR, Goldring MB. J Musculoskelet Neuronal Interact. 2006; 6:376-378.

7. Kraus VB. Advances in Rheumatology. 1997;81:85-112.

be prescribed methotrexate as monotherapy or in combination with a biologic DMARD, if their disease has either progressed or poor prognostic factors have evolved over the course of their disease. Therefore, referring patients suspected of having RA to rheumatology specialists is key to their management and helping prevent the development of irreversible joint destruction.14,18

8. Centers for Disease Control and Prevention. Obesity: causes and consequences. www.cdc.gov/obesity/adult/causes/index.html.

9. Ogden C, Carroll MD, Kit BK, et al. NCHS Data Brief. 2012;82:1-8.

10. Murphy L, Hemlick CG. Am J Nurs. 2012;112(3 Supp 1):S13-S19.

11. Rindfleisch JA, Muller D. Am Fam Physician. 2005;72:1036-1047.

12. Karlson EW, Deane K. Rheum Dis Clin North Am. 2012;38:405-426.

13. Punzi L, Oliviero F, Plebani M. Critical Reviews in Clinical Laboratory Sciences. 2005;42:279-309.

Novel options for rheumatoid arthritis While many efficacious treatment options are currently available for RA patients, medications utilizing different mechanisms to treat RA are being developed which target specific inflammatory cytokines or cell signaling pathways.

Tofacitinib is one novel oral biologic DMARD medication which has concluded phase III clinical trials and is currently being reviewed by the FDA for approval. Tofacitinib targets the Janus kinase (JAK) intracellular pathway.28 Fostamatinib, an oral Syk inhibitor is also being investigated for RA. It is currently in a phase III clinical development program (OSKIRA) and its new drug application is expected to be filed with the FDA in 2013.29

14. Singh JA, Furst DE, Bharat A, et al. Arthritis Care Res (Hoboken).

2012;64:625-639.

15. Altman R, Asch E, Bloch D, et al. Arthritis and Rheumatism. 1986:29:1039-1049.

16. Aletaha D, Neogi T, Silman AJ, et al. Arthritis & Rheumatism.

2010;62:2569-2581.

17. National Institute for Health and Clinical Excellence. Osteoarthritis: National clinical guideline for care and management in adults. London: Royal College of Physicians, 2008.

18. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis & Rheumatism. 2002;46:328-346.

19. Hochberg MC, Altman RD, April KT. Arthritis Care and Research.

2012;64:465-474.

20. Vlieland V, et al. Rheumatology. 2007;46:1397-1404.

21. Theodora PM, Vlieland V, van den Ende CH. Curr Opin Rheumatol.

Conclusion

2011;23:259-264.

The differences between OA and RA, though both affect joints, exist in the pathophysiology, common symptoms, and diagnostic criteria; and reinforce the importance of understanding and correctly identifying these conditions. There is some overlap in management with the use of NSAIDs and glucocorticoids for OA and RA. The similarity ends there, as RA treatment with DMARDs continues to change disease outcomes. The clinician’s role is to keep patients involved in the care of their arthritis.

The self-care component of OA and RA treatment is aided by the useful information now available to patients on the internet. They can better manage their symptoms and improve their self-efficacy which ultimately leads to better outcomes (Table 2). ■

22. Zhang W, Moskowitz RW, Nuki G, et al. Osteoarthritis and Cartilage.

2008;16:137-162.

23. Adebajo A. BMC Family Practice. 2012;13:1-7.

24. Yeomans ND,Tulassay Z, Juhász L, et al. New Eng J Med.1998;338:719-726.

25. Miyake K, Ueki N, Suzuki K, et al. Aliment Pharmacol Ther.2005;21(Suppl2):67-72.

26. Buttgereit F, Mehta D, Kirwan J, et al. [Epub ahead of print]. Ann Rheum Dis. May 5, 2012.

27. Howes F, Buchbinder R, Winzenberg T. J Fam Pract. 2011;60;206-212.

28. Pfizer Inc. Pfizer pipeline–our medicines in development. www.pfizer.com/research/product_pipeline/product_pipeline.jsp.

29. Rigel Pharmaceuticals, Inc. Pipeline: fostamatinib (R788). www.rigel.com/rigel/rheumatoid_arthritis.

All electronic documents accessed September 15, 2012.

51 THE CLINICAL ADVISORIS•PROVIDED FEBRUARY BY 2012 • www.ClinicalAdvisor.com www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 51 THIS ARTICLE THE NURSE PRACTITIONER HEALTHCARE FOUNDATION THROUGH AN EDUCATIONAL GRANT FROM HORIZON PHARMA.

Physician Assistants Get your master’s degree in as little as one year— part-time and online.

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LEGAL ADVISOR CASE

© PHOTO RESEARCHERS, INC. / AJPHOTO

Incorrect triage caused critical delay A woman in her early 60s presented with chest pain and was miscategorized in the emergency department.

BY ANN W. LATNER, JD

Ms. Q was a nurse working in the emergency department (ED) of a regional medical center. She’d been employed at the medical center for about five years, and, although she liked the work in general, she was not thrilled about having to work nights and weekends. However, she liked her coworkers and found her job interesting.

One of the most challenging aspects of the job was the initial assessment of patients coming into the ED. After a brief examination and history, Ms. Q would decide how the case should be triaged. That decision is extremely important, as it affects how quickly each patient will be treated.

Ms. Q was on duty one night when Mrs. B, aged 61 years, came in. Mrs. B said that she suddenly began experiencing chest pain earlier in the day. She came into the ED at about 8:15 pm, and was seen by Ms. Q at 8:20 pm.

Mrs. B reported a history of smoking and hypertension, and told Ms. Q that the chest pain she was experiencing was severe and radiated down her arm, back, and neck. Mrs. B rated

The patient had a history of smoking and hypertension and reported severe chest pain that radiated down her arm, back, and neck.

48 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

her pain as “10,” the highest possible level.

Ms. Q took Mrs. B’s BP, which was elevated at 228/104 mm Hg. Based on these factors, Ms. Q placed the patient in the triage category of “urgent,” which was second only to the most severe category of “emergent.”

Dr. R, the attending physician, came to see the patient 15 minutes after initial assessment.

Dr. R reviewed Ms. Q’s notes and performed a physical exam. At about 8:30 pm, Dr. R ordered a diagnostic panel, chest x-ray, placement on a monitor, sublingual nitroglycerin, and GI medications for the patient. Because Mrs. B was not in the most severe triage category, these orders were not carried out immediately; it took about one hour for Mrs. B to be placed on a monitor and given medications.

The results of the diagnostic tests indicated that Mrs. B’s vital signs and cardiac enzymes 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.

LEGAL ADVISOR were normal, her chest x-ray was negative, and an ECG did not show any acute ischemic changes. Her BP had decreased to 154/88.

Late that night, Dr. R contacted Mrs. B’s regular physician, Dr. C, and advised him about the situation. Dr. C had the patient admitted for observation and testing, and he ordered that she be put on a blood-thinner. Dr. C also scheduled a stress test to rule out ischemic heart disease. However, by that evening Mrs. B was still doing very poorly. A second ECG was performed and the attending physician diagnosed an acute inferior-wall MI. Because the medical center did not have the capability for heart surgery, Mrs. B was transferred to another hospital for

The medical center has deeper pockets than an individual clinician does, so the plaintiff goes after the bigger target. a cardiac catheterization at 1:00 am. The catheterization revealed that Mrs. B had an aortic dissection—a tear in the ascending aorta above her heart—requiring emergency surgery. During surgery, a large hemorrhage and a hematoma were discovered, with excessive bleeding into the tissue around the right coronary artery and in the right ventricle.

The surgeon believed that Mrs. B had less than a 1% chance of surviving surgery and decided not to proceed.

Over the next week, Mrs. B had progressive deterioration of multiple organ systems since her heart was not able to pump enough blood throughout her body. She died about a week after going to the ED. Once Mrs. B’s husband recovered from the shock, he consulted with an attorney. After reviewing Mrs. B’s medical records with an expert, the attorney decided to take the case.

“Unfortunately, many things went wrong in your wife’s situation,” he told the widower. “It started right away when she wasn’t categorized as an emergency in the ED. That slowed down her treatment from the start. Then, the ED physician made the wrong diagnosis, and he didn’t order a CT scan. Your wife’s personal physician made things worse by presribing blood-thinners. My expert tells me that aortic dissection should have been suspected from the start, as your wife was exhibiting all the typical signs—sudden continuous chest pain, back pain, and hypertension. That, along with her age and the fact that she was a smoker, required

Dr. R to consider aortic dissection as a differential diagnosis. Yet, he merely ordered a chest x-ray, which does not out aortic dissection. Had your wife’s triage been properly categorized, she would have been given a CT scan, and the tear would have been discovered. Immediate surgery could have saved her life.”

The attorney initiated a suit against Dr. R, Dr. C, and the medical center, alleging that the nursing staff had incorrectly triaged the patient, leading to a delay in diagnosis and treatment, and ultimately, to Mrs. B’s death.

Ms. Q consulted with the medical center’s team of attorneys, who asked questions about her triage procedure. Had Mrs. B been a man, Ms. Q admitted, she probably would have rated the triage category “emergent,” but female patients with similar symptoms were generally considered “urgent,” since such patients were less likely to be having a heart attack.

The defense attorneys eventually filed a motion to dismiss the case against the medical center, but the court refused, on the grounds that there was enough evidence for a trial based on whether the treatment delay contributed to the patient’s death.

The case was settled out of court with Dr. R, Dr. C, and the medical center each contributing an undisclosed amount to the plaintiff.

Legal background

Ms. Q was sued through the medical center, not individually. This is quite common in cases involving clinicians who are not physicians, for two reasons. First, the medical center is ultimately liable for Ms. Q’s actions as an institutional employee. Second, the medical center has deeper pockets than an individual clinician does, so the plaintiff goes after the bigger target. Sometimes a plaintiff will sue both the medical center and the clinician.

Protecting yourself

When it comes to cardiovascular issues, research has shown that women may not be diagnosed or treated as aggressively as men. Studies have also shown that women are more likely than men to experience delays in emergency care for cardiac symptoms. It is important for clinicians to assess each patient without regard to gender stereotypes. Any delay in treatment, as this case demonstrated, can be the difference between life and death. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

Clinical Challenge Sudden onset of neurologic symptoms in an adolescent girl MARGARET QUINN, DNP, CPNP

Dizziness, photophobia, nausea, and an unsteady gait develop following a routine annual check up.

Ms. K, aged 16 years, presented to the emergency department (ED) after being seen by her primary-care clinician 48 hours earlier for an annual physical exam and immunization update. Physical assessment was unremarkable at that time. During that exam, Ms. K received her third dose of the human papillomavirus (HPV) vaccine, Gardasil.

Approximately one hour after administration, Ms. K’s mother found her unconscious and drooling and called 911.

Ms. K was seen in the local ED, where this was diagnosed as a transient reaction to the immunization. Following her discharge, Ms. K developed headache, photophobia, nausea, and an unsteady gait. Since falling unconscious, the teen reported a headache on a pain scale of 7/10, photophobia, dizziness and difficulty walking.

Ms. K’s pediatrician referred her to a regional pediatric center for further evaluation.

CASE

1. HISTORY Ms. K was an active teenager and honor-roll student who worked in a restaurant on weekends. She lived at home with both her parents and a younger healthy sibling. Ms. K’s medical history was significant for polycystic ovaries and irritable bowel syndrome. She had been healthy prior to the physician visit two days prior. All her immunizations were up to date, and family history was negative for any medical conditions.

Ms. K was not taking any medications and denied drug or alcohol use

© THINKSTOCK

2. EXAMINATION

Vasovagal responses occured spontaneously, which suggested an earlier trigger.

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

Ms. K’s vital signs in the ED were as follows: temperature 98.7° F, pulse 73 beats per minute (BPM), BP 110/69 mm Hg, respiration rate 20 inspirations per minute, pulse 93 BPM with oximetry 100% on room air. BP was 115/63 lying down, 117/73 while sitting, and 60/40 while standing. The teen appeared to be welldeveloped and well-nourished, but her behavior

Clinical Challenge was anxious and tearful. Ms. K’s lungs were clear and her heart sounds were normal, but she complained of nausea.

Her extremities were warm, and an unsteady gait was apparent. A detailed neurologic exam revealed that cranial nerves I-XII were intact, and the patient exhibited rapid, alternating movements that were coordinated and smooth.

Ms. K’s reflexes were intact, and there was evidence of a symmetrical response to pain with cutaneous hyperesthesia in soft-tissue areas. There were no meningismus signs.

3. LABORATORY DATA AND DIAGNOSIS A CT scan of the head, brain, and sinuses was ordered to rule out increased intracranial pressure; the findings were normal.

The following blood panels were performed and all were negative: a complete blood count, comprehensive metabolic profile, Epstein-Barr virus, erythrocyte sedimentation rate, and blood culture. The teen’s ECG was normal. Pediatric neurology was called in on consultation and advised that Ms. K be admitted to the hospital for observation. Ms. K’s diagnosis on her admission form included post-Gardasiladministration headache and syncope, vasovagal orthostatic hypotension, rule out sinusitis, rule out meningitis, and rule out transverse myelitis.

4. TREATMENT The adolescent was hydrated intravenously with both 0.9% normal saline solution and ketorolac (Toradol). She was also given strict bed-rest orders. Her BP increased with fluid hydration. After twenty-four hours of IV hydration and ketorolac, Ms. K was discharged from the hospital.

Her discharge orders included a prescription for naproxen (Naprosyn) 375 mg every eight hours and minimal activity, as tolerated. Over the course of 10 days, Ms. K’s body aches, headache, and dizziness subsided, and she was weaned from naproxen, returning to school and full activity.

5. DISCUSSION Two HPV vaccines are licensed by the FDA and recommended by the CDC. These vaccines are Cervarix and Gardasil. Both vaccines are very effective against diseases caused by HPV types 16 and 18; HPV 16 and 18 cause most cervical cancers, as well as other HPV-associated cancers.

Gardasil also protects against HPV types 6 and 11, and is the only HPV vaccine that has been approved for administration in males.

In the United States, the FDA- and CDC-sponsored Vaccine Adverse Event Reporting System (VAERS) collects and summarizes reported data on adverse events during immunization. VAERS uses a clinically validated standardized terminology for aggregating data and events.

Manufacturer reporting to VAERS is mandatory; however, most collected information comes from physicians, parents, or other primary reporters. Two and a half years after the recommendation for quadrivalent HPV vaccine administration, a summary of VAERS reports about Gardasil was published.1 An adverse event following immunization is classified as one that is “life threatening, and can result in death, permanent disability, congenital anomaly, hospitalization or prolonged hospitalization; or [one that] necessitates medical or surgical intervention to preclude these outcomes.”2 At the time this article was written, VAERS reports specific to Gardasil were triple the rate of all other vaccines combined. One reason was considered to be a greater public awareness about a “new product.”1 Syncope, dizziness, nausea, vasovagal responses, and headache were the most commonly reported side effects. A study from Australia acknowledged a higher-than-average anaphylaxis rate after the administration of the HPV vaccine as well. All reported patients in that study recovered after treatment with adrenaline.3 After the summary report was published, a Gardasil advisory was issued by the CDC. Clinicians were asked to observe patients for 15 minutes after administration of the vaccine. The Gardasil package insert acknowledges that syncope is sometimes associated with tonic-clonic movements, and has been reported after administration. The insert also states that this type of muscle spasm is transient and responds to the supine or Trendelenburg position.

The increased reporting of syncope after administration of HPV vaccination among teenage girls is attributed in part to an adolescent fear of medical procedures, dehydration, or pain responses.

Relative to the post-syncopal reports to VAERS in children older than age 5 years, 49% of Gardasil-reactive patients were adolescent females aged 11 to 18 years. At least one of the three adolescent vaccines (HPV vaccine; meningococcal conjugate vaccine; and tetanus, diphtheria, pertussis vaccine) was implicated in 60% of reports involving a single vaccine; HPV was the most frequently reported vaccine type (in 52% of single-vaccine reports).4 A statement on the CDC website detailed the Gardasilrelated adverse events on fi le.

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

Continues on page 56

Traumatic Brain Injury

Defense and Veterans Brain Injury Center More than 250,000 service members have sustained TBI in the past decade. National Guardsmen and Reservists returning home have unique clinical histories and presentations from war experiences. DVBIC in collaboration with the Department of Defense, Veterans Administration and its civilian partners advances the recovery of our wounded warriors with TBI. Visit us for extensive resources for you and your patients.

Clinical expertise and patient care Patient/family outreach Care coordination

Provider training Multimedia education Innovative clinical research

Serving Those Who Have Served Clinical Care. Education. Research. That’s DVBIC. BRAINLINEMILITARY.ORG

“It’s chicken, lightly battered in flour, dropped on a dirty floor by mistake the sautéed in lemon sauce anyway.”

INFO@DVBIC.ORG

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 55

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

DVBIC.ORG

Clinical Challenge As of September 15, 2011, approximately 40 million doses of Gardasil were distributed in the U.S. and VAERS received a total of 20,096 reports of adverse events following Gardasil vaccination: 19,075 reports among females and 569 reports for males, of which 504 reports were received after the vaccine was licensed for males in October 2009.

VAERS received 452 reports of unknown gender. Of the total number of VAERS reports following Gardasil, 92% were considered to be nonserious, and 8% were considered serious. As of September 15, 2011, there have been a total of 71 VAERS reports of death among those who have received Gardasil. There were 57 reports among females, three were among males, and 11 were reports of unknown gender.4 The alternative vaccine, Cervarix, which was licensed in October 2009, has a significantly lower level of adverse events, as reported to VAERS. As of September 2011, there have been only 52 reported adverse events with the majority (98%) being nonserious.

“How’s my inane chitchat?”

6. SUMMARY

“As far as we can tell, Mr. Schroeder, your glasses are smudged.” © The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

Reports of neurologic side effects of vaccinations are frequently received with varying degrees of skepticism. The CDC and FDA continually monitor all adverse events reported in conjunction with vaccines licensed in the United States. As providers involved in the distribution of the Vaccine Information Sheet, these organizations ensure that all vaccine information is included for parents and patients.

Vaccine safety is essential to preventing disease, but patient safety postimmunization is also vital. ■ Dr. Quinn is a clinical assistant professor at Rutgers College of Nursing. Her research interests include childhood-obesity interventions, primary-care pediatric issues, and vaccination safety.

References 1. Slade BA, Leidel L,Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302:750-757.

2. Chen RT, Rastogi SC, Mullen JR, et al. The vaccine adverse event reporting system (VAERS). Vaccine. 1994;12:542-550.

3. Brotherton JM, Gold MS, Kemp AS, et al. Anaphylaxis following quadrivalent human papillomavirus vaccination. CMAJ. 2008;179:525-533.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2527382/.

4. Human papillomavirus (HPV) vaccines page. Centers for Disease Control and Prevention website. Available at www.cdc.gov/hpv/vaccine.html.

All electronic documents accessed on September 15, 2012

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

“No refunds.”

CME CE

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

■ COMPLETE THE POSTTEST: Page 73

■ ADDITIONAL CME/CE: Pages 28, 67

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

CASE #1

Extremely pruritic rash on the back and chest ESTHER STERN, NP-C

A woman, aged 64 years, presented with an itchy rash on her back and chest of several weeks’ duration. She reported that small red dots appeared on the middle of her back and spread to the rest of the back and the upper chest within a few days. The itching was intense at times, and the patient could not control herself from vigorously scratching. No fever, malaise, or pain was reported. The woman had not started any new medications in the previous month. Physical exam revealed numerous discrete pink and red papulovesicles and erosions on the back and chest, along with scattered linear excoriations. The extremities, groin, and face were spared.

What is your diagnosis? Turn to page 58

CASE #2

Facial pustules after radiation treatment ADAM REES, MD

A man, aged 79 years, was referred by his radiation oncologist for treatment of a rash on his face and oral cavity. The man had a history of head and neck squamous cell carcinoma and had been undergoing radiation therapy for several months. This eruption developed six days after the most recent radiation treatment. The patient reported burning and “gnawing” pain. Multiple vesiculopustules were found on the upper right side of his face extending from his ear to his nasal tip, and he had conjunctival injection of the right eye. The right side of the palate was covered with confluent pustules and erosions.

What is your diagnosis? Turn to page 59 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 57

CME CE

CASE #1

Dermatology Clinic

Grover disease

Transient acantholytic dermatosis is more commonly referred to as Grover disease. In 1970 Grover described a pruritic transient eruption in persons older than age 50 years.

Although this condition is benign and eventually selflimiting, the rash tends to be persistent and recurrent for months to a few years. For this reason, several authors suggest renaming the condition persistent and recurrent acantholytic dermatosis.1 The middle-aged and senior population is most commonly affected. In addition, whites appear to be affected at a significantly higher rate. Incidence is slightly greater in men than in women.

Clinical findings in Grover disease typically consist of numerous discrete 3- to 5-mm red, pink, or brown papules, papulovesicles, and erosions. On palpation, lesions may appear to be hyperkeratotic or verrucous. Although the central trunk is affected most often, lesions may infrequently be found on the proximal extremities. The palms, soles, and scalp are almost always spared.

Pruritus, usually of abrupt onset, is a hallmark of Grover disease. However, the severity of dermatitis is not always consistent with the severity of itching. While patients may report being unable to sleep because of the pruritus, few papules or erosions may be present on physical examination.

Diagnosis is usually clinical, but there is also a high rate of misdiagnosis, particularly in the nondermatologic setting. A high index of suspicion for this condition is often necessary to make the diagnosis. Biopsy may aid in the diagnosis, but because the histologic features of Grover disease are very similar to other conditions, clinical correlation is necessary.

The characteristic histopathologic fi nding in Grover disease is acantholysis (separation of keratinocytes in the epidermis), often in conjunction with varying degrees of spongiosis. Five distinct histologic findings exist and include fi ndings simulating Darier disease, pemphigus vulgaris, pemphigus foliaceus, Hailey-Hailey disease (benign familial pemphigus), and spongiotic dermatitis.2 One biopsy specimen may contain several of these patterns.

Although Grover disease is often classified as a nonimmune vesiculobullous disease, direct immunofluorescence findings are negative and nondiagnostic.

The differential diagnosis for papulovesicles and erosions on the trunk include dermatitis herpetiformis, herpes infection, arthropod assault, scabies, miliaria, syphilis, Darier disease, folliculitis, and drug eruption.

Although there is no known etiology, several factors have been suggested to contribute to the disease. Some studies reported an association between Grover disease and exposure to heat3 and excess sweating,4 as can often be seen in bedridden patients. Patients often describe a history of preceding sun exposure, heavy sweat-inducing exercise, or fever.

Individuals with a history of atopic dermatitis are affected at a higher rate. A small number of cases have been described in association with lymphoma or other malignancies.

Treatment of Grover disease is aimed at reducing pruritus. Topical medium-potency corticosteroids are often the preferred treatment to reduce inflammation and relieve itching. Topical products containing menthol or pramoxine are also helpful. Oral antihistamines may be recommended, with the sedating variety reserved for nighttime use. In addition, hydroxyzine can be used as needed for itching.

Oral steroids, oral retinoids,5 phototherapy, dapsone, and methotrexate (Rheumatrex, Trexall) are reserved for more severe and refractory cases.

Instruct patients to avoid extreme heat and activities that may cause excess sweating. Skin care should include use of emollients and avoidance of very hot or prolonged bathing.

Education should include instructions regarding proper use of prescription medications and the risks associated with long-term use of topical corticosteroids. Advise patients that lesions may resolve with postinflammatory hyperpigmentation, and scarring may result from vigorous scratching.

Although Grover disease is usually a self-limiting disorder, some cases may persist or relapse intermittently. Many patients often return for frequent office visits to report that the rash is not resolving. For this reason, education regarding the chronic nature of the disease and natural history for spontaneous resolution will reassure many patients.

The patient in this case was educated regarding the chronic nature of her condition. Fluocinonide cream b.i.d. as needed for itching provided good relief. After three months, a significant decrease in the skin lesions was noted.

Ms. Stern is a family practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. James WD, Berger TG, Elston DM. Andrewsâ&#x20AC;&#x2122; Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-Elsevier; 2011:478.

58 THE CLINICAL ADVISOR â&#x20AC;˘ OCTOBER 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

2. Davis MD, Dinneen AM, Landa N, Gibson LE. Grover’s disease: clinicopathologic review of 72 cases. Mayo Clin Proc. 1999;74:229-234.

3. Hu CH, Michel B, Farber EM. Transient acantholytic dermatosis (Grover’s disease). A skin disorder related to heat and sweating. Arch Dermatol. 1985;121:1439-1441.

4. French LE, Piletta PA, Etienne A, et al. Incidence of transient acantholytic dermatosis (Grover’s disease) in a hospital setting. Dermatology.

1999;198:410-411.

5. Helfman RJ. Grover’s disease treated with isotretinoin. Report of four cases. J Am Acad Dermatol. 1985;12:981-984.

CASE #2

Herpes zoster

Herpes zoster (commonly known as shingles) is caused by reactivation of varicella zoster virus (VZV), which is the virus that causes chickenpox. After the initial chickenpox infection, the virus remains latent in the dorsal root ganglion cells of sensory nerves. In herpes zoster, the VZV becomes reactivated in selective dorsal root ganglia, travels down the length of the nerve axon, and infects the skin in the region of the corresponding dermatome. Older age, immunosuppressive drugs, lymphoma, AIDS, and radiation therapy are risk factors for reactivating the virus.1,2 The risk of developing zoster is as high as 30% for whites older than age 80 years. Blacks are four times less likely to develop zoster, for reasons that remain unknown.1,2 While the risk of developing recurrent zoster is quite low in immunocompetent patients, up to 25% of patients with AIDS will develop the condition.1,2 Classically, herpes zoster occurs unilaterally within a dermatome. The adjacent dermatomes directly above and below the primary dermatome may also be affected. The most frequently involved dermatomes are the thoracic (60%) and cranial (20%, with the trigeminal nerve being the most common), followed by the lumbar and sacral. The cutaneous eruption is often preceded by several days of pain in the affected dermatome. The eruption begins with red and sometimes edematous plaques involving some or all of the dermatome with vesicles of various sizes that may become purulent. Crops of vesicles occur for one week and subsequently crust over. As seen in the man in this

case, lesions may develop in the mouth when the maxillary and/or mandibular branches of the trigeminal nerve are involved. Elderly and debilitated patients may have more severe presentations complicated by hemorrhagic blisters, eschar-like crust, and significant scarring.1,2 Cutaneous disseminated herpes zoster is defined as greater than 20 lesions outside of the primary and immediately adjacent dermatomes. This type occurs primarily in elderly or debilitated patients, such as those with AIDS or Hodgkin lymphoma.1,2 Ophthalmic zoster occurs when the ophthalmic division of the trigeminal nerve is involved. Vesicles on the side and tip of the nose (i.e., the Hutchinson sign) specifically indicate involvement of the nasociliary branch of the ophthalmic division. When the Hutchinson sign is present, the risk of eye involvement is approximately 75%. Involvement of the eyelid margin portends an almost 100% risk of eye involvement. Prompt antiviral therapy reduces the risk of ocular complications from 50% to 25%. An urgent referral to an ophthalmologist should be made in all suspected cases of ophthalmic zoster.1,2 Pain is one of the most troubling and common complications of herpes zoster and may occur before, during, and/or after the cutaneous eruption. Pain that persists after the resolution of skin lesions is termed postherpetic neuralgia (PHN). In individuals older than age 70 years, for example, 75% continue to have pain beyond one month. In some cases, the persistent pain can be quite disabling.1,2 Other potential complications of herpes zoster include Ramsay Hunt syndrome (involvement of facial and auditory nerves), motor-nerve neuropathy, maxillary and mandibular alveolar bone necrosis, neurogenic bladder (involvement of sacral dermatomes), and vasculopathy of the central nervous system that can cause stroke.1,2 It is vital that clinicians recognize and diagnose herpes zoster, since prompt antiviral therapy can limit many of the sequelae of infection. The diagnosis of zoster should be considered any time a patient presents with pain or a rash in a dermatomal distribution. The diagnosis is most frequently made on clinical grounds. When further workup is required, a Tzanck smear may be performed in which the base of a vesicle is scraped with a blade, spread on a glass slide, and stained to evaluate for multinucleated giant cells. Viral culture has poor sensitivity. Direct fluorescentantibody (DFA) and polymerase chain reaction (PCR) tests are more sensitive.1,2 Antiviral therapy is used to treat herpes zoster and should be instituted immediately on suspecting the diagnosis. The most

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

CME CE

Dermatology Clinic

commonly prescribed antivirals are valacyclovir (Valtrex), famciclovir (Famvir), and acyclovir (Zovirax). One of the major benefits of therapy is reducing the duration and severity of herpes-associated pain and speeding the resolution of the skin lesions. In complicated cases or in the setting of immunosuppression, IV acyclovir is administered. Acyclovir is also the drug of choice in the setting of significant renal failure. In uncomplicated cases, valacyclovir 1,000 mg t.i.d. by mouth for seven days is the treatment of choice and is likely more effective than oral acyclovir, which must be given five times daily.1,2 Pain management acutely consists of nonsteroidal antiinflammatory medications and opioids in addition to such medications targeting neuropathic pain as gabapentin. In cases of complicated PHN, serotonin reuptake inhibitors, tricyclic antidepressants, and anticonvulsants are sometimes used. Topical lidocaine or capsaicin is occasionally beneficial.1,2 It has recently been shown that starting an oral gabapentin titration along with antiviral therapy at the time of diagnosis reduces the incidence of PHN.3

the patient was promptly evaluated by ophthalmology. The ophthalmologist noted only blepharitis and conjunctivitis and recommended cool compresses and topical lubrication with follow-up in two weeks. The patient started oral valacyclovir 1,000 mg t.i.d. and a gabapentin titration. After two weeks, all of the lesions had crusted over, but persistent burning over the right cheek was noted. The patient also reported excessive sedation from the gabapentin. The gabapentin was decreased, and nortriptyline (Aventyl, Pamelor) was started. At the two-month follow-up, the patient continued to complain of occasional paroxysms of pain. Fortunately, he suffered no serious ophthalmologic sequelae. ■ Dr. Rees is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

References 1. Habif TP. Warts, herpes simplex, and other viral infections. In: Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. Philadelphia, Pa: Mosby; 2009:474-479.

2. James WD, Berger TG, Elston DM. Viral diseases. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-

In uncomplicated cases of herpes zoster, valacyclovir 1,000 mg t.i.d. by mouth for seven days is the treatment of choice.

Elsevier; 2011:372-376.

3. Lapolla W, Digiorgio C, Haitz K, et al. Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study. Arch Dermatol.

2011;147:901-907. Available at archderm.jamanetwork.com/article. aspx?articleid=1105538.

4. Bolognia JL, Jorizzo JL, Rapini RP, eds. Human herpesviruses. In: Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1204-1208.

All electronic documents accessed September 15, 2012 © The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

The diagnosis in this case was made on clinical grounds based on the vesiculopustular eruption in a perfectly dermatomal distribution. No other dermatologic entity fits this presentation. Most cases of herpes zoster can be diagnosed clinically with no further workup. In rare instances in which the diagnosis is uncertain, the differential may include contact dermatitis, cellulitis, or bullous impetigo. Additionally, herpes simplex virus (HSV) can occasionally present in a zosteriform distribution. However, HSV is frequently a recurrent eruption, whereas zoster rarely recurs. When in doubt, VZV and HSV can be distinguished through DFA or PCR testing. Viral culture can also distinguish between VZV and HSV but is limited by poor sensitivity. All viral studies are negative in a bacterial infection or contact dermatitis.4 In this case, the patient’s age, debilitated state secondary to cancer, and recent history of radiation were risk factors for developing the eruption. The dermatomes involved were the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve. Because of the obvious involvement of the ophthalmic branch and the positive Hutchinson’s sign,

“Someday, son, all this will be yours.”

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

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ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

DHEA

© PHOTO RESEARCHERS INC. / SPL

Dehydroepiandrosterone (DHEA) is an endogenous, steroid hormone that many people consider to be the modern-day Fountain of Youth.

It’s widely marketed as an alternative means of perking up a lagging libido, building muscle, and even reversing the effects of aging. DHEA is produced by human adrenal glands and is secreted in the testes in men. It can be converted into the primary sex hormones—testosterone and estrogen.1 Scientists don’t yet know everything about how DHEA works in the body, but it’s clear that DHEA levels peak when we’re in our 20s and then go into a steady decline.

Background DHEA quickly became a controversial research topic when it was discovered in the 1930s.1 Scientists felt certain they had stumbled upon the perfect anti-aging compound.

Unfortunately, regulatory agencies saw the potential for abuse, and the FDA banned the sale of DHEA supplements in 1985. Although this ban was subsequently lifted in 1994, many sports organizations—including the National Football League, National Basketball Association, and National Collegiate Athletic Association—still forbid the use of DHEA supplements.2

Science In spite of DHEA’s potential, there are very few human trials documented before the 1990s, and none large enough to yield statistical significance.2 In addition, there are no studies to date on the long-term effects of DHEA.2 But as a precursor

to the dominant sex hormones, DHEA can cause higherthan-normal levels of androgens and estrogens in the body, thus potentially increasing the risk of hormone-sensitive cancers, such as prostate, ovarian, and breast cancers.

Initial research on DHEA supplementation (DHEA-S) in schizophrenia patients shows some benefits in the management of anxiety and depressive symptoms. In a randomized, double-blind study investigating the effects of DHEA administration on medication-induced extrapyramidal symptoms (EPS) in schizophrenics, DHEA-S appeared to have a significant effect on EPS with marked improvement in Parkinsonian symptoms.3 Collective research has suggested that DHEA-S may have adverse cognitive effects in postmenopausal women. A study conducted by researchers in the Department of Neurology at the University of North Carolina at Chapel Hill, indicates the like: In an analysis of 24-hour measurements of endogenous DHEA and DHEA-S, investigators found an increase in negative associations between DHEA-S levels

62 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE and cognition, suggesting a correlation between exogenous DHEA and impaired cognition.4 A recent review assessing the benefit of DHEA-S on muscle strength and physical functioning in adults older than age 50 years, was inconclusive.5 Several studies examined varying measures of muscle strength—handgrip, chest press, leg press, knee extension, and flexion—and showed no substantive differences between the DHEA-S cohort and controls for any endpoint.5 DHEA and circulating sex hormones (endogenous and exogenous) have also been linked to a decreased risk of heart disease. In one study, more than 2,000 middle-aged white men with no known cardiovascular disease (CVD) at baseline were enrolled in a 10-year study. Participants were tested for a multitude of indices, which were later correlated with any development of CVD during the trial. In this large, communitybased sample, the findings indicated that higher endogenous serum estradiol levels—as would be seen with DHEA-S—were consistent with a lower risk of CVD.6 One trial tested the effect of DHEA-S in patients with systemic lupus erythematosus (SLE).7 Prior studies evaluating the impact of DHEA-S in SLE patients were inconsistent in their findings. This review also failed to find evidence to substantiate or refute the benefits of DHEA-S in this patient population. The trial demonstrated improved quality-of-life scores and a reduction in flares in the DHEA cohort, but up to 30% of participants dropped out of the study prior to conclusion. The potential negative effects in the DHEA group included a lowering of serum HDL, a known antioxidant.7

DHEA-S. DHEA-S is not recommended for pregnant or lactating women.2

How supplied, dosage DHEA is supplied in capsules, tablets and injections. Dose-range recommendations are from 25 mg to 250 mg daily. A 5% -10% topical cream containing DHEA is also available for daily use.

Summary In schizophrenic patients, DHEA may aid in anxiety management.

DHEA and circulating sex hormones (endogenous and exogenous) have been linked to a decreased risk of heart disease.

While there is the potential for substantive health benefits with DHEA-S, the lack of consistent, positive clinical trial data at present makes this a weak therapeutic choice. DHEA-S may be a star of the future, but it is not shining brightly enough for selection at this time. ■ References 1. About herbs, botanicals, and other products: dihydroepiandrosterone page. Memorial Sloan Kettering Cancer Center website. Available at www.mskcc.org/ mskcc/html/69201.cfm.

2. DHEA page. Mayo Clinic website. Available at mayoclinic.com/health/dhea/NS_patient-dhea.

3. Nachshoni T, Ebert T, Abramovitch Y, et al.

Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: A randomized, double-blind placebo controlled trial.

Schizophr Res. 2005;79:251-256.

4. Parsons TD, Kratz KM, Thompson E, et al. DHEA supplementation and cognition in postmenopausal women.

Int J Neurosci. 2006;116:141-155.

5. Baker W, Karan S, Kenny AM. Effect of dehydro-

Safety, interactions

epiandrosterone on muscle strength and physical function in older adults: A systematic review.

66 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

J Am Geriatr Soc. 2011;59:997-1002.

6. Arnlöv, J,Pencina MJ, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men.

Ann Intern Med. 2006;145:176-184.

7. Sawalha AH, Kovats S. Dehydroepiandrosterone in systemic lupus erythematosus. Curr Rheumatol Rep. 2008;10:286-291.

All electronic documents accessed on September 15, 2012.

© PHOTO RESEARCHERS INC. / SPL

In recommended doses, few side effects were reported when DHEA-S were administered orally. Common side effects include fatigue, headache, tachycardia, nasal congestion, and acne.2 For women, the most common side effects are abnormal menses, emotional changes, headache, and insomnia. Patients with a history of heart disease, abnormal heart rhythms, hypercoagulability, and liver disease should avoid

CME CE

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

■ COMPLETE THE POSTTEST: Page 73

■ ADDITIONAL CME/CE: Pages 28, 57

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

White plaques in the oral cavity KERRI ROBBINS, MD, AND DAMJAN JUTRIC

CASE #1

CASE #2

A woman, aged 56 years, under care for treatment of angular cheilitis, presented to the dermatology clinic after noticing white plaques on her bilateral buccal mucosa. The lesions were asymptomatic. Application of clotrimazole 1% cream, which was given at a prior appointment for treatment of the angular cheilitis, had provided no relief. No other skin or vulvovaginal lesions were reported. Social history was negative for alcohol or tobacco use. Physical examination was significant for lacy-white plaques on bilateral buccal mucosa.

A man in his early 50s presented with complaints of an asymptomatic white patch on his left ventral tongue.

The lesion had been present for six months and did not appear to be increasing in size. No prior or current trauma was associated with the lesion. Social history was notable for a history of tobacco use. On physical examination, a well-defined and homogenous white plaque with erythema at the proximal border was appreciated on the left ventral tongue. There was no induration of the lesion or cervical lymphadenopathy.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 67

CME CE

CASE #1

Dermatologic Look-Alikes

Lichen planus

In 1869, British physician Erasmus Wilson first described lichen planus (LP).1 Wilson likely derived the after observing that the skin lesions were flat in appearance (planus is the Latin word for flat) and looked similar to lichens, primitive plants composed of symbiotic algae and fungi.

LP is a common, chronic, inflammatory dermatologic disease. Cutaneous LP is used to describe lesions that affect the skin, whereas oral lichen planus (OLP) is the term used to describe lesions that primarily affect the tongue and oral mucosa. OLP affects approximately 1% to 4% of the adult population and typically develops between age 30 years and age 60 years. There is no overt racial predisposition, but women may be affected twice as often as men. OLP may be the only manifestation of the disease; however, OLP can also be observed in up to 75% of patients with cutaneous LP.2 Interestingly, only 10% to 20% of patients whose initial presentation is that of OLP will go on to develop cutaneous LP.2 Although the etiology remains unknown, an increasing amount of evidence suggests that LP is caused by autoimmune T-cell mediated damage to basal keratinocytes.

Such exogenous agents as viruses, medications, and contact allergens may cause an alteration in the antigenicity of epidermal cells. This alteration leads to an inflammatory reaction that causes T cells to migrate from the circulation into a particular skin site. These T cells then function to eliminate abnormal keratinocytes, which are altered by these exogenous agents. Such autoaggressive reactions can then lead to a situation in which T cells initially responding to self-antigens modified by exogenous agents subsequently become cross-reactive with self-epitopes. Therefore, these T cells chronically respond to self-epitopes, leading to a perpetuated autoimmune attack.

Of the many exogenous antigens, viruses—especially the hepatitis C virus (HCV)—are thought to play a major role in the development of LP. OLP is the form that is most commonly viewed as a manifestation of HCV infection. In one study, HCV RNA was detected in 93% of OLP lesions.3 Such contact allergens as gold, mercury, and palladium are commonly used in dental restorations, and easy penetration of these metals through damaged mucosa may exacerbate or

induce lesions of OLP. Patch testing should be considered in patients with OLP, especially if the lesions are in close contact with amalgam fi llings. Strangely, while approximately 95% of individuals with a positive patch test had improvement of their OLP after removal of the sensitizing metal, 75% of individuals with a negative patch test also reported improvement.2 Finally, cutaneous eruptions that mimic LP (clinically and histologically) have been linked to a variety of medications.

OLP favors the buccal mucosa, tongue, and gingival tissue. Clinically, there are seven different subtypes of OLP; reticular, pigmented, atrophic, erosive, papular, bullous, and plaque-type. Patients may exhibit one or several forms, with the reticular and erosive subtypes being the

Cutaneous eruptions that mimic lichen planus (clinically and histologically) have been linked to a variety of medications. most common presentations. Reticular OLP is characterized by white linear plaques that are most commonly seen forming a lacelike pattern (Wickham’s striae). These lesions are usually asymptomatic, tend to wax and wane, and are typically found bilaterally on the posterior buccal mucosa. In contrast, the lesions of erosive OLP are often symptomatic, with patients complaining of mild to severe burning pain. Clinically, atrophic erythematous plaques are seen with varying degrees of central ulceration. When lesions are restricted to the gingival mucosa, the reaction pattern is termed desquamative gingivitis.

Cutaneous LP lesions are characterized by hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis with a “sawtooth” appearance, liquefactive degeneration of the basal cell layer, and a lymphocytic lichenoid infiltrate. Lesions of OLP often show parakeratosis rather than hyperkeratosis, and the epidermis is usually atrophic or ulcerated. Direct immunofluorescence (DIF) reveals shaggy deposits of fibrinogen at the dermal-epidermal junction with occasional granular deposits of immunoglobulin (Ig) M or linear deposits of C3 and/or IgG. While the DIF findings are characteristic of LP, immunofluorescent studies are not necessary in classic cases.

Reticular OLP may be confused with the localized form of discoid lupus erythematosus, which is characterized by white plaques with an erythematous halo. White sponge

68 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

nevus and leukoplakia are common white lesions in the oral cavity that may also mimic reticular OLP. In cases of erosive OLP or desquamative ginigivitis, biopsy specimens should be obtained for light microscopic and immunofluorescent studies of perilesional tissue because pemphigus vulgaris and mucous membrane pemphigoid may demonstrate a similar clinical presentation. Erythroplasia and carcinomas must also be histologically differentiated from OLP. Because of its asymptomatic nature, reticular OLP does not usually need treatment and commonly undergoes spontaneous remission approximately five years after onset.4 Erosive OLP rarely resolves spontaneously and can cause significant discomfort. First-line treatment often includes a strong topical corticosteroid (fluocinonide, betamethasone, clobetasol gel) applied several times a day. Tacrolimus (Hecoria, Prograf) 0.1% ointment has also been found to be effective in reducing the symptoms of OLP. Most lesions tend to resolve within one to two weeks but will undoubtedly recur. For more recalcitrant cases, consider oral prednisone, cyclosporine, or retinoids.

Patients should be encouraged to eliminate alcohol and tobacco, eat a nutritious diet, and perform regular selfexaminations to evaluate for change within the lesions.

Individuals with OLP have a slightly increased risk of oral squamous cell carcinoma and should be followed regularly by a health-care provider.

Since the patient in this case was asymptomatic, no treatment was initiated. A screen for hepatitis C was negative.

She continues to be followed in the dermatology clinic to monitor for disease progression.

CASE #2

Oral leukoplakia

Oral leukoplakia (OL) is strictly a clinical term and does not imply a specific histopathologic disease process.

OL is considered a diagnosis of exclusion that is given after all other entities that appear as white plaques in the mouth have been ruled out. While it is not associated with a specific histopathologic diagnosis, it is considered by most to be a precancerous lesion. Approximately 1% to 5% of the U.S. adult population has OL, and males are twice as likely to be affected by the disease as females. Typical age

of onset is older than 30 years, with a peak incidence older than age 50 years.

While the etiology of OL remains unknown, there is a strong association with tobacco use, UV radiation, and candidiasis. Tobacco use seems to be the most common cause, with approximately 80% of OL patients being tobacco users. Those who are heavy smokers have more lesions and larger lesions than do light smokers. In addition, many who stop smoking either have resolution or improvement of the leukoplakia within the first year of cessation.5 People who use smokeless tobacco products produce a distinctive white oral plaque called tobacco pouch keratosis, which is not considered a true OL. Some believe that the use of alcohol may be a risk factor for developing OL, while others believe that alcohol consumption may lead to grayish buccal mucosal plaques, which are not considered a true OL. OL caused by UV radiation is often found on the lower lip vermilion in transplant or immunocompromised patients.

Candida is a known pathogen associated with the production of a thick white and erythematous plaque on the oral mucosa, which is termed candidal leukoplakia. Biopsies of these lesions may show dysplastic or hyperplastic changes. It is unknown whether Candida induces these changes within the epithelium or preferentially infects previously altered epithelium. The dysplasia often resolves or improves after antifungal treatment.

Physical trauma or chronic irritation to the oral mucosa may lead to a thickened hyperkeratotic white plaque known as frictional keratosis. Although clinically similar to leukoplakia, the lesion is thought to be a normal hyperplastic response (like a callus) and is not considered precancerous.

OL most commonly appears as a homogenous or nonhomogenous white plaque. The former is the more common variant, often appearing as a smooth white plaque with welldemarcated borders. The surface may appear translucent, fissured, or wrinkled, and lesions are typically soft and flat.

Non-homogenous (speckled or granular) lesions of OL develop more surface irregularities. When the surface becomes so irregular that it develops sharp or blunt projections, the condition is termed verruciform leukoplakia. Approximately 70% of OLs are found on the lip vermilion, gingiva, and buccal mucosa. More than 90% of OLs that show dysplasia or undergo malignant transformation are non-homogenous lesions that are found on the lip vermilion, tongue, and floor of the mouth. Clinical features alone are not sufficient to determine malignant versus premalignant lesions, so a biopsy with histologic examination is mandatory.

Lesions of OL will typically demonstrate such benign features as hyperkeratosis and acanthosis.5 Various degrees

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ OCTOBER 2012 69

Dermatologic Look-Alikes

of dysplasia may also be seen. Mild epithelial dysplasia is characterized by alterations that are limited to the basal and parabasal layers. Moderate epithelial dysplasia is characterized by dysplastic changes that extend to the midpoint of the spinous layer. Severe epithelial dysplasia demonstrates atypical cells that involve most of the epithelial thickness.

Carcinoma in situ is the term used when the dysplastic changes involve the entire thickness of the epithelium.

Lichen planus, morsicatio (chronic cheek nibbling), frictional keratosis, tobacco pouch keratosis, nicotine stomatitis, leukoedema, and white sponge nevus all can be mistaken for OL. Careful clinical and histologic examination can help to differentiate between these disorders.

Because of the malignant nature of OL, a biopsy specimen in the most severe region of the lesion is mandatory.

If no dysplasia or mild dysplasia is present at a low-risk site, then the decision is often made to clinically evaluate the lesion every six months and discontinue any potentially carcinogenic habits. Approximately 4% of OL patients will eventually develop carcinoma.6 If there is moderate or severe dysplasia, lesions may be removed with surgical excision, laser ablation, cryosurgery, or electrocautery. Long-term follow-up after removal is necessary because recurrences are frequent.

In this case, a biopsy of the lesion was performed, revealing hyperkeratosis, acanthosis, and mild dysplasia. The man was advised to discontinue tobacco use and is being followed in the clinic every six months to monitor for malignant transformation. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. Mr. Jutric is a second-year dental student at The University of Texas School of Dentistry, also in Houston.

“You call that nudity, strong language, and scenes of a sexual nature. ”

“The scales say ‘alien overlord,’ but the rolled-up sleeves say ‘man of the people.’”

References 1. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25:593-619.

2. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008: 159, 167-168, 170, and 1049-1050.

3. Nagao Y, Kameyama T, Sata M. Hepatitis C virus RNA detection in oral lichen planus tissue. Am J Gastroenterol. 1998;93:850.

4. Mignogna MD, Lo Muzio L, Lo Russo L, et al. Oral lichen planus: different clinical features in HCV-positive and HCV-negative patients.

Int J Dermatol. 2000;39:134-139.

5. van der Waal I, Schepman KP, van der Meij EH, Smeele LE. Oral leukoplakia: a clinicopathological review. Oral Oncol. 1997;33:291-301.

6. Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer. 1967;20:2189-2193.

“I regret that my poor choice of words caused some people to understand what I was saying.”

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

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

CME CE

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

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CLASSIFIEDS NP/PA WANTED

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

PA WANTED

NP WANTED

Physician Assistant Program

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

The University is completing a new $27 million building, with state-of-the-art facilities. EOE

Didactic Faculty

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

Clinical Coordinator

DeSales University seeks a Clinical Coordinator for its Physician Assistant Program. This 12-month, full-time, nontenure-track position is responsible for obtaining and maintaining clinical training sites for students and visiting and evaluating students and their preceptors during their clinical rotations within the greater Lehigh Valley. One day per week is given for continued clinical practice. Clinical experience as a certified physician assistant required; master’s degree and successful teaching experience preferred. Salary and rank will be commensurate with experience.

All positions begin prior to the fall semester 2013. For each position, please send letter of application, curriculum vitae, three letters of recommendation, and photocopies of educational transcripts to: Father Peter Leonard, OSFS, Dean of Graduate Education, DeSales University, 2755 Station Ave., Center Valley, PA 18034-9568 or to peter.leonard@desales.edu. Review of applications begins immediately and continues until the positions are filled.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2012 71

CLASSIFIEDS

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

NP WANTED

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Flagstaff Medical Center was recently

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Berkshire Health Systems offers a competitive salary and benefits package, as well as the opportunity to work in an environment where you will be challenged, supported, and respected. Relocation assistance offered as well. For more information about how you can become a part of our team, please contact:

Antoinette Lentine Berkshire Medical Center 725 North St. Pittsfield, MA 01201 Phone: (413) 395-7866 Fax: (413) 496-6817 Email: alentine@bhs1.org EOE Please visit our website at: www.berkshirehealthsystems.com 72 THE CLINICAL ADVISOR • OCTOBER 2012 • www.ClinicalAdvisor.com

CE

POSTTEST Expiration date: October 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 0.5 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

CREDITS: 0.5

Dermatology Clinic

Dermatologic Look-Alikes

page 57

page 67

Case #1: Grover disease

Case #1: Lichen planus

1. What is a hallmark of Grover disease? a. Abrupt onset of pruritus b. Diffuse telectangias c. Small vesicles in clusters d. Excessive skin friability

1. Oral lichen planus (OLP) is most commonly associated with a. Hepatitis C virus b. Hepatitis B virus c. Human papillomavirus d. Herpes simplex virus

2. What is the preferred initial treatment of Grover disease? a. Phototherapy b. Dapsone gel (Aczone) c. Methotrexate (Rheumatrex, Trexall) d. Hydroxyzine

2. What is the treatment of choice for reticular OLP? a. Oral prednisone b. Cyclosporine c. Oral retinoids d. Watchful waiting Oral leukoplakia

Case #2: Herpes zoster 3. What is a risk factor for reactivation of the varicella zoster virus? a. Older age b. Immunosuppressive drug therapy c. Radiation therapy d. All of the above 4. Which cranial nerve dermatome is most commonly affected in herpes zoster infection? a. Optic b. Trigeminal c. Facial d. Vagus

3. Which of the following is the most common cause of oral leukoplakia (OL)? a. Chronic irritation b. Tobacco smoking c. Candidiasis d. UV radiation 4. What is used to determine whether an OL lesion demonstrates dysplasia? a. Biopsy b. Wood’s lamp c. Tzanck smear d. Diascopy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermOct2012

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

CME

POSTTEST Expiration date: October 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 2012. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 0.5 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 57

page 67

Case #1: Grover disease

Case #1: Lichen planus

1. What is a hallmark of Grover disease? a. Abrupt onset of pruritus b. Diffuse telectangias c. Small vesicles in clusters d. Excessive skin friability

1. Oral lichen planus (OLP) is most commonly associated with a. Hepatitis C virus b. Hepatitis B virus c. Human papillomavirus d. Herpes simplex virus

2. What is the preferred initial treatment of Grover disease? a. Phototherapy b. Dapsone gel (Aczone) c. Methotrexate (Rheumatrex, Trexall) d. Hydroxyzine

2. What is the treatment of choice for reticular OLP? a. Oral prednisone b. Cyclosporine c. Oral retinoids d. Watchful waiting Oral leukoplakia

Case #2: Herpes zoster 3. What is a risk factor for reactivation of the varicella zoster virus? a. Older age b. Immunosuppressive drug therapy c. Radiation therapy d. All of the above 4. Which cranial nerve dermatome is most commonly affected in herpes zoster infection? a. Optic b. Trigeminal c. Facial d. Vagus

3. Which of the following is the most common cause of oral leukoplakia (OL)? a. Chronic irritation b. Tobacco smoking c. Candidiasis d. UV radiation 4. What is used to determine whether an OL lesion demonstrates dysplasia? a. Biopsy b. Wood’s lamp c. Tzanck smear d. Diascopy

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermOct2012

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

COMMENTARY Catherine A. Yorio, MSN, FNP, CCRN, practices in the University of Pittsburgh Medical Center (UPMC) Health System in Pittsburgh, Pa.

Selling your patients on health As health-care providers, best practice would have us become professional educators. In acute-care settings, the priority in patient/caregiver education is often reactive, focused on disease processes and the steps needed to restore health. Proactive disease prevention and health-promoting patient education is a hallmark in the venue of primary-care providers. The opportunity for proactive patient education is present with every patient encounter.

Health promotion and the prevention of chronic disease are topics at the forefront of national discussions on health care. But are we doing enough to promote health? Are we engaging

We need to develop sales tactics to engage the customer to want our product— health—and to put forth some effort to achieve it.

individuals in a way that makes them want the outcome of compliance with evidence-based guidelines for a healthful lifestyle? We need to promote a new culture—a culture that values health and values an improved quality of life.

We know we are excellent educators, but we need to develop sales tactics to engage the customer to not only want our product—health— but also to be willing to put forth some effort and sacrifice to achieve it. Do people know that physical exercise is a form of primary prevention?

The health-promotion movement would benefit from dynamic marketing strategies. It is difficult to engage patients in active behavioral and lifestyle changes when the effects of bad choices and loss of health are distant and often hard to envision until they are upon us; for example, the instant gratification of poor food choices vs. the comorbidities associated with obesity in the long-term.

Motivational patient education must come from each health-care provider, selling personal health responsibility to patients. Every intervention we promote (vaccines, safety, lifestyle habits, screenings, weight management) influences health and quality of life. Each encounter should include time spent identifying the patient’s needs, his or her motivations for making a healthful change, and his or her personal goals.

Can we engage the patient’s commitment to ensure health or pursue improved health?

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

As practitioners, we need to provide information that helps patients understand the modifiable risks to their health, including the ramifications of allowing risk factors to go unchecked on long-term health and quality of life. Our patients need to be aware of the consequences of poor choices and have to want to maintain or restore their health as much as we want it for them. We need to foster in them a sense of responsibility for achieving and maintaining health and encourage their confidence to make the lifestyle changes needed to succeed.

We are empowering patients when we invite them to play an active role in their own health through better understanding of how the choices they make today affect their long-term quality of life. Proactive health promotion and disease-prevention education in the pediatric setting has the potential to influence an entire generation of adults to value health and to take personal responsibility for maintaining it.

Focusing patient education on evidence-based guidelines ensures that we are consistent in our message. Also, encourage patients to consult such valid websites as the Centers for Disease Control and Prevention (www.cdc.gov) and the National Institutes of Health (www.nih .gov). These resources are available to the public and provide evidence-based practice guidelines for health promotion, disease prevention, and disease management. ■

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. Brief Summary Retin-A Micro® (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1% or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.

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

The physician should be thoroughly familiar with the complete prescribing information before prescribing the product.

INDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the use of this product in the treatment of other disorders have not been established.

CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.

PRECAUTIONS: General: • The skin of certain individuals may become excessively dry, red, swollen, or blistered. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established.

If a reaction suggesting sensitivity occurs, use of the medication should be discontinued.

Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful.

• Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided.

• Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.

• Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.

• Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

Information for Patients: A Patient Information Leaflet has been prepared and is included with each package of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%.

Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is begun.

Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of these clinical formulations (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose applied topically, when normalized for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose applied topically is defined as 1 gram of Retin-A Micro (tretinoin gel) microsphere, 0.1% applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).

Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel) microsphere, 0.04% or 0.1%.

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photo­carcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

The components of the microspheres have shown potential for genetic toxicity and teratogenesis.

EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay.

In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topically and normalized for total body surface area) and above were observed. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area).

Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) micro­sphere, 0.1% or 0.04%, have not been performed in any species.

Pregnancy: Teratogenic Effects: Pregnancy Category C. In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.5 to 1 mg/kg/day on gestation days 6-15 (4 to 8 times the maximum human systemic dose of tretinoin normalized for total body surface area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%) some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant

New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.2, 0.5, and 1.0 mg/kg/day, administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. There appeared to be increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 3 times the maximum human systemic dose of tretinoin after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area. In a repeat study of the highest topical dose (1.0 mg/kg/day) in pregnant rabbits, these effects were not seen, but a few alterations that may be associated with tretinoin exposure were seen. Other pregnant rabbits exposed topically for six hours to 0.5 or 0.1 mg/ kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects at doses up to 17 times (1.0 mg/kg/day) the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for total body surface area, but fetal resorptions were increased at 0.5 mg/kg. In addition, topical tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in rats and rabbits when given in doses of 42 and 27 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% gel topically).

At these topical doses, however, delayed ossification of several bones occurred in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed.

Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin was teratogenic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is more similar to humans than other species in its handling of tretinoin, fetal malformations were reported for doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose normalized for total body surface area), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.

Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids.

There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

Non-Teratogenic Effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose applied topically and normalized for total body surface area), resulting in fetal resorptions and variations in ossification. Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (21 times the maximum human systemic dose applied topically and normalized for total body surface area).

There are, however no adequate and well-controlled studies in pregnant women.

Animal Toxicity Studies: In male mice treated topically with Retin-A Micro (tretinoin gel) microsphere 0.1%, at 0.5, 2.0, or 5.0 mg/kg/day tretinoin (2, 8, or 21 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area) for 90 days, a reduction in testicular weight, but with no pathological changes were observed at the two highest doses. Similarly, in female mice there was a reduction in ovarian weights, but without any underlying pathological changes, at 5.0 mg/kg/day (21 times the maximum human dose). In this study there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.2, 0.5, or 1.0 mg/kg/day tretinoin (5, 12, or 25 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathological changes.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.

Geriatric Use: Safety and effectiveness in a geriatric population have not been established.

Clinical studies of Retin-A Micro did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

ADVERSE REACTIONS: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate.

However, efficacy has not been established for lower dosing frequencies.

True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin.

OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical use only. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Rx only.

Distributed by: Ortho Dermatologics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Los Angeles, CA 90045 11DD0126 07/11 © OMP 2011 RETIN-A MICRO ® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc. ® MICROSPONGE is a registered trademark of AMCOL International Corporation.