August 2012 Clinical Advisor

THE CLINICAL ADVISOR • AUGUST 2012

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IMPORTANT CORRECTION NOTICE FROM THE SPONSOR You may have seen this advertisement for LYRICA® (pregabalin) in the May 2012 issue of this publication.

That ad did not include the correct “brief summary” of the prescribing information for the drug’s Fibromyalgia indication. The correct brief summary is printed on the following pages.

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 PBP487014-01

© 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.

August 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: [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)* ≥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

CONTENTS AUGUST 2012

NEWS AND COMMENT 15

71

55

■ A teenager develops painful, itchy vesicles and bullae on his feet.

Newsline ■ CKD as much of a risk as previous MI? ■ Unnecessary colorectal cancer screening ■ Not all patients should get CVD risk counseling ■ And more

■ Multiple providers misdiagnose a man’s papulosquamous plaques.

59

Alternative Meds Update Topical calendula is used to reduce inflammation and treat leg ulcers.

61

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

Minimize admissions for heart failure Novel approaches may be required to help patients make lifestyle changes.

65

CME/CE Posttest

66

Evidence-Based Medicine

CME/CE Infections, tumors, and lumps affecting the scrotal content A lump, enlarging scrotum, or pain can conjure up images of testicular cancer, but other conditions are possible.

ADVISOR FORUM

Commentary

CKD as a predictor of coronary risk 15

FEATURES 23

36

CME/CE Dermatology Clinic

42 Alleviating anxiety over scrotal abnormalities 36

44

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

49

Legal Advisor Poor communication on the surgical team leads to a fire in the OR.

52

Clinical Challenge An older woman on dialysis develops a painful skin ulcer on her breast.

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Clinical Pearls ■ Polishing off a sticky situation ■ Avoid vitamin A supplementation

48

MAKING CONTACT

Consultations ■ Inflammation on a Pap smear ■ And more

in smokers

Calendula is used to treat skin irritations 59

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THERAPEUTIC NUTRITION

For the varying needs of your pediatric patients.

POLYMERIC (INTACT PROTEIN)

Abbott Nutrition Pediatric Therapeutic Nutrition

AGES: 1–13

PEPTIDE AGES: 1–13

AMINO ACID AGE: BIRTH TO 12 MONTHS

AGE: 1 YEAR AND UP

Complete nutrition for your patients’ unique needs.

Trust the Abbott portfolio of nutritional products to help maximize each patients’ potential.

As they grow and experience new challenges, there’s a formula that can help support their nutritional needs.

USE UNDER MEDICAL SUPERVISION. EleCare®, EleCare® Jr, and PediaSure® are trademarks of Abbott Laboratories. © 2012 Abbott Laboratories 79489.001/JUNE 2012 LITHO IN USA

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives 2012 U.S. pertussis rates expected to reach record level During the first six months of 2012, Washington state reported 2,520 pertussis cases — a 1,300% increase from the first six months of 2011, the CDC reports.

Dogs at home mean fewer breathing problems for children Frequent contact with dogs during the first year of life may protect children from respiratory illness.

Artificial sweeteners may aid weight loss Artificial sweeteners may help people reach and maintain a healthy body weight, as long as those who use them do not compensate for the calories cut.

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

Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Leigh Montejo, MSN, FNP-BC Improving health literacy in primary care The U.S. Department of Health and Human Services has made improving health literacy in the primary-care setting a priority, adding it to the list of Healthy People 2020 initiatives.

Sharon M. O’Brien, MPAS, PA-C Making sense of somniloquy Sleep-talking is relatively common, but could it be a symptom of another health problem?

Robyn Carlisle, MSN, CNM, WHNP Teaching the art of doing nothing on the maternity ward Labor, particularly one that is left to progress naturally, can be a perfect time to teach new clinicians that not everything needs to be managed.

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A patient with erosions and reddish urine Mildly painful blisters and erosions on the back of a patient’s hands, forearms, and neck leave small scars after healing.

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The Waiting Room

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.

Newsline A U G U S T 2 0 12

Who should get CVD risk counseling? page 16

Walking speed may indicate cognitive troubles page 22

Another reason to get at least six hours of sleep page 22

© PHOTO RESEARCHERS, INC / BIOPHOTO ASSOCIATES

CKD as much of a risk as previous MI?

CHRONIC KIDNEY DISEASE (CKD) could earn a spot near “previous heart attack” on the list of criteria defining people at highest risk of future coronary events, suggest the findings of a study led

by Marcello Tonelli, MD, and described in The Lancet.

In a population-based cohort of more than 1.2 million persons with measures of estimated glomerular filtration rate (eGFR) and proteinuria, 11,340 were hospitalized with an MI during a median follow-up of 48 months.

The unadjusted MI rate was highest in those with previous MI (18.5 per 1,000 person-years).

Among people without previous MI, the rate of MI was higher in those with CKD but without diabetes (6.9 per 1,000 personyears) than in those with diabetes but without CKD (5.4 per 1,000 person-years). The rate of incident MI in people with diabetes

Exudative lesions (dark) associated with diabetic renal disease

(6.6 per 1,000 person-years) was substantially lower than the rate among those with CKD (12.4 per 1,000 person-years) when defined by eGFR of less than 45 mL/min/1.73m2 and severely increased proteinuria.

Another large study addressed the cardiovascular risk factor of even just slightly elevated blood glucose levels. Data from 80,522 individuals from Copenhagen, Denmark, showed that 14,155 patients developed ischemic heart disease (IHD) and 6,257 suffered an MI. Risks for both conditions rose with increasing nonfasting glucose levels. The hazard ratio for IHD in persons with nonfasting glucose levels of 198 mg/dL or higher compared with persons with levels below 90 mg/dL was 6.9 when adjusted for age and sex and 2.3 adjusted multifactorially. Corresponding values for

MI were 9.2 and 4.8 ( J Am Coll Cardiol. 2012;59:2356-2365).

Finally, a review of four studies originally conducted in Sweden and a fifth study originally conducted in Finland demonstrated a link between moderate coffee consumption and a lower risk of heart failure. As Murray A. Mittleman, MD, DrPH, and colleagues reported online ahead of print in the journal Circulation Heart Failure, in 6,522 heart failure events among 140,220 men and women, an association emerged between moderate coffee consumption—the equivalent of approximately two typical 8-oz American coffees—and a risk of heart failure up to 11% lower than the risk seen in non-coffeedrinkers. Excessive coffee consumption, however, conferred no protection against heart failure, and might even raise the risk.

EHR satisfaction among office-based physicians The majority of physicians (85%) were satisfied with their electronic health record system.

38% Very satisfied

Very dissatisfied 5% 10%

Source: CDC/NCHS, Physician Workflow study, 2011

Somewhat dissatisfied

47% Somewhat satisfied

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 15

Newsline A SIGNIFICANT proportion of primary-care physicians (PCPs) would recommend colorectal cancer screening for elderly patients with a severe illness, a recent survey revealed. Although guidelines recommend such screening for persons aged 50 years and older, elderly patients with severe illnesses are unlikely to benef it from early cancer detection and may suffer harm from the screening process.

A total of 1,266 general internal medicine, family practice, and obstetrics-gynecology physicians were given nine clinical scenarios representing patients aged 50, 65, and 80 years who were either healthy with no illness, moderately severely ill (with ischemic cardiomyopathy), or severely ill (with advanced lung

cancer). The respondents were then asked which, if any, screening tests they would recommend for a given patient.

For an 80-year-old patient with inoperable non-small cell lung cancer, 25% of the PCPs would recommend colorectal cancer screening. For an 80-year-old person with ischemic cardiomyopathy, 71% of the respondents recommended colorectal cancer screening.

David A. Haggstrom and fellow researchers also reported in Journal of General Internal Medicine that the physicians were more likely to recommend fecal occult blood testing than colonoscopy as the preferred screening modality for a healthy 80-year-old than for healthy 50- or 65-year-old patients (19%, 5%, and 2%, respectively).

© PHOTO RESEARCHERS, INC. / OLIVIER VOISIN

Unnecessary colorectal cancer screening

A virtual colonoscopy creates 3-D images of the large intestine.

Obstetrician-gynecologists were the physicians most likely to recommend colorectal cancer screening for the oldest, sickest patients, and physicians working from a full electronic medical record were less likely to recommend screening.

DESPITE ITS recent recommendation that all adult patients be screened for obesity, the United States Preventive Services Task Force (USPSTF) is also advising primary-care clinicians to be selective about which patients they counsel regarding behavioral interventions to improve diet and physical fitness and ultimately reduce cardiovascular disease (CVD) risk.

In a grade C recommendation published by Annals of Internal Medicine, Virginia A. Moyer, MD, MPH, and her USPSTF coauthors acknowledge that the

Primary-care clinicians may choose to counsel patients selectively.

correlation among healthful diet, physical activity, and CVD incidence is strong. However, the investigators explain, existing evidence indicates that the health benefit of initiating behavioral counseling in the primary-care setting in an effort to promote a healthful diet and physical activity is small.

Therefore, rather than incorporate such counseling into the care of all adults in the general patient population, primary-care clinicians may choose to counsel patients selectively instead, rather than lose the opportunity

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

to provide other services that may have a greater health effect for the patient.

To guide the decision regarding which patients should receive counseling interventions, clinicians can consider whether a person has other risk factors for CVD that need to be addressed more urgently, whether the person is ready to make a change, whether the person has social support and community resources to help him or her make behavioral changes, and whether the person has other health-care and preventiveservice priorities.

© THINKSTOCK

Not all patients should get CVD-risk counseling

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.

PBP01859A/291945-01

© 2011 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.

For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com.

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 2011

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 1 0 1 3 2 0 Thinking abnormal† 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 3 1 3 6 4 2 Blurry vision‡ 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, 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.

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], suggestive of physical dependence.

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 pregabalintreated 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-0294-21.0 June 2011

PBP01873/291898-01

© 2011 Pfizer Inc.

All rights reserved.

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)* ≥60 150 300 450 600 30–60

75

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

75

100–150

150

QD or BID

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 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 co-administering 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 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% 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 LYRICAtreated 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 LYRICAassociated 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, 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 LYRICAtreated, 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 (3%). 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”.

Newsline Treatment Walking speed and MCI of HIV can also be prevention Participants with naMCI were more likely to be in the slow speed group.

well-functioning diabetes patients were associated with worse cognitive function and greater decline in a nine-year study of nearly 3,100 elderly adults (mean age 74.2 years). At the start of the study, 717 (23%) of the men and women had prevalent diabetes mellitus (DM) and 2,353 (76.6%) did not, but 159 members of the latter group developed DM throughout follow-up.

Those who had diabetes at baseline showed a faster cognitive decline than did those who developed diabetes during the course of the study, and members of both groups tended to have more marked cognitive decline than the men and women who never developed diabetes at all.

More rapid cognitive declines were recorded in patients with more severe diabetes who had uncontrolled blood glucose levels, according to the report by Kristine Yaffe, MD, and fellow researchers published online ahead of print in Archives of Neurology.

Insufficient sleep boosts stroke risk Routinely getting fewer than six hours of sleep per night significantly increases the rate of stroke symptoms, beyond other risk factors, among middle-aged to older individuals of normal weight and at low risk of sleep-disordered breathing.

At the SLEEP 2012 meeting, Megain Ruiter, PhD, and colleagues reported on their analysis of data from 5,666 participants aged 45 years and older with no history of stroke. After adjusting for BMI, a

22 THE CLINICAL ADVISOR • AUGUST 2012 • www.ClinicalAdvisor.com

strong association was found between daily sleep periods of less than six hours and a greater incidence of stroke symptoms.

However, no such associations emerged among overweight or obese participants.

“Sleep and sleep-related behaviors are highly modifiable,” noted a statement issued by the American Academy of Sleep Medicine. “These results may serve as a preliminary basis for using sleep treatments to prevent the development of stroke.” ■

© THINKSTOCK

OR A L PR E-EX POSU R E prophylaxis (PrEP) in persons at high risk of acquiring HIV helps prevent the transmission of the infection, a recent review of studies has demonstrated.

An evaluation of 12 randomized controlled trials suggests that PrEP with the antiretroviral therapy agent tenofovir (Viread) alone or given with another anti-HIV drug, emtricitabine (Truvada), reduces the risk of HIV infection in HIV-negative people in relationships with an HIV-positive partner, in men who have sex with men, and in other high-risk individuals (Cochrane Database Syst Rev. 2012;7:Cd007189).

Data from four of the trials, involving 8,813 high-risk individuals, showed that the combination therapy reduced the risk of HIV infection by about half, from 37 in 1,000 to 19 in 1,000. Data from two trials involving a total of 4,027 high-risk subjects showed that tenofovir alone reduced the risk of HIV infection by nearly two thirds, from 26 in 1,000 to 10 in 1,000.

Separately, while the FDA has approved the OraQuick In-Home HIV Test—the first OTC selfadministered HIV test kit—the CDC has launched a pilot project to train pharmacists and retailstore clinic staff to deliver confidential rapid HIV testing.

WALKING SPEED in late life may be an early marker of the development of mild cognitive impairment (MCI).

In a study of elderly persons aged 70 years and older, 54 had intact cognition at baseline, 31 had nonamnestic MCI (naMCI; mainly characterized by language, visuospatial, attention, and other impairments rather than by memory problems) and eight had amnestic MCI (in which memory problems are the main impairment).

Over the course of a three-year monitoring period, the subjects with naMCI proved to be nine times more likely to have a slow average weekly walking speed than a fast or moderate speed.

The degree of f luctuation in walking speed was also associated with MCI (Neurology. 2012;78; 1946-1952).

On a related note, the severity of diabetes may contribute to accelerated aging: Both diabetes and poor glucose control among

FEATURE: AMANDA ERMIS, RNC, MSN, FNP-BC, AND SHEILA MELANDER, DSN, ACNP-BC

Minimize admissions for heart failure The need to educate patients and help them make difficult lifestyle changes requires clinicians to think differently and offer novel treatment approaches.

© PHOTO RESEARCHERS, INC. / SPL

I

In left ventricular failure (shown), the left side of the heart fails to empty completely.

n a time when all other industries are trying to become more efficient, hospitals are building bigger waiting rooms. Health-care costs are skyrocketing, and the federal government is stepping in to try to help.1 Everyone knows about the inefficiencies of the current healthcare system, but the jury is still out on how to correct the problems. From a provider’s point of view, the goal is to take care of the patient in the best way possible and make a living in the process. Although evidence-based medicine has been part of the literature since the 1990s, patients continue to be admitted and readmitted to hospitals at an alarming rate.2-4 The statistics for heart failure (HF), in particular, are staggering. HF is the primary reason for hospital admissions in patients older than age 65 years and accounts for more than 1 million admissions each year. Even more frightening is the overall five-year mortality of >50%.5,6 Research shows that many HF patients who have been hospitalized will be readmitted almost as soon as they are discharged.7 Of the Medicare patients admitted with HF, approximately 27% will be readmitted within 30 days of discharge, costing Medicare about $17.4 billion each year.6 The question now is, how do we turn this around?

The only good news is that providers and patients alike are ready for change. Providers are looking for new ways to treat old problems more effectively and not only deliver evidence-based medicine, but actually break down the barriers and get effective treatment to the patient.

Continues on page 24

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HEART FAILURE ADMISSIONS

TABLE 1. Risk factors for heart failure

POLL POSITION n=153

Which approach is most likely to reduce hospital readmissions for heart failure (HF)?

Condition

How it affects risk

Abnormal heart valves

Valves that do not function properly also do not keep the blood flowing in the proper direction. Valves that are constricted do not allow blood to flow freely through them. Both defects cause increased strain on the heart.

Arrhythmias

If the heart pumps too rapidly, too slowly, or irregularly, it may not adequately perfuse the body or the coronary muscle itself. A heart rate that is too fast does not allow time for oxygen and nutrients to cross the vessel wall. A heart rate that is too slow or that is irregular may not get enough blood to the tissues for adequate perfusion.

Alcohol consumption

Moderate alcohol consumption (one to two drinks/day for men, one drink/day for women), or less, can have a beneficial effect on the heart; however, more than this becomes detrimental and increases the patient’s risk in direct proportion to the volume consumed.

Congenital heart defects

Defects in the structure of the heart impede normal cardiac function, causing extra strain on the rest of the cardiac muscle.

Coronary artery disease (CAD)

Atherosclerosis impedes blood flow through the arteries, increasing BP and decreasing perfusion to the heart muscle.

Diabetes

When glucose remains in the vasculature rather than passing into the cells, the cells “starve”; this includes heart muscle as well as other cells in the body. Patients with diabetes are also more likely to have comorbid CAD.

Heart muscle disease

Dilated, hypertrophic, or ischemic cardiomyopathy leads to increased workload on a heart that is already compromised because the diseased heart is not pumping effectively.

Hypertension

Elevations in BP require the heart to work harder in order to pump blood to the body, which strains and weakens the heart over time.

Previous MI

Previous infarction is caused by ischemia to heart muscle, which leaves behind damaged muscle that functions ineffectively, if at all.

3% 16% 46% 35%

Specialized HF clinics Home Care On-site Clinics Other

For more polls, visit www.ClinicalAdvisor/polls

Traditional therapy

Treatment of HF is based on a multimodal approach and requires patient and provider to establish a partnership that focuses on preventing exacerbations and improving quality of life. Traditional treatment regimens include identifying risk factors, modifying lifestyle, maximizing pharmacologic therapy, and sometimes surgery.8-10 Risk factors include hypertension, coronary artery disease (CAD), diabetes, and alcohol consumption (Table 1); many of these are modifiable.8 By far, the most difficult aspect of HF treatment is addressing the lifestyle changes required for any regimen to be successful. Patients may be unwilling to accept the need for them to change their way of life. Some of the required lifestyle changes include losing weight, eating a healthy diet, and exercising daily (Table 2 ).8 Medications necessary to support a failing heart include beta blockers, ACE inhibitors, spironolactone (Aldactone), and loop diuretics (Table 3 ).8 Patients with more severe symptoms often benefit from inotropes. In some cases, an implantable cardiac defibrillator, cardiac resynchronization therapy, or a heart transplant is necessary to decrease mortality and improve cardiac function.9,10 Education at hospital discharge, with an emphasis on symptom recognition for potential exacerbation, is vital to turning the tide of readmissions. The patient needs to be taught to watch for signs of increasing fluid retention, including shortness of breath, edema, and weight gain.10 Postdischarge follow-up has been shown to reduce readmission rates significantly.11 Whatever the approach, the goals of treatment are to increase survivability and exercise capacity and improve quality of life while decreasing

Sources: American Heart Association. Understand your risk for heart failure. Available at www.heart.org/HEARTORG/Conditions/HeartFailure/UnderstandYourRiskforHeartFailure/ Understand-Your-Risk-for-Heart-Failure_UCM_002046_Article.jsp; Kloner RA, Rezkalla SH. To drink or not to drink? That is the question. Circulation. 2007;116:1306-1317. Available at circ.ahajournals.org/content/116/11/1306.long. Both articles accessed July 15, 2012.

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HEART FAILURE ADMISSIONS

morbidity, disease progression, neurohormonal changes, and clinical symptoms.4,5,9,10,12 Impediments to effective therapy

Providers know what to do and what patients need to do, so why is the plan not working for so many? What are the barriers to optimizing care for HF? The problem has three components: the providers, the patients, and the cost in the current health-care system.

Trust must be built between the provider and the patient.

Patients need to understand the cause and effect of their disease processes. They need to understand why the provider is asking that they make changes, because understanding is the first step toward compliance. Providers must educate their patients in the limited amount of time available while remaining sensitive to the patients’ needs and sacrifices.

Ironically, patients sometimes have to give up the few aspects of their lives that bring them pleasure to effect the changes necessary to improve their quality of life.5,6 In addition to taking care of their patients, providers have to be businesspeople. Because of legislative initiatives, providers are now faced with significant cuts in reimbursement, and the potential for skewed numbers caused by noncompliant patients in the “pay for performance” race increases that stress. This leaves providers with a moral dilemma: Should they continue to treat the noncompliant patient in the hopes of making a difference, or “fire” the patient for noncompliance? 6 Frustration over the patient’s lack of compliance can be a natural response to what is sometimes seen as a personal insult or challenge. Such feelings often lead providers to stop communicating. Providers must be aware of their feelings before they attempt to engage the patient.6 Addressing cost is a much more complicated problem and the component requiring the most innovation. The rising cost of health care and prescription medications, along with wages lost when patients take time off from work to attend medical appointments, are adding up. Patients have plenty of time to think about all these costs as they sit in the reception area, sometimes for hours, waiting for care. They think about the cost of the medications and the

PEER PERSPECTIVES

TABLE 2. Lifestyle changes to prevent heart failure Avoid alcohol Avoid flu and pneumonia (get vaccinations) Avoid or limit caffeine Develop support Follow guidelines for sexual activity Follow a heart-healthy diet Get adequate rest Lose (or maintain) weight Manage stress Monitor BP Monitor symptoms Quit smoking Remain physically active Track daily fluid intake Treat heart muscle disease (cardiomyopathy) Wear appropriate clothing Adapted from American Heart Association. Lifestyle changes for heart failure. Available at www.heart.org/HEARTORG/Conditions/HeartFailure/PreventionTreatmentofHeartFailure/ Lifestyle-Changes-for-Heart-Failure_UCM_306341_Article.jsp. Accessed May 15, 2012.

medical bills that are piling up. If patients cannot afford insurance, cannot afford to purchase the medications prescribed, and cannot afford to come for office visits because they do not have the money for the co-payment, they will not be compliant, no matter how much they may want to be.6 These factors must be addressed to reverse the current trend of hospital readmissions.

Innovative approaches

Home care. One alternative to consider is home visits for follow-up of patients discharged from the hospital after treatment for HF. The goal is to provide the initial posthospital follow-up and get patients started on the path to recovery.

ElderWell is a long-term HF disease management program for patients with HF and diabetes treated at Suburban Hospital in Bethesda, Md., an affiliate of Johns Hopkins Medicine.13 Patients are visited at home monthly by registered nurses

“The authors have gone one step further in their APRN intervention by making the site of care more convenient and easier to access. So there you have it—the right provider in a convenient site applying evidence-based practices in partnership with the patient equals success for all.”

Virginia Trotter Betts, RN, MSN, JD, Memphis, Tenn. (via ClinicalAdvisor.com)

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HEART FAILURE ADMISSIONS

AT A GLANCE ●

Many heart failure patients who have been hospitalized will be readmitted almost as soon as they are discharged.

●

Traditional treatment regimens include identifying risk factors, modifying lifestyle, maximizing pharmacologic therapy, and sometimes surgery.

●

Early, regularly scheduled follow-up care after hospital discharge is essential to decreasing the rate of readmissions.

●

With an on-site clinic, a provider is at the workplace and readily available to the patient.

●

On-site clinics offer an opportunity for the providerpatient relationship to grow into a stronger, more trusting bond that encourages compliance.

who coordinate patient care with the providers. During these visits, the cardiac nurse is able to monitor progress, provide HF education, and discuss treatment strategies. Suburban Hospital also has a free educational program designed to decrease 30-day HF hospital readmissions.13 Specialized HF clinics. Another alternative is to provide a posthospital HF clinic specifically designed to meet the needs of HF patients. In the Memphis area, the Methodist Teaching Practice’s Heart Failure Clinic, which is affiliated with Methodist University Hospital, provides this service.

At this clinic, the goal is to get patients into the clinic within two days after discharge to verify that the outpatient treatment plan is being followed. The clinic is operated by a nurse practitioner (NP) who sees posthospital patients and provides more intensive one-to-one education for the patient and his or her family members. The patients in Memphis are often uninsured and they pay minimal to no fees, depending on their financial situation. The NP assists with medication acquisition, reinforces discharge education, and coordinates follow-up primary care in the collaborating resident physicians’ clinic to address the multiple comorbid conditions these patients also face. In addition, the NP continues to follow the patients from a HF standpoint, coordinating her HF appointments to coincide with the resident physicians’ primary-care appointments at subsequent visits. This further minimizes fees and makes the best possible use of the patient’s in-office time, thus reducing time lost from work and the patient’s out-of-pocket expenses.

On-site clinics. A third treatment strategy that has historically been underutilized but has been gaining momentum in recent years is the on-site clinic, located at the patient’s workplace. With an on-site clinic, a provider is at the workplace and readily available to the patient. These

clinics traditionally have been used primarily for on-thejob injuries; however, that model has given way to a new concept.14,15 Today’s on-site clinics are staffed according to the number of personnel served. The clinic can be staffed by a single NP for a few days each week, or it can be as fully staffed as any freestanding primary-care office, complete with diagnostic capabilities.14 While on-site programs may start off with claims analysis, they often grow significantly once their value is demonstrated.1 Nationally, on-site clinics are gaining in popularity, going from 11% of companies with more than 500 employees in 2009 to 15% in 2010.16 Rather than using a fee-for-service model, on-site clinics typically negotiate a set-fee contract, according to the needs of the company. Benefits for the employer include the immediate availability of medical care, minimal loss of employee time for medical appointments, and increased productivity. The patient benefits from the easy access to medical care and minimal time lost from work.

There is no need to use vacation or sick leave for medical appointments. On-site clinics do not usually require a copay, and they are readily available to the patient.5,15-17 Quite simply, on-site clinics save time, and time is money.15 Some on-site clinics report as much as a 30% savings on group health costs as soon as the first year.14 Although some companies encourage employees to use these on-site clinics as their primary-care home, most patients do not. Instead, the clinic staff collaborates with the primary-care provider for ongoing tracking and follow-up care.17 On-site clinics are the ideal place to monitor chronic diseases, such as HF, and to provide education to promote wellness. Many companies, particularly those that are self-insured, have partnered with their employees in a wellness contract that enables individuals to save money on insurance premiums as wellness goals are met. Working daily alongside employees, the provider becomes more than the person who sees them once or twice each year: On-site clinics provide an opportunity for the provider-patient relationship to grow into a stronger, more trusting bond that encourages compliance.15 The clinics also give the provider the ability to monitor atrisk patients closely and talk with them frequently without cost standing in the way. For medical conditions that have the potential for rapid deterioration, such as HF, an on-site clinic is ideal because early recognition of symptoms and prompt intervention can prevent what might otherwise become yet another hospitalization. Close follow-up care and education have already been shown to improve outcomes in HF patients, and on-site clinics allow for both.11

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Continues on page 30

TABLE 3. Medications for heart failure Medication

Examples

Mechanism of action

ACE inhibitor

• Benazepril (Lotensin) • Captopril (Capoten) • Enalapril (Vasotec) • Fosinopril (Monopril)

• Lisinopril (Zestril) • Perindopril (Aceon) • Quinapril (Accupril) • Ramipril (Altace)

Decreases levels of angiotension II; the effect is vasodilation, which decreases vascular resistance, lowering BP and thereby reducing the workload of the heart.

Angiotension II receptor blocker (ARB)

• Candesartan (Atacand) • Eprosartan (Teveten) • Irbesartan (Avapro)

• Losartan (Cozaar) • Telmisartan (Micardis) • Valsartan (Diovan)

Blocks angiotension II from producing its normal effects on the heart and blood vessels; this decreases vascular resistance, thereby lowering BP and reducing the workload of the heart.

Anticoagulant

• Dalteparin (Fragmin) • Enoxaparin (Lovenox) • Heparin • Warfarin (Coumadin, Jantoven)

Interferes with the body’s clotting factors, either by blocking production of vitamin K in the liver or causing inactivation of thrombin. Inhibits the blood’s ability to form clots but does not dissolve existing clots. This, in turn, helps to prevent stroke or recurrent stroke.

Antiplatelet agent

• Aspirin • Clopidogrel (Plavix) • Dipyridamole (Persantine) • Ticlopidine

Inhibits clot formation by preventing platelet aggregation (sticking together); used preventively in patients with atherosclerosis.

Beta blocker

• Acebutolol (Sectral) • Atenolol (Tenormin) • Betaxolol • Bisoprolol (Zebeta) • Carvedilol (Coreg) • Metoprolol (Lopressor, Toprol-XL) • Nadolol (Corgard) • Propranolol (Inderal, Innopran XL) • Sotalol (Betapace, Sorine) • Timolol

Slows the heart rate, which allows the left ventricle to fill more completely. This improves the ejection fraction of the heart. Slowing the heart rate also decreases the workload and oxygen demand of the heart while improving overall function.

Calcium channel blocker

• Amlodipine (Norvasc) • Diltiazem • Felodipine (Plendil) • Nifedipine (Adalat CC, Afeditab CR, Procardia) • Nisoldipine (Sular) • Verapamil (Calan, Covera HS, Verelan)

Blocks movement of calcium into the cell, decreasing contractility, slowing the heart rate, and relaxing vessels, which lowers BP. (Use the non-vasoselective agents with caution.)

Diuretic

• Bumetanide • Chlorothiazide (Diuril) • Chlorthalidone (Thalitone) • Furosemide (Lasix) • Hydrochlorothiazide (Microzide, Oretic) • Indapamide (Lozol) • Spironolactone (Aldactone)

Increases excretion of salt and excess fluid, decreases cardiac workload, and decreases fluid retention, especially in the lungs and lower extremities.

Inotrope

• Digoxin (Lanoxin)

Increases strength of cardiac muscle contraction and slows heart rate.

Vasodilator

• Hydralazine • Isosorbide dinitrate (Dilatrate SR, Isordil, Monoket) • Minoxidil • Nesiritide (Natrecor) • Nitrates

Dilates arteries, increasing blood flow to the heart and decreasing vascular resistance, thus lowering BP.

Sources: American Heart Association. Understand your risk for heart failure. Available at www.heart.org/HEARTORG/Conditions/HeartFailure/UnderstandYourRiskforHeartFailure/UnderstandYour-Risk-for-Heart-Failure_UCM_002046_Article.jsp; Kloner RA, Rezkalla SH. To drink or not to drink? That is the question. Circulation. 2007;116:1306-1317. Available at circ.ahajournals.org/ content/116/11/1306.long. Both articles accessed July 15, 2012.

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

HEART FAILURE ADMISSIONS

Conclusion

10. Lopes R. Chronic Heart Failure: The Basics. Clinical Ops Presentation.

Albert Einstein has been credited with saying, “Insanity is doing the same thing over and over again and expecting different results.” Evidence-based guidelines have proven that timely interventions will make a difference in patients’ lives.

The task now is to identify and break through the barriers that stand in the way of providing that care and making that difference. With health-care costs rising, the time has come to let go of the traditional models of patient care that are not working and start thinking outside the box. ■

May 16, 2008. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC. Available at www.ctnbestpractices.org/education/ fyi-series-therapeutic-area-lectures/cardiovascular/20080516_lopes_ slides.pdf/view?searchterm=heart+failure.

11. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/ AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;53:1343-1382.

12. Romeo, Ortiz, Miller, et al. Heart failure. Heart Failure Online Web

Acknowledgment: The author wishes to thank Stephen Miller, MD, medical director for graduate medical education at Methodist University Hospital/University of Tennessee Health Science Center and Methodist Teaching Practice, Memphis, for granting permission to identify their programs by name in this article.

site. Available at www.heartfailure.org/eng_site/hf.asp.

13. Michael S. Heart health at home. Johns Hopkins Nursing.

2010;8:49. Available at www.suburbanhospital.org/documents/ ElderwellarticleWinter2010.pdf.

14. Klepper B. Onsite clinics within a competitive health care marketplace.

Available at www.kevinmd.com/blog/2011/02/onsite-clinics-competitivehealth-care-marketplace.html.

Ms. Ermis is an instructor at the University of Tennessee Health Science Center College of Nursing in Memphis. Dr. Melander, whose area of practice is cardiovascular nursing, is a professor at the University of Tennessee in Memphis.

15. Helfand D. More employers are offering on-site medical clinics. Los Angeles Times. July 3, 2011. Available at articles.latimes.com/2011/jul/03/ business/la-fi-company-clinics-20110703.

16. Micek K. CISD to open onsite employee health clinic. August 27, 2011. Available at www.yourhoustonnews.com/woodlands/news/cisd-to-

References

open-onsite-employee-health-clinic/article_2d2e6182-d06d-11e0-a119-

1. OnSiteClinics. NASCAR, on-site clinics, and medicine. Available at

001cc4c03286.html.

onsiteclinics.org/2011/09/27/on-site-clinics-nascar-cardiology-forbes.

17. Andrews M. Many workplace clinics offer primary-care services.

2. Guyatt G, Cairns J, Churchill D, et al. Evidence-based medicine. A new

Los Angeles Times. May 25, 2011. Available at articles.latimes.com/2011/

approach to teaching the practice of medicine. JAMA. 1992;268:2420-2425.

may/25/health/la-he-workplace-clinics-20110525.

3. Oh J. 10 proven ways to reduce hospital readmissions. Becker’s Hospital Review. September 21, 2011. Available at www.beckershospitalreview.com/

All electronic documents accessed July 15, 2012.

quality/10-proven-ways-to-reduce-hospital-readmissions.html.

4. Fabregas L, Conte A. Little progress found in expensive hospital at www.pittsburghlive.com/x/pittsburghtrib/news/s_759028. html?_s_icmp=NetworkHeadlines.

5. Welcome to first onsite Frankfort. Available at firstonsitefrankfort.com.

6. The art of patient care. Patient Compliance. June 26, 2009. Available at www.art-of-patient-care.com/patient-compliance.html.

7. Herper M. The most powerful doctor you never heard of. Forbes Magazine. September 27, 2010. Available at www.forbes.com/forbes/2010/ 0927/opinions-harlan-krumholz-yale-medicine-ideas-opinions.html.

8. Prevention and treatment of heart failure. American Heart Association.

June 13, 2011. Available at www.heart.org/HEARTORG/Conditions/ HeartFailure/PreventionTreatmentofHeartFailure/Prevention-Treatmentof-Heart-Failure_UCM_002048_Article.jsp.

9. Mann DL, Chakinala M. Heart failure and cor pulmonale. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine.

Vol 2. 18th ed. New York, N.Y.: McGraw-Hill 2012:1901-1915.

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

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

readmissions. Pittsburgh Tribune-Review. September 28, 2011. Available

Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept.

We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit.

CLINICAL FEATURES update our readers with the latest information about conditions seen in everyday practice. Running no more than 2,500 words, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view.

If at all possible, articles should be accompanied by clinical photos, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and Web sites. In addition, include your curriculum vitae, which should list all current titles and affi liations.

CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general.

We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affi liations, and curriculum vitae.

DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a brief description of the patient and/or his presentation, without giving away the diagnosis.

This is followed by a 750- to 1,000-word summary that includes a fuller description of the ailment, how the correct diagnosis was achieved, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome.

Topics must be approved by the editor prior to submission.

COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 700 words in length.

To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@clinicaladvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

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

“Enough about me, but nothing about you just yet.”

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

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

“Honey, look how much better I am at this than you are.”

CME CE

PROGRAM OUTLINE AUGUST 2012

0.5 CREDITS

Page 36 FEATURE Infections, tumors, and lumps affecting the scrotal content Craig Ensign, MPAS, PA-C, and William O. Brant, MD Craig Ensign, MPAS, PA-C, and William O. Brant, MD, FACS have no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Describe the diagnostic characteristics of a spermatocele.

• Name the organism primarily associated with epididymitis.

• Identify the test used to definitively diagnose testicular torsion.

• Describe the primary treatment for testicular cancer.

0.5 CREDITS

Page 55 DERMATOLOGY CLINIC Painful, itchy vesicles on the feet Audrey Chan, MD Audrey, MD, has no relationships to disclose relating to the content of this article.

Enlarging annular plaques and patches Joe Monroe, PA-C Joe Monroe, PA-C, 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 61 DERMATOLOGIC LOOK-ALIKES Erythematous scaling lesions Kerri Robbins, MD Kerri Robbins, MD has no relationships to disclose relating to the content of this article.

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

Page 65 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of July 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

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

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

■ LEARNING OBJECTIVES :

CME CE FEATURE

• Describe the diagnostic characteristics of a spermatocele.

• Name the organism primarily associated with epididymitis.

• Identify the test used to definitively diagnose testicular torsion.

• Describe the primary treatment for testicular cancer.

■ COMPLETE THE POSTTEST: Page 65 ■ ADDITIONAL CME/CE: Pages 55, 61 Turn to page 35 for additional information on this month’s CME/CE courses.

CRAIG ENSIGN, MPAS, PA-C, AND WILLIAM O. BRANT, MD

Infections, tumors, and lumps affecting the scrotal content A lump, enlarging scrotum, or pain can conjure up images of testicular cancer, but other conditions involving the scrotal content are possible.

© PHOTO RESEARCHERS, INC. / DR. P. MARAZZI

A

A hydrocele (center) can be caused by infection, injury, or inflammation of the testicle.

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

man, aged 35 years, presents with a “lump” in his testicle that he first noticed three weeks earlier. The lump is not painful unless bumped or touched. No voiding symptoms are reported, and he has had no fever or other systemic symptoms. The patient thinks his cousin had his testicle removed years ago because of cancer, but he does not know any details. The man tries to appear calm, but a certain level of anxiety is obvious.

Is the problem life-threatening or just causing discomfort? Does the patient need surgery, or can the problem be left alone? Should we treat it, monitor it, or forget about it? We ask these questions about every patient and condition we treat. When the patient’s worry and concern are added to the equation, not only are our clinical abilities put to the test but our compassion and communication skills as well. Even if we are completely confident in the diagnosis and treatment, does the patient feel the same confidence at the end of the encounter?

Problems involving the male genitalia seem to heighten these concerns. Getting a man to come

The key to diagnosis of spermatocele on physical examination alone is palpation of a well-demarcated cystic lesion that clearly lies outside the testicle. to the clinic is difficult enough, so when he does show up, you can be sure there is significant anxiety and concern— either on the part of the patient or on the part of the loved one who scheduled the appointment. Problems originating in the scrotum can range from small benign cysts to life-threatening cancer. Between these two extremes are a number of conditions that leave the patient wondering how worried he should be.

Most scrotal-content lesions are benign, cystic, and found in the paratesticular tissue. Unlike adult testicular lesions, which are malignant 95% of the time, extra-testicular lesions are almost always benign.1 The clinical challenge is determining which is which and helping the patient feel confident in the assessment and treatment plan.

In this review article, we will look at a number of the conditions that may elicit the complaint, “There is a lump in my scrotum.” The biggest concern for most men is cancer, which should be at the top of our list of differentials as well. Nevertheless, the likelihood of developing testicular cancer is quite low. Only nine in 100,000 men will develop testicular cancer each year. For white Americans, the lifetime risk is 0.2%; for black Americans, it is even lower—0.05%. There is significant variance between cultural groups and socioeconomic status and prevalence of testicular cancer as well (there is a higher incidence among men who come from homes with higher education and income).2 The statistics notwithstanding, fear of cancer is the reason most men seek evaluation of lumps in the scrotum. Pain is another motivating factor, although it actually pushes testicular cancer down on the differential list because it is present in only 10% of men with a testicular tumor.2 This article will review six of the most common scrotal content problems for which men seek treatment. In order, from least morbidity to greatest, we will review spermatoceles, hydroceles, varicoceles, epididymitis, torsion, and testicular cancer.

Spermatoceles

Cystic lesions that develop in the head of the epididymis, spermatoceles grow out of the efferent tubules, where sperm are stored and mature after spermatogenesis in the testicle. On examination, the lesion is a soft, freely movable, transilluminating mass that is separate from and superior to the testicle.3 At ejaculation, sperm are propelled out of the epididymis and through the vas deferens to combine with the rest of the ejaculatory content, which is produced in the seminal vesicles and prostate.

When found by the patient or his partner, spermatoceles are alarming because of concern for testicular cancer. Clinically, spermatoceles, which are present in about 30% of men who undergo ultrasonographic evaluation of the scrotum,4 are extratesticular cystic lesions that are first palpable when they reach 1 cm to 2 cm in size. They can get to be as large as 15 cm, and some patients will present with concern that they “have a third testicle.” The consistency of a large spermatocele is, in fact, similar to that of a normal testis. Spermatoceles rarely cause pain.

If both scrotal pain and a spermatocele are present, the pain is likely a secondary issue. Another possible reason for a painful spermatocele is that once the patient finds the lesion, he keeps checking to see if it is still present or getting bigger. Constant palpation of a spermatocele can lead to discomfort.

The cause of spermatocele development is unknown. One theory is that spermatoceles arise from trauma, infection, or some other inflammatory process. Another hypothesis is the epididymal ducts become obstructed, causing proximal dilation; obstruction is secondary to epithelium continually shedding immature germ cells that deposit in the efferent ducts.5 The fluid within a spermatocele contains protein and dead sperm. Although aspiration and evaluation of the fluid is one way to verify the diagnosis, this is not usually done because of the risk of infection and discomfort for the patient.6 For the most part, diagnosis can be made on physical examination alone. The key to diagnosis is palpation of a well-demarcated cystic lesion that clearly lies outside the testicle. Spermatoceles transilluminate well. If there is any question, ultrasound (US) is an appropriate imaging modality.

Once the diagnosis is clear, the patient needs to know that he does not have cancer, nor does he have precancer. Spermatoceles do not affect fertility. Some men report spermatocele size change with ejaculation. The spermatocele may get smaller because the content is expelled or larger because the cyst fills, but for the most part, the lesion does not change size appreciably. Over time, however, spermatoceles may get larger. While spermatoceles do not resolve on their own, surgical removal is not typically warranted because of their benign nature. Moreover, surgical intervention carries inherent risks, such as infertility on the ipsilateral side and chronic pain. If the lesion is large enough to cause problems, however, spermatocelectomy is available.

Hydroceles

Hydroceles are the most common cause of painless scrotal swelling and occur when fluid accumulates between either

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

CME CE

SCROTAL ABNORMALITIES

While hydroceles themselves are almost always benign, they can mask testicular cancer. A hydrocele is present in 10% of men with testicular tumors. the tunica albuginea and the tunica vaginalis or the parietal and visceral layers of the tunica vaginalis.1 A dense white membrane, the tunica albuginea is the outer covering of each testicle and the penis (in females, it covers the ovaries). The tunica vaginalis is a pouch of serous membrane that lines the peritoneum. Embryologically, as the testicles descend from the abdomen through the inguinal ring into the scrotum at about week 29 of gestation, the tunica vaginalis encapsulates the testicle and forms a peritoneal diverticulum. By the time a boy is age 2 years, the tunica vaginalis between the proximal testicle and the inguinal ring is obliterated and communication between the abdominal cavity and testicle is closed. Because of its pathophysiology, a hydrocele in a child is quite different from that in an adult.

Hydroceles in children are congenital. Since the testicle has created a diverticulum from the process vaginalis of the peritoneum, communication between the testicular cradle and the peritoneum is open. A patent tunica vaginalis is present in about 80% of infant boys and is clinically observed in about 30% of them. Spontaneous resolution is expected by age 18 months to 2 years as the communicating tunica vaginalis is obliterated. Surgical repair is typically delayed until the child is age 2 years and, if required, is similar to a hernia repair.7 Hydroceles in adults are acquired and rarely present before the fourth decade of life. They are the most common cause of scrotal swelling in adults and are typically found on routine physical examination or incidentally on US. Hydroceles are present, clinically or subclinically, in up to 40% of men.

Unlike congenital hydroceles, fluid accumulation in an adult is the result of an insult to the tunica albuginea or the portion of the tunica vaginalis that remains and encapsulates the testicle.

Insults that may lead to a hydrocele include trauma, surgery, infection, radiation to the pelvis, and testicular cancer, but in many cases, no offending factor is identified.6 Note that AT A GLANCE ●

The presence of scrotal pain actually pushes testicular cancer down on the differential list because it is present in only 10% of men with a testicular tumor.

●

Constant palpation of a spermatocele can lead to discomfort.

●

Hydroceles in adults are acquired and rarely present before the fourth decade of life.

●

Testicular cancer is quite uncommon.

while hydroceles themselves are almost always benign, they can mask testicular cancer. A hydrocele is present in 10% of men with testicular tumors.2 The pathogenesis of hydroceles is simply that there is an imbalance between fluid secretion and reabsorption in the closed sac between the tunica albuginea and the tunica vaginalis. There is also significant evidence that a defect in lymphatic drainage plays a role as well. Evidence for lymphatic involvement is substantiated by the finding that protein content of fluid aspirated from idiopathic hydroceles is similar to that found in lymphatic fluid. Lymphatic obstruction probably has an important role in the pathogenesis of hydroceles.8 On physical examination, hydroceles can range from not palpable to grapefruit size and larger; consistency varies from firm to soft. Typically painless, hydroceles can feel heavy and may cause discomfort when bumped or squeezed. As cystic structures, they will transilluminate well unless the tunica vaginalis wall is too thick. US will help with diagnosis; more important, it can assess the underlying testicle, which may not be palpable on physical examination.9 Treatment options include no treatment at all if the lesion is not bothersome for the patient. Surgical treatment involves removal or inversion of the tunica vaginalis so that fluid is not trapped in the pouch. Aspiration of a hydrocele will effectively reduce its size. However, the defect that caused the swelling and the compartment that houses it will remain, and the hydrocele will refill as quickly as the fluid is formed. Aspiration, therefore, is not an adequate treatment option.

Varicoceles

About 15% of all men will have a varicocele,9 and 40% of subfertile men are found to have a varicocele, which is defined as dilated, tortuous veins within the pampiniform plexus of the spermatic vein.2 A simpler description is varicose veins in the scrotum. A typical vein in the pampiniform plexus measures 0.5 mm to 1.5 mm; in a palpable varicocele, the veins can get as large as 5 mm to 6 mm.10 The lesion rarely develops before puberty. It is found by the patient, by the clinician at physical examination, or incidentally on US of the scrotum. Varicoceles are graded based on visual examination and palpability (Table 1).

Generally, varicoceles are painless, but some patients will describe an achy, heavy sensation in the scrotum, especially with performance of a Valsalva maneuver or physical activity. On physical examination, the lesion, when visible, is

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

Indications for treatment include infertility, atrophy of the ipsilateral testicle, and pain that can reasonably be attributed to the varicocele. described as “a bag of worms” that is appreciated proximally and anterior to the testicle. Additionally, especially in teenagers who are still growing, the ipsilateral testicle may be smaller. Repair of the varicocele may allow the atrophied testicle to catch up in growth.11 The varicocele will disappear temporarily when the patient is prone and the scrotum is elevated. If the lesion remains visible, further evaluation is warranted for pelvic pathology.

Although varicoceles are occasionally found bilaterally, these lesions are most commonly found on the left side for reasons that are not completely understood. One hypothesis stems from the fact that compared with the right spermatic vein, the left spermatic vein is about 8 cm to 10 cm longer, and it drains at a right angle into the left renal vein. This causes more resistance than is found on the right side, where drainage is directly into the vena cava. A second, less common, factor is that some men have compression of the renal vein, which causes increased resistance in addition to that generated in the left spermatic vein.11 The compression of the left renal vein occurs as it passes between the aorta and the superior mesenteric artery. This condition is often referred to as “the nutcracker phenomenon.”

The reason for decreased fertility is not conclusive, but once again, there are reasonable hypotheses to consider. The first is that pooling of blood in the pampiniform plexus increases the temperature in the scrotum. Testicles are positioned outside the body (in the scrotum) because spermatogenesis is most effective at a temperature lower than 37°C. Pituitarygonadal hormone dysfunction and internal spermatic vein reflux are other possible causes. All three problems are likely to contribute in varying degrees to infertility.1 Indications for treatment include infertility, atrophy of the ipsilateral testicle, and pain that can reasonably be attributed to the varicocele. Varicocele repair will improve fertility in 70% of subfertile patients.3 Noted improvement on semen analysis includes increased sperm count and greater sperm motility. Treatment is usually a urologic surgical repair, in which a suprapubic incision is made and the pampiniform plexus is tied off. An interventional radiologist can repair a varicocele with embolization of the spermatic vein. A surgical procedure is generally the initial treatment since fertility and testicular health are a significant part of the workup and treatment of a varicocele. Interventional radiology (embolization) is most often utilized if surgical repair does not correct the lesion.

TABLE 1. Grading system for varicoceles Lesion grade

Characteristics

Subclinical

Seen on US but not visible or palpable on physical examination

Grade 1

Not visible but palpable with performance of a Valsalva maneuver

Grade II

Not visible but palpable without a Valsalva maneuver

Grade III

Visible on examination

Key: US=ultrasound.

Epididymitis/orchitis

Inflammation in the epididymis (i.e., epididymitis) can progress and involve the testicle. Epididymitis is generally an infectious process that can be either sexually transmitted or the result of a urinary tract pathogen, primarily Escherichia coli. In almost all cases, bacteria migrate through the urethral meatus into the bladder and are forced retrograde through the vas deferens into the epididymis as a result of straining with physical activity or lifting. The rule of thumb is that epididymitis in a patient younger than age 35 years is more likely to be associated with a sexually transmitted infection, whereas epididymitis a patient older than age 35 years is most likely caused by a urinary tract infection (UTI).12 However, many cases of epididymitis are not infectious but rather are caused by an idiopathic inflammatory process.

Only rarely is the testicle infected without spread from the epididymis; mumps is one example. The typical presentation of epididymitis is insidious onset of pain and swelling over hours to days, UTI symptoms, fever, and erythema.13 Severe pain eventually prompts a visit to the clinic. On physical exam, the epididymis is tender and swollen, and the scrotal surface may be erythematous. Even if the patient would allow you to try, the lesion would not transilluminate. A clinical test for epididymitis is the Prehn sign, in which the scrotum of a patient in the prone position is raised over the pubic bone. Pain that diminishes is considered to be positive for epididymitis.

Differentiation between epididymitis, torsion (described below), and tumor is generally straightforward but can be quite difficult on occasion. History, systemic pathology, and physical exam are the keys to making the appropriate diagnosis.

Epididymitis specifically has an insidious onset, is painful, and may also include systemic pathology.14 Torsion has an acute onset, and tumors usually are not associated with pain.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 39

CME CE

SCROTAL ABNORMALITIES

Testicular cancer is misdiagnosed in 25% of patients, and the average time from initial signs and symptoms to definitive treatment is three to six months.

Treatment includes antibiotics to address the appropriate pathogen. If a sexually transmitted source is suspected, treat with ceftriaxone (Rocephin) and azithromycin (Zithromax, Zmax). Otherwise, treat with ciprofloxacin (Cipro) or other agents likely to be effective against E. coli. Empiric treatment while waiting for culture results is appropriate. A negative result on urine culture is common. The patient should be instructed to lie prone with his scrotum elevated (a rolled-up towel under the scrotum is effective). Applying an ice pack will help quicken recovery and effectively reduce the pain.

Torsion

Testicular torsion is a result of a congenital defect that allows the testicle to rotate freely between the tunica albuginea and the tunica vaginalis. Normally, the testicle is safely anchored between the two layers and movement is limited. Torsion occurs when the testicle twists on the suspensory cord, which contains the vasculature, vas deferens, and nerves that support it in the scrotum. Age of onset is usually between puberty and the early 20s.15 Torsion occurs less often in older men because the congenital defect would most likely have been manifested and treated at a younger age.

Clinically, the patient presents with acute-onset, severe testicular pain. Swelling will be significant. Classically, the testicle will be malrotated and riding high in the scrotum.

Most cases of torsion occur when the patient rolls over in bed and the rubbing together of the thighs twists the testicle. A classic presentation is sudden onset of severe pain that wakes the patient and may be associated with vomiting. Trauma is an uncommon but possible cause. Differentiation between a torsion and infection is based primarily on the history— specifically, the rapidity of onset—and systemic findings.

Testicular torsion is an emergent surgical condition. Any patient in whom torsion is suspected needs an urgent scrotal US to definitively diagnose the condition. The absence of blood flow on Doppler US is diagnostic. If no ultrasound is readily available, it is reasonable to proceed directly to surgical management based on symptoms and examination alone. A torsed testicle must be repaired within four to six hours in order to be saved. Detorsion can sometimes be accomplished manually. Manual detorsion allows surgery to be delayed, but surgery is still required to prevent future events. A surgically detorsed testicle is tacked to the scrotal wall (orchiopexy). The contralateral testis will be anchored as well because it is also at risk for torsion.11

Testicular cancer

Despite being the most common type of cancer among men aged 15 to 34 years, testicular cancer is quite uncommon. Significantly, testicular cancer is extremely curable in most men and is generally cited as one of the greatest medical success stories of this century. This success serves as an example of how to approach cancer treatment, as significant cure rates have been reached as a result of effective diagnostic techniques, improved tumor markers, effective multidrug chemotherapeutic regimens, and modifications of surgical technique.16 Tumor types are divided into two primary categories—germ cell and non-germ cell. Germ cell tumors are by far the most common and account for 95% of testicular cancers. These tumors are further subdivided into seminoma (40%) and nonseminoma germ cell tumors (60%).2 Non-germ cell tumors account for only five percent of all testicular cancers, but they can be quite aggressive and more difficult to manage.

Patients will present with concern for a lump in the testicle.

The nodule is painless in at least 90% of patients, and misdiagnosis is common: Testicular cancer is misdiagnosed in 25% of patients, and the average time from initial signs and symptoms to definitive treatment is three to six months.2 Other presenting features may include a sensation of “heaviness” in the testicle, lymphadenopathy in the pelvis and supraclavicular areas, gynecomastia, and hemoptysis. As previously noted, 10% of testicular cancer patients will also have a hydrocele that masks the underlying tumor. For that reason, US evaluation is essential for the testicle that is not palpable on physical examination, especially in patients aged 15 to 40 years.

Once a tumor has been identified, treatment includes several steps: 1. Check tumor markers, including ␣-fetoprotein, ␤-human chorionic gonadotropin, and possibly lactate dehydrogenase and follicle-stimulating hormone.

2. Perform orchiectomy. There is no application for testicuar biopsy. The testicle is removed and sent to pathology to identify the type of tumor.

3. Get a CT of the abdomen and pelvis as well as a chest x-ray to further stage the cancer.

4. Offer the option of banking sperm. Although fertility should be maintained by the remaining testicle, it can be stressed by surgery. Moreover, the remaining testicle may not be completely healthy to start with, and if radiation or chemotherapy is required, fertility can be jeopardized.

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

Many times, the scrotal discomfort and lesion take on less significance for the patient once a testicular tumor has been ruled out.

Follow-up care includes CT, chest x-rays, complete blood count, basal metabolic panel, and physical examination. The frequency with which these studies and examinations are done is based on the pathology report and staging of the tumor. Initially, some patients will require follow-up every three months, with visits and studies spreading out over time.

After the initial monitoring phase, all testicular cancer patients will require annual checkups for the rest of their lives.2 The differential diagnoses for every patient with scrotal content concerns should include testicular cancer. If the diagnosis is not definitive or if the patient’s follow-up capability is questionable, US is a very specific diagnostic tool.

4. Leung ML, Gooding GA, Williams RD. High-resolution sonography of scrotal contents in asymptomatic subjects. AJR Am J Roentgenol.

1984;143:161-164. Available at www.ajronline.org/content/143/1/161.long.

5. Itoh M, Li XQ, Miyamoto K, Takeuchi Y. Degeneration of the seminiferous epithelium with ageing is a cause of spermatoceles? Int J Androl.

1999;22:91-96.

6. Orlando MS, Schlecker BA, Wein, AJ. Benign diseases of the testicle and paratesticular tissues. AUA Update Ser. 1986;5:1-7.

7. Skoog SJ. Benign and malignant pediatric scrotal masses. Pediatr Clin North Am. 1997;44:1229-1250.

8. Rinker JR, Allen L. A lymphatic defect in hydrocele. Am Surg. 1951;17:681-686.

9. Hermans BP, Foster RS, Donohue JP. Paratesticular masses. AUA Update Ser. 1998;17:290-295.

Final steps

10. Metin A, Bulut O, Temizkan M. Relationship between the left spermatic

Because men are not always eager to see a health-care provider, their appearance in the clinic mandates a thorough evaluation and careful communication to address their anxiety. When scrotal-content concerns bring men in for evaluation, pain and fear of cancer are the most significant driving forces. Although testicular cancer is uncommon, it is still a major problem carrying significant morbidity and mortality. After cancer has been ruled out with confidence, the patient needs to hear the words, “This is not cancer” loud and clear. Many times, the scrotal discomfort and lesion take on less significance for the patient once a testicular tumor has been ruled out.

Torsion and infections will require treatment and followup and typically have very favorable outcomes when treated promptly. Other scrotal lesions, including varicoceles, hydroceles, and spermatoceles, can be simply monitored for changes or, in some cases, managed surgically—especially if fertility is an issue. Referral to urology is always appropriate when surgery is necessary or when further assessment is desired. ■

vein diameter measured by ultrasound and palpated varicocele and Doppler ultrasound findings. Int Urol Nephrol. 1991;23:65-68.

11. Tanagho EA, McAninch JW. Smith’s General Urology, 17th edition. New York, N.Y.: McGraw-Hill; 2008:705.

12. Tanagho EA, McAninch JW. Smith’s General Urology, 17th edition. New York, N.Y.: McGraw-Hill; 2008:210 13. McPhee SJ, Papadakis MA, Rabow MW. Current Medical Diagnosis & Treatment 2012, 51st edition. New York, N.Y.: McGraw-Hill/Lange; 2012:918.

14. Stewart A, Ubee SS, Davies H. Epididymo-orchitis. BMJ. 2011;342:d1543. Available at www.bmj.com/content/342/bmj.d1543.

15. Mellick LB. Torsion of the testicle: it is time to stop tossing the dice.

Pediatr Emerg Care. 2012;28:80-86.

16. Campbell MF, Retik AB, Vaughn ED, Walsh PC. Campbell’s Urology, 7th

All electronic documents accessed July 15, 2012.

Mr. Ensign in a physician assistant at The University of Utah School of Medicine, Division of Urology, in Salt Lake City, where Dr. Brant is an assistant professor of surgery.

References 1. Rubenstein RA, Dogra VS, Seftel AD, Resnick MI. Benign intrascrotal lesions. J Urol. 2004;171:1765-1772.

2. Tanagho EA, McAninch JW. Smith’s General Urology, 17th edition. New York, N.Y.: McGraw-Hill; 2008:375-381.

3. Oliva E, Young RH. Paratesticular tumor-like lesions. Semin Diagn Pathol.

2000;17:340-358.

“Say when.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 41

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

edition. Philadelphia, Pa.: W.B. Saunders Co; 1998:2411.

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 AUGUST 2012

Consultations What does inflammation on a Pap smear mean? . . . . . . . . . . . . . . .42 How much insulin does it take to lower blood sugar? . . . . . . . . . . . . .43 Acute renal failure related to topical acyclovir. . . . . . . . . . . . . . . .43 Options for onychomycosis . . . . . . . .44

Clinical Pearls Polishing off a sticky situation . . . . . . .44 Avoid vitamin A supplementaition in smokers . . . . . . . . . . . . . . . . . . . .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.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

CONSULTATIONS WHAT DOES INFLAMMATION ON A PAP SMEAR MEAN? What is the recommendation for monitoring or treating Pap smear results that show inflammation without any other abnormalities? Is this age-dependent?—MARY RYAN, MSN, ARNP, FNP-C, Shawnee Mission, Kan. Inflammation on a Pap smear can be found in a patient of any age and may be attributable to a benign infection—such as Candida vaginitis—that need be treated only if the patient is symptomatic.

Sexually transmitted infections can also cause an inflammatory reaction on the cervix and should be treated accordingly. If a Pap result comes back as “inflammation,” but the smear is otherwise satisfactory (assuming the previous test was satisfactory and normal), the Pap should be repeated in one year. The one exception would be if the patient is HIV-positive, in which case she needs a follow-up Pap in four to six months.

There have been many recent changes in the recommendations as to how frequently Pap smears should be done. Although the main professional organizations (i.e., the American Cancer Society, the U.S. Preventive Services Task Force, and the American Congress of Obstetricians and Gynecologists) vary somewhat in their recommendations, the overarching message from all three is that health-care professionals are doing Pap smears too frequently. The rationale behind this assertion is that cervical cancer is slow-growing and therefore

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 • AUGUST 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.

it can be adequately screened at less frequent intervals than every year. Too-frequent Pap smears lead to many unnecessary procedures and treatments, some of which put women at an increased risk of such pregnancy complications as preterm labor.—Mary Newberry, CNM, MSN (166-1)

HOW MUCH INSULIN DOES IT TAKE TO LOWER BLOOD SUGAR? A patient with newly diagnosed diabetes mellitus has a hemoglobin (Hb) A1c of 12.2% and glucose 350 mg/dL, despite increasing insulin (glargine [Lantus]) to 25 units. The patient has a history of cirrhosis. All labs are normal, including magnesium and phosphorus. What else can I do to lower blood sugar?—CYNDI PHUNG, NP, Philadelphia This patient may be “under-insulinized.” The recommended starting dose for basal insulin for type 2 diabetes is 0.2 units/kg.

A patient weighing 100 kg would need a minimal starting dose of 20 units of glargine daily, with titration of dose upward by 10% every three days to obtain a goal fasting glucose of 130-180mg/dL. Once you reach a total basal dose of more than 0.5 units/kg daily, consider adding mealtime insulin (Clinical Diabetes. 2009;27:7276; available at clinical.diabetesjournals.org/content/27/2/72.full, accessed July 15, 2012).

As evidenced by the HbA1c, this patient may also be experiencing glucose toxicity, which happens when blood glucose levels are very high. Insulin secretion by the pancreas is blunted in this state, along with abnormally high glucagon levels (that drive more glucose production by the liver) and subsequent worsening insulin resistance.

Insulin resistance will also worsen if the patient is severely obese and insulin-resistant with a poor diet.

The history of cirrhosis brings up an interesting point. Patients with severe cirrhosis and liver dysfunction can sometimes develop

“liver diabetes,” which is usually manifested clinically as mild glucose intolerance, not the out-of-control diabetes described above.

Individuals with cirrhosis can have decreased hepatic glycogen stores and thus may be at higher risk for hypoglycemia, so insulin titration should be performed slowly and accompanied by frequent home glucose monitoring (Clinical Diabetes. 2004;22:42-44; available at clinical.diabetesjournals.org/content/22/1/42.full, accessed July 15, 2012).—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, family nurse practitioner program, Duke University School of Nursing, Durham, N.C. (166-2)

ACUTE RENAL FAILURE RELATED TO TOPICAL ACYCLOVIR Is it common to see renal failure triggered by high doses of topical acyclovir (Zovirax) (i.e., 800 mg five times a day)?

The patient in question was obese, diabetic, and hypertensive.

Other medications include lisinopril (Zestril) 40 mg daily, metformin (Fortamet, Glucophage, Glumetza, Riomet) 1,000 mg b.i.d., and aspirin for pain. The last creatinine kinase level was 1.3 U/L.—DAVID LAUBENSTEIN, RPAC, Fayetteville, N.Y. High-dose parenteral acyclovir has long been known to be a cause of acute renal dysfunction, particularly if a patient does not remain well hydrated or experiences volume contraction. Some data show that high-dose oral regimens—particularly those for varicella zoster virus (VZV) manifestations in the elderly—may exacerbate renal dysfunction, but this documentation is less extensive than that for parenteral therapy. Drug-induced nephrotoxicity appears to be attributed to renal tubular damage caused by acyclovir-induced crystalluria (Pathol Lab Med. 2002;126:753-754).

Topical acyclovir is available by prescription as a 5% cream and a 5% ointment. Applying roughly 0.5 inches (0.5 g of product)

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

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

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

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

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

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

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

Advisor Forum with 40% urea ointment ( for affected nail plate removal with chemical avulsion) ( J Eur Acad Dermatol Venereol. 1995;4:S3S10). Photodynamic treatment (PDT) uses a photosensitizer (a light-activated agent) to generate singlet oxygen and destroy microbial cells. Fungal nail infections caused by various dermatophytes have been successfully treated after repeated sessions with red light 5-aminolevulinic acid-mediated PDT (Photochem Photobiol.

2011;87:2-13). Lasers (predominantly Nd:YAG laser systems) have also been used to successfully treat onychomycosis (J Drugs Dermatol.

2010;9:1109-1113).—Philip R. Cohen, MD (166-4)

CLINICAL PEARLS POLISHING OFF A STICKY SITUATION Patients often complain they have a difficult time completely removing the adhesive from ECG pads. If there is a great deal of hair under the area, this process can be painful as well. Using a paper towel, apply a small amount of fingernail polish remover to the area and gently rub. This method completely and painlessly removes the adhesive.—STEPHANIE BARTLESON, RN, Morristown, N.J. (166-5)

AVOID VITAMIN A SUPPLEMENTATION IN SMOKERS Prior to ordering vitamin and mineral supplementation for patients with macular degeneration, ask about smoking history. Individuals who smoke or have ever smoked should avoid high-dose vitamin A supplementation due to a high correlation between smoking, vitamin A, and lung cancer.

As an alternative, prescribe a formulation that does not contain vitamin A.—DEBRA HUNT, ARNP, Orlando, Fla. (166-6) ■

OPTIONS FOR ONYCHOMYCOSIS What is an effective alternative to oral medications or topical ciclopirox (Penlac) for onychomycosis?—GLENN PHILLIPS, PA-C, Lake Forest, Calif.

Other topical agents that may be useful in the treatment of onychomycosis include 5% amorolfine (a morpholine derivative with fungicidal and fungistatic effect) nail lacquer and 1% bifonazole (Mycospor)

“You’re the lapdog. Tell us what they’re saying.”

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

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

to a 4.5 in2 area of skin normally delivers approximately 25 mg of acyclovir. The topical cream is available in 2-g and 5-g tubes that contain only 100 mg and 250 mg of active drug, respectively.

The ointment formulation is available in a 30 g tube that contains 1,500 mg of active drug.

Systemic absorption of topical acyclovir is poor. Several pharmacokinetic studies conducted by the manufacturer have demonstrated a minimal amount of systemic exposure following application, with many healthy subjects having undetectable levels. Only one uncontrolled study involving one patient with renal dysfunction showed any significant systemic absorption (zoviraxhcp.com/public/downloads/ Zovirax_Cream_PI_July_2009.pdf, and zoviraxhcp.com/public/ downloads/Zovirax_Ointment_PI_September_2010.pdf, accessed July 15, 2012). The subject’s levels were still well below what would normally be expected with even the lowest oral dose (us.gsk.com/ products/assets/us_zovirax.pdf, accessed July 15, 2012).

The etiology of this patient’s renal failure is unlikely to be secondary to topical acyclovir. A more plausible explanation might be his risk factors for renal failure. Diabetes mellitus and hypertension are leading causes of end-stage renal disease. Additionally, depending on the patient’s baseline level, the ACE inhibitor lisinopril can increase the serum creatinine by decreasing the glomerular filtration rate and reducing intraglomerular pressure (Nephrol Dial Transplant. 2003;18:1973-1975; available at ndt.oxfordjournals.org /content/18/10/1973.full, accessed July 15, 2012). Rarely does an ACE inhibitor induce renal failure unless in a setting of an elevated serum creatinine, dehydration, or other risk factors. Further, depending on the dose and length of time used, permanent kidney damage can result from aspirin and other common nonsteroidal anti-inflammatory drugs via prostaglandin synthesis inhibition.

More rarely, a patient can develop analgesic-associated nephropathy from these products, which occurs acutely and is reversible (Annu Rev Pharmacol Toxicol. 1993;33:435-65).—Keri C. Anderson, PharmD, BCPS, Assistant Professor, Department of Pharmacy Practice; Mike Schwartz, PharmD, Chair, Associate Professor, Department of Pharmacy Practice; Tricia A. Howard, MHS, PA-C, Academic Coordinator/Assistant Professor, Physician Assistant Program, South University, Savannah, Ga. (166-3)

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.

A patient with erosions and reddish urine A patient presents with a several-month history of blisters and erosions on the back of his hands, forearms and posterior neck. The lesions are mildly painful, and heal with small scars.

WHAT IS YOUR DIAGNOSIS?

• • • •

Porphyria cutanea tarda Pseudoporphyria Erythropoietic protoporphyria Variegate porphyria

● See the full case at ClinicalAdvisor.com/DermDx0812A

Itchy red plaques and blisters A patient presents with a several-month history of extremely itchy red plaques on her trunk and extremities. The eruption began on the shins and subsequently generalized. Read the full case and make the diagnosis.

WHAT IS YOUR DIAGNOSIS?

• • • •

Porphyria cutanea tarda Bullous pemphigoid Pemphigus vulgaris Stevens-Johnson syndrome

● See the full case at ClinicalAdvisor.com/DermDx0812B

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.

Teen with palmar desquamation

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

Dark papules after melanoma

LEGAL ADVISOR CASE

Fire in the operating room

BY ANN W. LATNER, JD

Mr. D, aged 46 years, was a nurse anesthetist who worked for an anesthesiology services practice. The practice had contracts with various area hospitals and would send anesthetists as needed. Each week, Mr. D would get an assignment sheet informing him of what procedures he would be providing anesthesia for, and at which hospital.

He had been working for this particular company for close to a decade and liked the diversity of working in different hospitals and with different physicians. His workweek tended to vary, with some weeks being far busier than others.

On this particular Monday, Mr. D only had one procedure on his schedule for the day. The patient, Mrs. H, was a 62-year-old woman who was suffering from left frontal headaches and pain behind the left eye. She was scheduled for a temporal artery biopsy. Prior to the procedure, Mr. D introduced himself to Mrs. H and spoke briefly with the surgeon, Dr. F, with whom he had worked once or twice in the past.

The procedure began smoothly. Mrs. H was anesthetized and the surgeon began the procedure

© THINKSTOCK

A lack of communication between the surgeon and the anesthetist leads to disastrous results.

The patient had suffered second-degree burns to her face and chest, as well as burns to her larynx, trachea, and lungs.

while Mr. D monitored the patient’s breathing.

Soon, however, the patient exhibited signs of respiratory difficulties and oxygen desaturation.

Mr. D administered oxygen to solve the problems, which it did. A few moments later the surgeon activated an electrocautery device, and a flash fire broke out.

The oxygen trapped under the surgical drapes ignited, and the drapes burst into flame.

Pandemonium ensued in the operating room (OR) as surgical staff rushed around grabbing for fi re extinguishers and trying to free the patient from the burning cloth. Shortly thereafter, the sprinkler system engaged, and while water was showering the OR the hospital’s alarm went off.

After the fire was extinguished, the OR team stabilized the patient and assessed the damage.

Mrs. H had suffered second-degree burns on Cases presented are based on actual occurrences.

Names of participants and details have been changed.

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 49

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LEGAL ADVISOR her face and chest as well as burns to her larynx, trachea, and lungs. She was in the hospital for several days while recovering from her injuries. When she was released, Mrs. H sought out a plaintiff’s attorney.

“I can’t sleep anymore,” she told the attorney. “I have horrible nightmares, and I still have trouble swallowing. My voice is much lower and hoarser than it was before.”

The attorney nodded sympathetically as he took notes.

“Look at me!” Mrs. H continued. “I have scars on my face and my chest. I get short of breath. I feel so ugly now. I want to sue everyone involved.”

The attorney examined her medical records and sent Mrs. H for an additional exam with another physician and for a workup with a psychologist. After reviewing the results of the exams, he initiated a lawsuit against Mr. D, the surgeon, and the hospital, citing negligence. The suit alleged that the hospital and its attending medical personnel created a hazardous environment by neglecting to properly communicate the use of oxygen to all surgical staff and to minimize oxygen buildup beneath the surgical drapes. The suit also alleged that the hospital was negligent for failing to properly train staff in fire-prevention practices.

Mr. D, notified of the lawsuit, sought counsel from the attorney assigned by his insurance company.

“I feel really bad about this,” Mr. D told the attorney. “It was a horrible accident. I have trouble sleeping at night.”

“Yes,” said the attorney. “But we must stress that it was an accident. And accidents do, unfortunately, happen. Perhaps the surgeon should have been more careful when using the cauterizing device.”

“I don’t want to blame a colleague,” responded Mr. D. “Well,” said the attorney, “you can be reasonably sure that they will be pointing the finger at you.”

The case inched toward trial. Attempts at settling the case proved futile as Mrs. H really wanted her day in court. Finally that day came.

Mr. D and the surgeon, their attorneys, and the representatives for the hospital all sat at the defense table and listened as the plaintiff’s attorney made an impassioned opening argument.

Mr. D, who had been living with a feeling of guilt about the incident since it happened, sunk lower in his seat.

During the course of the trial, the plaintiff’s attorney introduced various experts to testify about the plaintiff’s injuries, her emotional trauma, and the fact that it was improper practice for the anesthesiologist not to convey the use of oxygen to the surgeon during a procedure.

Then it was the defense’s turn to present its case. Each party retained separate attorneys. On advice from his attorney,

Mr. D did not take the stand. “The question would definitely come up as to whether you had conveyed the information about the oxygen, and why not” explained the attorney.

“It’s better if we try to avoid it.”

The surgeon, however, took the stand and testified that he would never have used the electrocautery device had he known that Mr. D was administering oxygen. The hospital representatives testified that all of its employees were trained in fire safety, and had behaved appropriately.

The case went to the jury, who deliberated for several hours before coming back with a verdict. The jury found Mr. D liable for $750,000 in damages, but it found no fault on the part of the surgeon or the hospital.

Legal background

In cases with co-defendants, such as this one, it is quite common for one or more defendants to blame another (or each other). For this reason, it is generally recommended that even if two individuals are being sued in the same case, that they retain separate defense counsel rather than share an attorney. In this case, the surgeon’s attorney probably made the decision to put him on the stand knowing that he would testify that Mr. D had not informed him of the use of oxygen, and thereby absolving the surgeon of guilt (while implicating Mr. D). Mr. D’s attorney was right that it isn’t generally a good idea to put someone on the stand who will be faced with a question he can’t (or shouldn’t) answer. Sometimes not taking the stand, in the eyes of the jury, is tantamount to an admission of guilt.

Protecting yourself

Unfortunately, Mr. D was careless. And in this case, his carelessness had disastrous consequences. Mr. D neglected to communicate with the surgeon and keep the surgeon apprised of what Mr. D was doing.

Good communication is one of the best ways to avoid being a party to a lawsuit. Whether it is talking with your patient or a colleague, when making referrals, or even in chart notes (an important form of medical communication), having clear, direct, and open lines of communication can prevent unfortunate results. Mrs. H would have never been injured had Mr. D simply notified the surgeon of the oxygen use. No amount of testimony could make up for those few missing words during the procedure. Communication is key to better patient outcomes and to protecting yourself. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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

Clinical Challenge Painful skin ulcer develops in an older woman on dialysis KIM ZUBER, MS, PA-C; BILL BARTOW, PA-C; JANE DAVIS, DNP

Metastatic calcification of the left breast in a patient with renal failure raises suspicion.

During dialysis rounds, 64-year-old Mrs. V complained of a painful sore on her left breast. Mrs. V was a thin, white woman who had been on hemodialysis for four years. She noted not only the tenderness and extreme pain in her breast, but also complained that this was accompanied by a significant amount of pain in her thighs.

Mrs. V denied any recent trauma and reported no new exercise routines or changes in medication. A review of her chart showed an episode of atrial fibrillation two months earlier that was treated with warfarin (Coumadin, Jantoven), but otherwise her medical history for the past year was unremarkable.

CASE

PHOTO COURTESY OF KIM ZUBER, MS, PAC

1. EXAMINATION AND LABORATORY TESTS

FIGURE 1. Examination showed vascular calcification and skin necrosis.

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

Examination of the left breast showed a black area with a red circumference without any drainage (Figure 1 ). The breast area was exquisitely tender.There were no palpable lymph nodes, and the right breast was slightly lumpy without any open lesions. Bilateral thighs had multiple moveable lumps, which were firm and approximately 3 × 4 cm each.The thigh masses were also hypersensitive to touch, but without accompanying skin lesions.

Mrs.V’s lungs were clear to auscultation. Her heart rate was regular without any murmur or ectopy. She dialyzed through an upper-left-arm arteriovenous fistula.The rest of the examination was noncontributory. Mrs.V’s hemoglobin level was 11.5 g/dL. (In adult women, the normal range is 12-16 g/dL.) Her calcium level was below normal at 7.8 mg/dL (baseline range 8.4-10.2 mg/dL), and her phosphorus level was significantly elevated at 7.6 mg/dL (3.55.5 mg/dL is the typical target range for dialysis patients). Mrs.V’s intact parathyroid hormone (PTH) level was 1,251 pg/mL (normal is 1472 pg/mL), her albumin level was 2.5 g/dL (normal 3.5-5.2 g/dL) and her hemoglobin A1c was 5.9% (standard range 4.8%-5.9%).

2. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes cholesterol emboli, necrosis from warfarin, cellulitis, nephrogenic sclerosing fibrosis (NSF), vasculitis, calciphylaxis, or gangrene.1 Cholesterol emboli and their close relatives (atherosclerosis and atheroemboli) can be excluded due to location of the lesion on the upper extremity as well as intact peripheral pulses. Gangrene is also excluded for this reason. Vasculitis is unlikely since the patient lacks the telltale signs—neuropathy and polyarteritis—plus, Mrs. V is older than the usual age group. NSF is also unlikely due to a lack of recent radiology tests. Heparin-induced necrosis was considered, but Mrs. V’s platelet count came back in the normal range, which made this diagnosis less likely. Cellulitis and calciphylaxis are usually hard to distinguish from each other without a biopsy, but the lumpy lesions in the patient’s thighs made calciphylaxis the most likely diagnosis.

3. TREATMENT AND OUTCOME Calciphylaxis is an ischemic disease of the arterioles.

Calcification of the vessels causes narrowing, decreased blood flow, and hypoxia, leading to necrosis of the skin. Since calciphylaxis has an 80% death rate once ulceration occurs, all known treatments were initiated simultaneously.2 IV sodium thiosulfate was started (12.5 mg with the first dialysis, then increasing to 25 mg with each subsequent hemodialysis). It is unknown how sodium thiosulfate works in calciphylaxis, but it is thought to dissolve the calcification in the tissues and move the previously insoluble calcium into the bloodstream.3 Empiric reports of the effectiveness of sodium thiosulfate treatment were a clinical guide here, although no rigorous, controlled studies have been conducted.

Mrs. V was referred to a local wound center and a breast surgeon. Her warfarin was discontinued since it is a known factor in the development of calciphylaxis. Mrs. V was started on oral cinacalcet (Sensipar), a calcimimetic that increases the sensitivity of the parathyroid gland to calcium.4,5 However, she was unable to tolerate cinacalcet, so it was stopped.

Pain control was an extremely important and difficult problem due to severe nausea and vomiting, and a palliativecare consult was obtained. A combination of patches and short- and long-acting oral narcotics were required.

The wound center began hyperbaric oxygen (HBO) treatments and local care of the lesions. There are case reports that indicate that HBO helps wound healing by increasing

oxygenation to the tissues affected by calciphylaxis.6 The breast surgeon was reluctant to operate due to the likelihood of poor wound closure and healing. He asked that we consider a parathyroidectomy prior to any breast surgery, unless the wound center was able to heal the lesions with conservative care.

Mrs. V’s breast lesions went from bad to worse over a two-month period. The open, necrotic tissue on the left breast gradually encased the entire breast and small lesions started forming on the right breast. Slowly, both breasts turned black from necrosis. The patient was in incredible pain with the lesions now manifesting as hard sores.

Immediately after the IV sodium thiosulfate was started, the lumps on Mrs. V’s breasts and thighs started to decrease and her leg pain diminished.

With the obvious failure of the conservative care (discontinuation of warfarin, HBO, local wound care, sodium thiosulfate, and attempted use of cinacalcet), it was time for a more aggressive approach. A parathyroidectomy was planned, but the anesthesiologist was reluctant to put Mrs. V under general anesthesia. However, when weighing the high risk of death from calciphylaxis versus the anesthesia risks, the anesthesia department decided to proceed.

Mrs. V’s parathyroid glands were removed, and she experienced a somewhat rocky postoperative course. On the positive side, the accumulated calcium, which had painfully hardened the patient’s breast tissue, markedly decreased within the first 24 hours. Mrs. V’s intact PTH level dropped after surgery from 1,251 pg/mL to 231 pg/mL (dialysisdependent patient goal 150-600 pg/mL).7 After the parathyroidectomy, the “hungry bone” syndrome that occurs caused the calcium in the tissues to reabsorb, and necrosis in the patient’s breast tissue was thwarted. HBO was restarted and Mrs. V’s breast tissue developed a demarcation line between the dead necrotic tissue and the tissue that had healed.

After eight days, the breast surgeon brought Mrs. V back to the operating room for a bilateral mastectomy. As he commented to Mrs. V after surgery, “Your breasts were so hard, I could have used them as bowling balls.” This comment clearly validates the characterization of this disease with the phrase, “When man turns to stone.”8

4. DISCUSSION Although calciphylaxis is a dermatologic diagnosis, most dermatology practitioners have never seen a case, yet most nephrology practitioners can identify calciphylaxis simply by viewing a lesion. Calciphylaxis is seen in 1% -4% of

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Clinical Challenge long-term dialysis patients, but can also be seen in patients with autoimmune diseases such as Crohn disease or lupus nephritis, cancer, hypercoagulable states, and parathyroid disease.9 Traditional risk factors for calciphylaxis, besides uremia, are as follows: female sex, obesity, Caucasian race, high phosphorus and/or intact PTH level, maintaining on medications such as warfarin, vitamin D analogues, oral calcium, and systemic corticosteroids.10 The natural course of the disease is indolent with a one-year survival rate of less than 50%, even with treatment.11 The pain that accompanies the lesion(s) cannot be overstressed.

It is searing and continuous, as though a part of the body is clotted off. Treatment is multifactorial, and various specialists need to be involved to maximize the chance of wound healing. With the high rate of death and limb loss associated with calciphylaxis, the more aggressive the treatment, the better the chance of overall and limb survival.12 Prevention is vital since survival rates are poor. While calciphylaxis is more common among dialysis patients, cases that occur in patients without renal disease are more likely to be missed. A report on breast calciphylaxis that occurred after coronary artery bypass graft was recently published.13 At present, there are no specialized laboratory tests for diagnosing calciphylaxis; the patient’s phosphorus, calcium and/or intact PTH levels may be elevated, but just as often, they are in the normal- or low-range.14 Skin necrosis, typically referred to as metastatic calcifi cation, can occur at normal levels.15 Even with normal readings, calcium and phosphate crystals can progressively accumulate in the small blood vessels of the fat tissue and skin. A high index of suspicion must be entertained when confronted with a suspicious lesion.

References 1. Fisher AH, Morris, DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol. 1995;26:1055-1064.

2. Ross EA. Evolution of treatment strategies for calciphylaxis. Am J Nephrol. 2011;34:460-467. Available at content.karger.com/produktedb/ produkte.asp?DOI=000332221&typ=pdf.

3. Singh RP, Derendorf H, Ross EA. Simulation-based sodium thiosulfate dosing strategies for the treatment of calciphylaxis. Clin J Am Soc Nephrol.

2011;6:1155-1159.

4. Raymond CB, Wazny LD. Sodium thiosulfate, bisphosphonates, and cinacalcet for treatment of calciphylaxis. Am J Health Syst Pharm.

2008;65:1419-1429.

5. Banerjee C, Woller SC, Holm JR, et al. Atypical calciphylaxis in a patient receiving warfarin then resolving with cessation of warfarin and application of hyperbaric oxygen therapy. Clin Appl Thromb Hemost.

2010;16:345-350.

6. Podymow T, Wherrett C, Burns KD. Hyperbaric oxygen in the treatment of calciphylaxis: a case series. Nephrol Dial Transplant. 2001;16:21762180. Available at ndt.oxfordjournals.org/content/16/11/2176.long.

7. National Kidney Foundation. NKF, K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.

Am J Kidney Dis. 2002;39:S1-S266.

8. Floege J. When man turns to stone: extraosseous calcification in uremic patients. Kidney Int. 2004;65:2447-2462. Available at www.nature.com/ ki/journal/v65/n6/full/4494554a.html.

9. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-1143.

Available at cjasn.asnjournals.org/content/3/4/1139.long.

10. Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569.

11. Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol.

2007;56:569-579.

5. SUMMARY

12. Goel SK, Bellovich K, McCullough PA. Treatment of severe metastatic calcification and calciphylaxis in dialysis patients. Int J Nephrol.

Mrs. V has been out of treatment for two years now. She spent two months in rehabilitation after her episode of calciphylaxis and was then weaned off of pain medications.

She claims to be the only patient ever who was thrilled to have a bilateral mastectomy. She is now teaching phosphorus control to the other dialysis patients at the unit, and often states that she counts her blessings that she was one of the few who survived. ■

2011;24:701603. Available at www.hindawi.com/journals/ijn/2011/701603/.

13. Cathenis K, Goossens D, Vertriest R, et al. Breast infarction due to calciphylaxis after coronary artery bypass grafting. Ann Thorac Surg.

2011;91:1603-1606.

14. Kalajian AH, Malhotra PS, Callen JP, Parker LP. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed.

Arch Dermatol. 2009;145:451-458. Available at archderm.ama-assn.org/ cgi/content/full/145/4/451.

15. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk

Ms. Zuber is a physician assistant practicing in Alexandria, Va.; Mr. Bartow is the Clinical Director of the INOVA Wound Healing Center in Alexandria, Va.; and Dr. Davis practices in Birmingham, Ala.

factors, outcome and therapy. Kidney Int. 2002;61:2210-2217. Available at www.nature.com/ki/journal/v61/n6/full/4493000a.html.

All electronic documents accessed July 15, 2012.

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

CME CE

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

■ COMPLETE THE POSTTEST: Page 65

■ ADDITIONAL CME/CE: Pages 36, 61

Turn to page 35 for additional information on this month’s CME/CE courses.

CASE #1

Painful, itchy vesicles and bullae on the feet AUDREY CHAN, MD

A Hispanic boy, aged 13 years, presented with vesicles and bullae on the medial aspects of the feet that had been present for several days.

Occasional pruritus and pain with ambulation was reported. The boy denied the use of any new topical prescription or OTC medications or products. The patient history was negative for new footwear. No personal or family history of atopic dermatitis were reported. The boy had been evaluated by his primary-care physician and started on oral griseofulvin one day prior to coming to the ED. What is your diagnosis? Turn to page 56

CASE #2

Enlarging annular plaques and patches JOE MONROE, PA-C

A white man, aged 63 years, was referred for evaluation of annular papulosquamous plaques and patches that first appeared on his arms and legs about one year earlier. Multiple providers had diagnosed him with psoriasis, fungal infection, and “ringworm.” Despite the application of triamcinolone 0.1% and clotrimazole/betamethasone (Lotrisone) creams, the lesions continued to grow. No night sweats, fever, myalgia, or cough were reported. Medications prior to the appearance of the lesions included BP medicine and occasional OTC ibuprofen. A biopsy performed by dermatology staff showed noncaseating granulomas composed of large, pale-staining epitheliod histiocytes.

What is your diagnosis? Turn to page 57 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 55

CME CE

CASE #1

Dermatology Clinic

Inflammatory tinea pedis

The patient was diagnosed with inflammatory tinea pedis with large bullae. Affecting up to 70% of the population, tinea pedis is the most common dermatophyte infection.1 The development of infection depends on a number of factors within the host and in the local environment.

Immunocompromised individuals or those with decreased barrier function attributable to such conditions as diabetes mellitus or atopic dermatitis may be at increased risk for infection. Such local environmental factors as sweating and occlusive footwear can also increase the risk of developing tinea pedis. Because dermatophytes thrive in warm and moist environments, the incidence of tinea pedis is higher in athletes.2 Not surprisingly, this condition is uncommon in populations that do not wear shoes.3 Trichophyton rubrum and T. mentagrophytes are the most commonly implicated dermatophytes of tinea pedis. 3 These dermatophytes are also common causes of tinea corporis and tinea cruris, so treatment for all three conditions is similar.

The four major clinical presentations of tinea pedis are interdigital, moccasin, inflammatory (vesicular/bullous), and ulcerative. Of these subtypes, interdigital is by far the most common, characterized by presentation with erythema, scaling, and fissure in the web spaces of the toes. Tinea pedis in a moccasin distribution presents with diffuse scaling on the plantar surfaces of the feet, a symptom that is often mistaken by patients for “dry skin.” The inflammatory subtype is notable for vesicles and bullae on the medial aspects of the feet. Finally, ulcerative tinea pedis is usually seen in immunocompromised individuals and in diabetic patients with exacerbation of existing interdigital tinea pedis, leading to ulcers and erosions in web spaces.3 Complications from tinea pedis include bacterial superinfection and cellulitis.

A thorough foot and toenail exam should be performed in individuals with recurrent cellulitis, especially those with diabetes, as tinea pedis can compromise the epidermal barrier, providing a portal of entry for bacteria.

The diagnosis of tinea pedis often can be made clinically.

A comprehensive skin exam should be performed, focusing on such areas commonly infected by dermatophytes as the toenails, inguinal folds, axillae, buttocks, and web spaces of

the toes. When possible, the diagnosis should be confirmed by such noninvasive modalities as KOH examination and/or fungal culture. Scale from the leading edge of the plaque or roof of vesicles has the highest yield when searching for hyphael elements with KOH preparation under microscopy. If a biopsy is performed, a periodic acid-Schiff stain should be requested to better visualize hyphae in the stratum corneum.

The differential diagnosis of vesicles and bullae on the soles of the feet include acute contact dermatitis and dyshidrotic eczema. Because of the natural arch of the foot, contact dermatitis from shoes classically spares the instep. Contact

The four major clinical presentations of tinea pedis are interdigital, moccasin, inflammatory, and ulcerative. dermatitis caused by topical medications often spares the web spaces, as it is unusual to apply medications in this area. Dyshidrotic eczema presents as extremely pruritic, deep-seated vesicles with “tapioca pudding-like” appearance. If it is difficult to distinguish between these entities clinically, then a KOH examination, fungal culture, or biopsy should be obtained. The differential diagnosis for tinea pedis without vesicles or bullae includes psoriasis, juvenile plantar dermatosis, and secondary syphilis.

Topical medications are usually sufficient for treatment of tinea pedis. All topical medications should be used b.i.d. for two to six weeks. There is in vitro evidence that topical butenafine (Lotrimin Ultra) and topical terbinafine (Lamisil, Turbinex) are 10 to 100 times and two to 30 times more effective than azole antifungals against common dermatophytes, respectively.3 Because of this, many dermatologists prefer butenafi ne for the topical treatment of tinea pedis.

Nevertheless, more studies are needed to determine whether greater in vitro efficacy correlates with greater clinical efficacy in the treatment of tinea pedis. A recent systemic review found no significant difference between cure rates or side-effect profi les among the various topical antifungals.4 However, as this study pooled data from all tinea infections, no specific conclusions can be made regarding topical treatment of tinea pedis.

Indications for treatment of tinea pedis with oral antifungals include toenail involvement, widespread or severe disease, and/or resistance to topical antifungals. The duration of treatment for superficial tinea infections is two weeks.

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

If there is evidence of toenail involvement, however, the patient should be treated for three months, as onychomycosis is a reservoir for future tinea infections. In pediatric patients, griseofulvin is often the treatment of choice. Common side effects include GI complaints, rash, and headache.

Hepatotoxicity has rarely been documented.

For adults with tinea pedis, terbinafine is the treatment of choice. The FDA recently approved a granule formulation of terbinafine that can be sprinkled on food. No baseline labs are necessary for treatment durations of fewer than six weeks. Side effects include diarrhea, taste disturbance, rash, and headache. Liver enzyme abnormalities (two times the upper limit of normal) may be seen after four to six weeks of therapy; therefore, if a prolonged course of treatment is expected, liver function tests should be obtained at baseline and after six weeks of therapy. Since griseofulvin and terbinafi ne may have significant interactions with other medications, a careful drug reconciliation is mandatory prior to administration of either medication.5 There are two formulations of both griseofulvin and terbinafine, so attention is required to ensure proper dosing.

This patient’s presentation was most consistent with infl ammatory tinea pedis, as he had notable bullae of vesicles and bullae on the medial instep of the bilateral feet. The key to clincal diagnosis was the scaling in all 10 interdigital spaces consistent with a fungal etiology. A KOH examination could not be obtained, but a fungal culture was positive. The preliminary report of this fungal culture revealed the fungus Fusarium, which is a well-established cause of tinea pedis. The patient was continued on oral griseofulvin as prescribed by his primary-care physician with improvement at his two-week follow-up.

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

References 1. Masri-Fridling GD. Dermatophytosis of the feet. Dermatol Clin.

1996;14:33-40.

2. Field LA, Adams BB. Tinea pedis in athletes. Int J Dermatol. 2008;47:485492.

3. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1144-1146, 1961-1967.

4. Rotta I, Sanchez A, Gonçalves PR, et al. Efficacy and safety of topical antifungals in the treatment of dermatomycosis: a systematic review. Br J Dermatol. 2012;166:927-933.

5. Wolverton SE. Comprehensive Dermatologic Drug Therapy. 2nd ed.

Philadelphia, Pa.: Saunders Elsevier; 2007:86-90.

CASE #2

Sarcoidosis

Sarcoidosis is a systemic granulomatous disease that involves the skin and many of the internal organs with an acute or persistent course interrupted by remissions and relapses.1 The etiology is unknown, but it likely represents a granulomatous reaction to an unknown antigen.2 Strong racial proclivity and outbreaks within families suggest a genetic predisposition. It appears likely that multiple genetic factors are to blame.1 Whatever the trigger, T-cells appear to play a significant role in the genesis of sarcoidosis. T-cells likely propagate an excessive cellular immune reaction, mostly composed of increased numbers of CD4 cells accompanied by the release of interleukin 2, such Th1 cytokines as interferon, and an increase in tumor necrosis factor (TNF) and TNF receptors. The fact that the disease responds well to such anti-TNF drugs as pentoxifylline (Pentopak, Pentoxil, Trental) and infl iximab (Remicade) appears to support this theory.3 In addition to the skin, which is involved in at least 25% of cases, other sites of involvement include the lungs, mediastinal and peripheral lymph nodes, eyes, phalangeal bones, myocardium, central nervous system, kidneys, spleen, liver, and parotid glands.

In the United States, black women between the ages of 30 and 39 years have the highest incidence of sarcoidosis (107 cases per 100,000 population). In Europe, the condition is most prevalent in Scandinavia, especially Sweden, with a prevalence of 64 cases per 100,000 population. Sarcoidosis can also affect children.1 Papules are the most common morphological form of cutaneous sarcoid. These lesions are typically <1 cm in diameter and may be localized or generalized. Commonly affected areas include the face, eyelids, neck, and shoulders, where the lesions are often arranged or coalesce into annular patterns. Hypopigmentation, obviously more noticeable in darker-skinned patients, may be the earliest sign of sarcoidosis. Cutaneous involvement is classified as either specific, which reveals granulomas on biopsy, or nonspecific, which is mainly reactive. Erythema nodosum is the most common nonspecific cutaneous lesion of sarcoidosis. Biopsy of erythema nodosum reveals septal panniculitis confined

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Dermatology Clinic

to adipose tissue,4 a nonspecific reaction associated with a number of other unrelated diseases and triggers.

The skin lesions of sarcoidosis do not generally correlate with the extent or nature of systemic involvement or with prognosis.

However, red to violaceous lesions on the cheeks, ears, nose (especially the nostril rim), and fingers can become severe to the point of disfigurement and may even lead to involvement of underlying bone, cartilage, or upper aerodigestive tract. Such cases are termed lupus pernio, which can also manifest with uveitis and bone cysts. This type of sarcoidosis is most often seen in black women in their fourth or fifth decade of life.5 Additional cutaneous forms of sarcoid include ulcerative, subcutaneous, scar, plaque-type, erythrodermic, icthyosiform, alopecia, morpheaform, and mucosal.

Sarcoidosis may first appear with fever, polyarthralgias, uveitis, bilateral hilar adenopathy, and fatigue. Sarcoidosis combined with erythema nodosum is known as Lofgren syndrome, a condition that is far more common in Scandinavian whites and uncommon in American blacks.6 Approximately 5% of sarcoidosis cases are asymptomatic and are detected on radiographs of the chest performed for other reasons. Fever may be the only symptom, or sarcoid may be accompanied by weight loss, fatigue, and malaise.

The disease can involve virtually every internal organ, and its manifestations are truly protean. It has been called “the great imitator” because of the extreme variation in its presentations.7 Blind liver biopsy showing hepatic granulomas is an excellent means of confirming the diagnosis, since about 60% of sarcoid patients will have hepatic involvement. Blood work can reveal an elevated erythrocyte sedimentation rate, leukopenia, lymphopenia, anemia, eosinophilia, and thrombocytopenia. Levels of angiotensin-converting enzyme may be elevated in all granulomatous diseases—including sarcoidosis—but are not diagnostic.1 The differential diagnoses for sarcoidosis include cutaneous TB, lichen planus, granuloma annulare, discoid lupus, plaque psoriasis, syphilis and leprosy, among others.

Cutaneous disease may remit without treatment. Systemic steroids are quite effective but are problematic for long-term use. Intralesional steroid injection of 2-5 mg/cc triamcinolone has been used to good effect. Topical steroids have been effective as well, albeit to a lesser extent. Systemic agents used to treat cutaneous sarcoidosis include methotrexate (Rheumatrex, Trexall) and the antimalarials chloroquine (Aralen) and hydroxychloroquine (Plaquenil, Quineprox).

Systemic corticosteroid use is indicated in acute systemic disease, especially in the presence of fever and weight loss,

active eye disease, active pulmonary involvement, or other overt systemic manifestation.

Since TNF is an important cytokine in the formation of granulomas, TNF inhibitors have been reported to be effective in refractory disease.8 As of this writing, this treatment is under consideration for this particular patient, since his disease has been resistant to all other commonly used medications. ■ Mr. Monroe is a physician assistant specializing in dermatology at Dawkins Dermatology in Oklahoma City.

References 1. James WD, Berger TG, Elston DM. Sarcoidosis. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:708-714.

2. Dover JS. Cutaneous Medicine and Surgery: Self Assessment and Review.

Philadelphia, Pa.: W.B. Saunders; 1996:161-163.

3. Medscape Reference. Sarcoidosis. Available at emedicine.medscape.com/ article/301914-overview.

4. Katta R. Cutaneous sarcoidosis: a dermatologic masquerader. Am Fam Physician. 2002;65:1581-1584. Available at www.aafp.org/afp/2002/0415/ p1581.html.

5. Jorizzo JL, Koufman JA, Thompson JN, et al. Sarcoidosis of the upper respiratory tract in patients with nasal rim lesions: a pilot study. J Am Acad Dermatol. 1990;22:439-443.

6. Giuffrida TJ, Kerdel FA. Sarcoidosis. Dermatol Clin. 2002;20:435-447, vi.

7. Tchernev G. Cutaneous sarcoidosis: the “great imitator”: etiopathogenesis, morphology, differential diagnosis, and clinical management. Am J Clin Dermatol. 2006;7:375-382.

8. Doherty CB, Rosen T. Evidence-based therapy for cutaneous sarcoidosis. Drugs. 2008;68:1361-1383.

All electronic documents accessed July 15, 2012.

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

“It’s a cookout—act stupid!”

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

CME CE

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.

Calendula

© PHOTO RESEARCHERS, INC. / BONNIE SUE RAUCH

Commonly known as “pot marigold,” Calendula officinalis is one of the numerous members of the aster or daisy family.1 Anyone who has ever had a flower garden tends to wrinkle his or her nose when thinking of marigolds, due to the pungent, unpleasant fragrance they produce. However, this flowering plant, native to the Mediterranean, has a long history of multiple medicinal uses.

Marigold is reportedly found in more than 200 cosmetics around the world, not to mention many undocumented compounds.

Background C. officinalis blooms profusely throughout spring, summer, and fall. The marigold boasts a variety of bright yellow and orange flowers and dark-green, thick, fernlike leaves.

Researchers have documented its medicinal properties, which include antiviral, anti-HIV, and anti-inflammatory effects.2 Studies discussing the potential antitumor activity of C. officinalis suggest additional medicinal uses.

Science Both the blossom and the leaves of C. officinalis contain flavonol glycosides, triterpene oligoglycosides, oleanane-type triterpene glycosides, saponins, and a sesquiterpene glucoside.3 Science is beginning to see more in-depth uses for these antiinflammatory chemicals.

Bench researchers are aggressively studying C. officinalis extracts for their anticarcinogenic potential. In one study

using cultured human cell lines, two of the triterpene glycosides exhibited potent cytotoxic effects against colon cancer, leukemia, and melanoma.3 In a broader study, a laser-activated calendula extract (LACE) was used to study its effects on multiple types of neoplastic cells.2 Trial results demonstrated that the LACE extract showed an in vitro inhibition of tumor cell growth that ranged from 70%-100%.2 The mechanisms of action observed were apoptosis and cell cycle arrest.3 In patients undergoing radiation therapy, C. offi cinalis extracts have mitigated painful dermatitis experienced by up to 80% of patients. One study enrolled more than 250 patients being treated for breast cancer with postoperative radiation.4 These patients were blindly randomized to either trolamine or calendula in a petroleum-jelly base. The participants were given instructions to apply the compound to the affected area a minimum of twice daily. A positive response was considered a 20% reduction in dermatitis. A significant finding at the end of treatment was that patients who had

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ALTERNATIVE MEDS UPDATE used the calendula ointment experienced over 20% fewer cases of radiation dermatitis of grade 2 or higher.4 This along with other studies has earned calendula an evidence rating of “B” (good scientific evidence for use) for use in cases of radiation skin protection.5,6 Marigold compounds have also been studied as potential remedies for such gastric conditions as irritable bowel syndrome, chronic constipation, and cramping. In a study using a rabbit intestine, researchers induced a spastic response on the tissue and then applied the calendula extract.7,8 The results showed a marked spasmolytic effect and subsequent smooth muscle relaxation.7 The action appeared to be induced by a calcium channel blockade, similar to that of verapamil (Calan, Covera, Isoptin, Verelan).7,8 Other conditions for which calendula may be beneficial include venous stasis ulcers of the leg, generalized wound healing, and otitis media. A lack of human trials gives calendula use in these ailments a weak-evidence rating.9 Claims of antiviral and antibacterial activity also fall below the required evidence level for credible use.9

Safety, interactions In clinical trials, allergic reactions to C. officinalis occur in just over 2% of participants.10 Overdoses of C. officinalis have produced a tranquilizer-like sedation as well as hepatic and renal overload, as evidenced by elevated alanine transaminase and elevated blood urea nitrogen.11 Calendula is not recommended for use in children or infants or in pregnant or nursing women.11

C. officinalis ointment for radiation dermatitis definitely warrants further study. Other claims— while supported in small, in vitro studies—are lacking in clinical data and, therefore, are not recommended. ■ References 1. About herbs, botanicals & other products: calendula page. Memorial Sloan-Kettering Cancer Center website.

Available at www.mskcc.org/cancer-care/herb/calendula.

2. Jiménez-Medina E, Garcia Lora A, Paco L, et al. A new extract of the plant Calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte

C. officinalis extracts have mitigated painful dermatitis in patients.

activation. BMC Cancer. 2006;6:119-133.

3. Ukiya M, Akihisa T, Yasukawa K, et al. Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constitu-

Marigold compounds have also been studied as potential remedies for such conditions as irritable bowel syndrome.

ents of marigold (Calendula officinalis) flowers. J Nat Prod.

2006;69:1692-1696.

4. Pommier P, Gomez F, Sunyach MP, et al. Phase III randomized trial of Calendula officinalis compares with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. J Clin Oncol. 2004;22:1447-1453.

5. Basch E, Bent S, Foppa I, et al. Marigold (Calendula officinalis L.): An evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother. 2006;6:135-159.

6. McQuestion M. Evidence-based skin care management in radiation therapy. Semin Oncol Nurs. 2006;22:163-173.

7. Bashir S, Janbaz KH, Jabeen Q, Gilani AH. Studies on spasmogenic and spasmolytic activities of Calendula officinalis flowers. Phytother Res. 2006;20:906-910.

8. Mohammad SM, Kashani HH. Pot marigold (Calendula officinalis) medicinal usage and cultivation. Sci Res Essays.

2012;7:1468-1472.

9. Reider N, Komericki P, Hausen BM, et al. The seamy side of natural medicines: contact sensitization to arnica (Arnica

How supplied, dosage

Montana L.) and marigold (Calendula officinalis L.). Contact 10. Silva EJ, Goncalves ES, Aguiar F, et al. Toxicological studies on hydroalcoholic extract of Calendula officinalis. L. Phytother Res. 2007;21:332-336.

11. Blumenthal M, ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines.

American Botanical Council. Austin, Tx.; 1998.

Summary

12. Sarell EM, Cohen HA, Kahan E. Naturopathic treatment for ear pain in children. Pediatrics. 2003;111(5 Pt 1): e574-e579.

Calendula products are a long way from mainstream use. The most promising application of 60 THE CLINICAL ADVISOR • AUGUST 2012 • www.ClinicalAdvisor.com

All electronic documents accessed July 15, 2012.

© PHOTO RESEARCHERS, INC. / NEUFRIED

Dermatitis. 2001;45:269-272.

Topical ointments of 2% to 5% strength, applied three to four times daily, are used for skin irritations.11 Liquid drops are available in compound with other agents, and may be used in cases of otitis media.12

CME CE

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

■ COMPLETE THE POSTTEST: Page 65

■ ADDITIONAL CME/CE: Pages 36, 55

Turn to page 35 for additional information on this month’s CME/CE courses.

Erythematous scaling lesions KERRI ROBBINS, MD

CASE #1

CASE #2

A 50-year-old woman with no significant medical history presented with complaints of an enlarging, erythematous eruption. The lesions started three weeks earlier as pink papules on her shoulders, back, and buttocks. Mild pruritus was relieved with diphenhydramine (Benadryl).

The woman had also been treating the lesions with an OTC antifungal with no relief. She had no complaints of pain, no history of new medications or recent travel, and no pets in the household. A review of systems was otherwise negative.

A man, aged 53 years, with a history of tobacco abuse, presented with a rash on his palms and soles that had begun three months earlier. He had been previously diagnosed with tinea manuum and tinea pedis. A three-month course of oral terbinafine (Lamisil, Terbinex) provided no relief of the eruption. He had no associated symptoms. On physical examination, erythematous scaling plaques that were studded with pustules, brown macules, and brown crusts were appreciated on bilateral palms and soles. No mucous membrane or nail involvement was noted.

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

CME CE

CASE #1

Dermatologic Look-Alikes

Erythema annulare centrifugum

Erythema represents a change in skin color that may vary from pink to red to violaceous. The color changes arise from the dilation of blood vessels located in the papillary and reticular dermis and may last anywhere from minutes to days to months.

Erythema may be caused by trauma, changes in temperature, and various skin diseases.1 The four major types of erythemas are diffuse, regional/ localized, reticulated, and figurate. Annular, arciform, or polycyclic lesions are used to describe figurate erythemas.

Erythema annulare centrifugum (EAC) is one such figurate erythema. The other disorders in this category include erythema marginatum, erythema migrans, and erythema gyratum repens.

EAC was first described as pruritic, persistent, ring-shaped lesions and was named erythema gyratum perstans in 1881 by Colcott-Fox.2 It would be almost three decades until Wende gave a different description of recurrent lesions with scaly crust, which he called erythema figuratum perstans. Darier finally came up with the current name of EAC in 1916.2 He described the condition clinically as an annular or arcuate erythematous eruption with or without scaling.

Although EAC may happen at any time in life, its peak incidence is during the fi fth decade. The disease does not discriminate by sex or race. EAC occurs in approximately one out of every 100,000 people.2 Although the precise pathogenesis is still unknown to scientists, EAC is thought to be a hypersensitivity reaction to many different antigens.

Dermatophytes are presumed the most likely cause, along with other fungi, parasites, ectoparasites, viruses, foods, and drugs.2,3 Graves disease, HIV, autoimmune hepatitis, and chronic lymphocytic leukemia are also potential causes.4 The mechanism of disease is still under investigation.

Current theory proposes that tumor necrosis factor-alpha and interleukin-2 may have a role in the pathogenesis of the disease, given the disappearance of the lesions after administration of interferon (Intron, Roferon).5 The initial lesions of both variants of EAC (superficial and deep) tend to be single or multiple erythematous, edematous papules that are located in greatest concentrations on the thighs, buttocks, and trunk. The lesions begin as pink papules that migrate centrifugally and clear centrally.

The rings extend approximately 1 mm to 3 mm per day; however, some lesions have been known to enlarge to approximately 6 cm within one to two weeks.6 The lesions are usually asymptomatic but may occasionally be associated with pruritus, especially if spongiosis is present in the histologic examination of the biopsy. The expansion may not be uniform, and the ring will break and form arcs and polycyclic lesions. The lesions will become slightly elevated and an apparent trailing scale will form. The scale is the desquamation of the inner margin. Deep EAC is more infi ltrative and does not usually have pruritus or trailing

The initial lesions tend to be single or multiple erythematous, edematous papules on the thighs, buttocks, and trunk. scale. Lesions are usually generalized or localized and rarely spread to involve the soles, hands, mucous membranes, and scalp. Lesions may be present for weeks to months.1,6 When EAC is associated with an underlying disorder, flares of the disorder may cause recurrences of EAC. The histology differs between the two variants of EAC. Superficial EAC has focal parakeratosis and spongiosis. In the superficial dermis, there is a tight perivascular lymphocytic infi ltrate surrounding dilated vessels, often referred to as a coat-sleeve anomaly.2 Eosinophils are rarely seen.

The epidermis is usually uninvolved in the deep variant, and the perivascular coat-sleeve infi ltrate favors the mid and lower dermis.

EAC must be annular, arciform, or polycyclic. If this arrangement is not present, EAC can be ruled out. EAC is often misdiagnosed, primarily because it may look like other erythematous annular diseases. Other diseases commonly mistaken for EAC include other gyrate erythemas, tinea corporis, annular urticaria, annular pustular psoriasis, lymphoma cutis, and erythema multiforme. Such autoimmune disorders as linear immunoglobin (Ig) A bullous dermatosis, SjĂśgren syndrome, and lupus erythematous can also have an appearance similar to that of EAC. Once a diagnosis of EAC is made, remember to obtain a thorough history and specific blood tests to determine if the cause is idiopathic or attributable to an underlying disorder. Underlying disorders must be treated and may lead to resolution of the skin disease. Topical corticosteroids may provide some benefit if applied to the advancing

62 THE CLINICAL ADVISOR â&#x20AC;˘ AUGUST 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

border of the lesion. Systemic corticosteroids often lead to complete resolution; however recurrences are common after the medication is discontinued. If pruritus is present, incorporate topical antipruritics and sedating antihistamines into the treatment plan.2 Some have advocated the empiric use of antibiotics or antifungals, even in the absence of an identifiable cause.2 The outlook for patients with EAC is excellent.

Fortunately, there is no residual scarring. However, there may be some associated postinflammatory hyperpigmentation or purpura.

In this patient, a 4-mm punch biopsy was obtained and confirmed the diagnosis of superficial EAC, showing parakeratosis, spongiosis and a superficial coat-sleeve pattern of inflammation. No underlying disorder was ever identified.

Given that the lesions were pruritic, they were treated with triamcinolone 0.1% ointment b.i.d. and hydroxyzine as needed. The lesions resolved within two months, and the patient has had no recurrences to date.

CASE #2

Pustular psoriasis

Pust u lar psor iasis is an uncommon disease that affects individuals from all racial backgrounds. Some studies done in Asian countries show that only 7.5 individuals per 1,000,000 are diagnosed with pustular psoriasis. In adults, both sexes are affected equally; in children, boys may be affected slightly more often than girls. The average age of onset is 50 years, but there have been nearly 300 documented cases in infants as young as age one week.1,7 Pustular psoriasis is an unusual variant of psoriasis that has many possible triggers, including pregnancy, rapid tapering of corticosteroids or other systemic therapies, hypocalcemia, infections, and local irritants.

The condition can be divided into generalized pustular psoriasis, acrodermatitis continua of Hallopeau, and pustulosis of the palms and soles. Baker and Ryan have proposed four different subcategorized patterns of generalized pustular psoriasis.2 These patterns include von Zumbusch, annular, exanthematic type, and localized.2,8 During the course of the disease, the lesions may transition from one pustular variant

to another and even into other manifestations of psoriasis.

The onset is fairly rapid and progresses quickly. The skin located in the flexures, genital regions, webs of the fingers, and periungual areas are most commonly affected.1 In the von Zumbusch pattern, the skin may become painful and begin to develop sheets of erythema and pustulation. The patient is often ill and suffers from a fever.

After several days, the pustules usually resolve and extensive desquamation and brown crusting in areas of the previous pustules may be observed.

The annular pattern is seen in up to 60% of children who are affected by pustular psoriasis.1 This pattern is characterized by annular inflammatory plaques that are studded with pustules that range from 2 mm to 3 mm in diameter.1 The plaque will enlarge centrifugally over hours to days, leaving behind desquamation as it heals. Patients may complain of fever, pain and general malaise.

An acute eruption of small pustules is characteristic of the exanthematic type. This variant usually follows an infection or is the result of administration of specific medications, most notably lithium (Eskalith, Lithobid). Systemic symptoms are rare.

In the localized pattern, pustules appear within or at the edge of pre-existing psoriatic plaques. This is often seen after the application or irritants such as tar. Impetigo herpetiformis is likely a manifestation of generalized pustular psoriasis during pregnancy and may be triggered by hypocalcemia. Lesions in mucous regions are also common, often affecting the mouth and tongue.1 The disease is cyclic and is associated with relapses that are common and become progressively more severe.1 Acrodermatitis continua of Hallopeau is a rare manifestation of psoriasis in which pustules are seen on the distal portions of the fingers and, rarely, the toes. These pustules may scale and crust as they are healing. The nails may thicken and can even separate due to subungual lakes of purulence.

Pustulosis of the palms and soles presents with erythematous scaling plaques on the palms and soles studded with pustules and yellow-brown macules. In contrast to generalized pustular psoriasis, this disease is chronic and the pustules remain localized. Infection and stress have been identified as triggering factors while smoking may aggravate the course. Rarely, pustulosis of the palms and soles may be associated with SAPHO syndrome. Seen in several neutrophilic dermatoses, SAPHO syndrome consists of s ynovitis, acne, pustulosis, h yperostosis, and osteitis.

Continues on page 64

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0 T

CME CE

Dermatologic Look-Alikes

Histologically, neutrophils within the stratum corneum and between keratinocytes are a characteristic feature of pustular psoriasis. Exaggerated microabscesses of Munro and spongiform pustules of Kogoj, the hallmarks of active psoriasis, are seen normally in pustular psoriasis.6,9 Microabscesses of Munro are described as the accumulation of neutrophil remnants in the stratum corneum, surrounded by parakeratosis. Spongiform pustules of Kogoj are described as the accumulation of neutrophils within a spongiotic pustule.

Some disorders that may be mistaken for pustular psoriasis include impetigo, superficial candidiasis, dermatophyte infection, pemphigus foliaceus, immunoglobulin A pemphigus, Sneddon-Wilkinson disease, EAC, contact dermatitis, acute generalized exanthematous pustulosis, and extensive bacterial folliculitis.2,10 In infants, transient neonatal pustular melanosis and acropustulosis of infancy must be considered. Differentiation from infectious causes may be resolved using viral, bacterial, and fungal cultures.

conservative treatments include vitamin D3 analogues, corticosteroids, and photo- or chemotherapy.

Case studies have shown patient prognosis to vary from excellent to poor. Complications can cause much patient distress.

Bacterial skin infections, hair loss, and nail loss are some of the most common complications a patient may experience.

The open pustules may lead to secondary bacterial infection or septicemia. Other complications include hypocalcemia, renal tubular necrosis, liver damage, and malabsorption. The von Zumbusch type of pustular psoriasis may cause death (heart and lung failure) if it is not treated in the acute phase. Older patients usually have a less favorable outcome. However, children diagnosed with pustular psoriasis tend to do well.2 This patient was diagnosed with pustulosis of the palms and soles. Treatment with acitretin led to a complete resolution of his disease. ■

Bacterial skin infections, hair loss, and nail loss are some of the most common complications of pustular psoriasis.

References

Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

1. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:89-91, 541-542.

2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008: 126-127, 277-281.

3. Furue M, Akasu R, Ohtake N, Tamaki K. Erythema annulare centrifugum

A KOH examination may help to exclude a dermatophyte infection. Acute generalized exanthematous pustulosis is a pustular drug eruption, and a thorough history may help to elicit the offending drug. Eosinophils will often be seen during histologic examination, which may also help to differentiate between the two disorders. For other etiologies, a biopsy may be needed to determine the definitive diagnosis.

Acitretin (Soriatane) has proved to be the most effective monotherapy in those with pustular psoriasis. The dose should be maximized to up to 1 mg/kg/day. The endpoint that is desired is a dosage that causes a cheilitis that is still tolerable.2 Much consideration should be given before starting a woman of childbearing age on acitretin given the teratogenicity. A woman of childbearing age placed on acitretin is required to be on two forms of birth control for one month prior to treatment, during treatment, and for three years after treatment (given the potential half-life). During treatment, the clinician must monitor the woman’s pregnancy status, cholesterol and triglycerides, serum creatinine, and liver function.2 An x-ray of the spine should be done yearly to monitor for the development of hyperostoses.2 Other more

induced by molluscum contagiosum. Br J Dermatol. 1993;129:646-647.

4. Gulati S, Mathur P, Saini D, et al. Erythema annulare centrifugum with autoimmune hepatitis. Indian J Pediatr. 2004;71:541-542.

5. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138:1019-1024.

Available at archderm.jamanetwork.com/article.aspx?articleid=478935.

6. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin.

10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:171-172, 178.

7. Ivker RA, Grin-Jorgensen CM, Vega VK, et al. Infantile generalized pustular psoriasis associated with lytic lesions of the bone. Pediatr Dermatol.

1993;10:277-382.

8. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:64-67.

9. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:51-52, 63-64.

10. Habif TP. Skin Disease: Diagnosis and Treatment. 2nd ed., Philadelphia, Pa.: Elsevier Mosby; 2005:108-111.

All electronic documents accessed July 15, 2012.

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

CE

POSTTEST Expiration date: August 2013

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

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

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 36

page 55

page 61

Infections, tumors, and lumps affecting the scrotal content

Inflammatory tinea pedis

Erythema annulare centrifugum

1. Which is a diagnostic characteristic of a spermatocele? a. Associated with sudden onset of acute pain b. Aspiration and examination of fluid needed for diagnosis c. A freely movable mass that transilluminates well d. Almost always requires surgical removal 2. What organism is primarily associated with epididymitis? a. Mycobacterium spp. b. Neisseria gonorrhoeae c. Chlamydia trachomatis d. Escherichia coli 3. What is used to definitively diagnose testicular torsion? a. CT scan b. Ultrasound c. Biopsy d. Serum tumor marker 4. What is the primary treatment for testicular cancer? a. Surgical removal b. Radiation therapy c. Chemotherapy d. Watchful waiting

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureAugust2012

1. What is the presentation of the most 1. What is the initial appearance of common subtype of tinea pedis? erythema annulare centrifugum (EAC)? a. Erythema, scaling, and fissures in a. Pink papules that migrate centrifugally the web spaces of the toe and clear centrally b. Diffuse scaling on the plantar b. Small, grouped vesicles that coalesce surfaces of the feet to form coin-shaped plaques c. Vesicles and bullae on the medial c. Solid, firm, thick plaques with little or aspects of the feet no scaling d. Pruritic burrows, vesicles, or d. Flat-topped, shiny, violaceous papules nodules with crusting with white lines on the surface 2. What is the treatment of choice for adults with tinea pedis? a. Itraconazole (Sporanox) b. Ketoconazole (Nizoral) c. Nystatin d. Terbinafine (Lamisil, Terbinex)

2. Which treatment often leads to complete resolution of EAC? a. Surgical excision b. Cryoablation c. Systemic corticosteroid therapy d. UVB phototherapy

Sarcoidosis

Pustular psoriasis

3. In the United States, what group has 3. Exanthematic pustular psoriasis is the highest incidence of sarcoidosis? caused by which medication? a. White men of Scandinavian a. Furosemide (Delone, Furocot, descent older than age 40 years Lasix, Lo-Aqua) b. Black women aged 30 to 39 years b. Lithium (Eskalith, Lithobid) c. Children younger than age 6 years c. Phenytoin (Di-Phen, Dilantin, Phenytek) d. Men and women older than d. Allopurinol (Lopurin, Zyloprim) age 65 years 4. What is the most effective 4. What is a presenting symptom monotherapy for pustular psoriasis? of sarcoidosis? a. Acitretin (Soriatane) a. Polyarthralgias b. Calcipotriene (Dovonex) b. Hilar adenopathy c. Methotrexate (Rheumatrex, Trexall) c. Uveitis d. Cyclosporine (Gengraf, Neoral, d. All of the above Sandimmune, Sangcya) TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermAugust2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 65

CME

POSTTEST Expiration date: August 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of October 2011. Participants may submit the self-assessment at any time during that period.

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

Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 36

page 55

page 61

Infections, tumors, and lumps affecting the scrotal content

Inflammatory tinea pedis

Erythema annulare centrifugum

1. Which is a diagnostic characteristic of a spermatocele? a. Associated with sudden onset of acute pain b. Aspiration and examination of fluid needed for diagnosis c. A freely movable mass that transilluminates well d. Almost always requires surgical removal 2. What organism is primarily associated with epididymitis? a. Mycobacterium spp. b. Neisseria gonorrhoeae c. Chlamydia trachomatis d. Escherichia coli 3. What is used to definitively diagnose testicular torsion? a. CT scan b. Ultrasound c. Biopsy d. Serum tumor marker 4. What is the primary treatment for testicular cancer? a. Surgical removal b. Radiation therapy c. Chemotherapy d. Watchful waiting

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureAugust2012

1. What is the presentation of the most 1. What is the initial appearance of common subtype of tinea pedis? erythema annulare centrifugum (EAC)? a. Erythema, scaling, and fissures in a. Pink papules that migrate centrifugally the web spaces of the toe and clear centrally b. Diffuse scaling on the plantar b. Small, grouped vesicles that coalesce surfaces of the feet to form coin-shaped plaques c. Vesicles and bullae on the medial c. Solid, firm, thick plaques with little or aspects of the feet no scaling d. Pruritic burrows, vesicles, or d. Flat-topped, shiny, violaceous papules nodules with crusting with white lines on the surface 2. What is the treatment of choice for adults with tinea pedis? a. Itraconazole (Sporanox) b. Ketoconazole (Nizoral) c. Nystatin d. Terbinafine (Lamisil, Terbinex)

2. Which treatment often leads to complete resolution of EAC? a. Surgical excision b. Cryoablation c. Systemic corticosteroid therapy d. UVB phototherapy

Sarcoidosis

Pustular psoriasis

3. In the United States, what group has 3. Exanthematic pustular psoriasis is the highest incidence of sarcoidosis? caused by which medication? a. White men of Scandinavian a. Furosemide (Delone, Furocot, descent older than age 40 years Lasix, Lo-Aqua) b. Black women aged 30 to 39 years b. Lithium (Eskalith, Lithobid) c. Children younger than age 6 years c. Phenytoin (Di-Phen, Dilantin, Phenytek) d. Men and women older than d. Allopurinol (Lopurin, Zyloprim) age 65 years 4. What is the most effective 4. What is a presenting symptom monotherapy for pustular psoriasis? of sarcoidosis? a. Acitretin (Soriatane) a. Polyarthralgias b. Calcipotriene (Dovonex) b. Hilar adenopathy c. Methotrexate (Rheumatrex, Trexall) c. Uveitis d. Cyclosporine (Gengraf, Neoral, d. All of the above Sandimmune, Sangcya) TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermAugust2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • AUGUST 2012 65

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

AMOXICILLIN FOR ACUTE RHINOSINUSITIS DOES NOT IMPROVE SYMPTOMS AT THREE DAYS BUT REDUCES LIKELIHOOD OF SYMPTOMS AT SEVEN DAYS Level 1: Likely reliable evidence Guidelines from the American Academy of Otolaryngology-Head and Neck Surgery Foundation and the CDC recommend deferring antibiotic treatment for individuals with acute bacterial rhinosinusitis for at least seven days after diagnosis and limiting initial management to symptomatic relief. If after at least seven days of symptoms the decision is made to treat with antibiotics, amoxicillin is the first-line therapy recommended for most adults (Otolaryngol Head Neck Surg. 2007;137[3 Suppl]:S1-S31, Ann Intern Med. 2001;134:479486). A new randomized trial evaluated the efficacy of amoxicillin in 166 adults with acute sinusitis treated according to these guidelines ( JAMA. 2012;307:685-692).

Patients aged 18-70 years meeting the CDC diagnostic criteria for acute bacterial rhinosinusitis with symptoms for seven to 28 days were randomized to amoxicillin 500 mg vs. placebo orally three times daily for 10 days. All patients had moderate to very severe symptoms with mean duration of 11 days. A five- to seven-day supply of symptomatic treatments was given to all patients. The primary outcome was change in disease-specific quality of life measured by the SNOT-16 score (Sinonasal Outcome Test16). The SNOT-16 score rates the severity of 16 sinus-related symptoms on a 0-3 scale, with a minimally important difference of 0.5 points.

Patients also rated their overall symptoms on a scale of 0-6, ranging from no symptoms to feeling “a lot worse.”

New guidelines recommend deferring antibiotic treatment for at least seven days in adults with acute bacterial rhinosinusitis.

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

On the third day of treatment, there were no significant differences in mean reduction in SNOT-16 score (0.59 vs. 0.54) or self-reported symptom improvement (symptoms rated as “a lot better” or no symptoms in 37% vs. 34%).

On day 7, the mean SNOT-16 score was statistically improved for the amoxicillin group (mean reduction 1.06 vs. 0.86, p=0.02) but this difference did not reach the threshold of clinical importance. However, the amoxicillin group did show clinically meaningful improvement in the proportion of patients rating themselves as a lot better or without symptoms (74% vs.

56%, p=0.02, NNT 6). At 10 days there were no significant differences in symptoms. There were no significant differences in adverse events, days of work missed, relapse or recurrence, or satisfaction with treatment at any time point.

TAI CHI REDUCES FALLS COMPARED WITH RESISTANCE TRAINING IN PATIENTS WITH PARKINSON DISEASE Level 1: Likely reliable evidence Patients with Parkinson disease have a high risk of falling, which may be due to impaired movement and balance. While medication can improve some motor deficits including bradykinesia and rigidity, it may be less effective for improving postural stability. Furthermore, though exercise can improve strength and slow the loss of motor function, exercise programs The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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PRESENTING THE BENEFITS OF SURGERY IN TERMS OF ABSOLUTE RISK INSTEAD OF RELATIVE RISK APPEARS TO DECREASE THE LIKELIHOOD OF PATIENTS ELECTING SURGERY Level 3: Lacking direct evidence A recent randomized trial investigated how different approaches to explaining the benefits of surgery may affect patients’ likelihood of choosing to have surgery (Neurology.

2012;78:315-321). A total of 420 adults attending an appointment at a neurology clinic for reasons unrelated to carotid artery disease were randomized to view a 30-second video presentation describing treatment options in a hypothetical clinical scenario of asymptomatic 70% carotid artery stenosis.

The videos used one of five methods to describe how much the risk of stroke would be reduced by the addition of surgery to best medical therapy. The descriptions were: 50% relative risk reduction over five years; absolute risk of stroke at five years of 5% with surgery vs. 11% without surgery; absolute five-year event-free survival of 95% vs. 89%; annualized absolute risk of 1% vs. 2% per year; or a qualitative description

In patients with Parkinson disease, tai chi improves balance and gait.

(“risk significantly less”) without numerical presentation.

The sex and race of the video presenter were also randomized, giving a total of 20 different scenarios. After the video, participants completed a survey regarding treatment choice of surgery plus medication vs. medication alone. No participants had any history of carotid stenosis.

About half of the participants reported that they would choose surgery plus medication, but the likelihood of choosing surgery varied with presentation method. Participants who saw videos explaining the benefits of surgery in terms of absolute risk reduction were significantly less likely to choose surgery than were those viewing the relative risk and qualitative conditions (p <0.001). Surgery was chosen by 63% for relative risk reduction, 43% for absolute risk, 37% for absolute event-free survival, 35% for annualized absolute risk, and 64% for qualitative presentation. Sex and race of the presenters were not associated with treatment choice. ■

“Yes, it’s a golden age—or would be, if we weren’t all swarming with lice.”

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

have shown inconsistent efficacy for preventing falls ( J Neurol Neurosurg Psychiatry. 2007;78:678-684; Mov Disord.

2010;25:1217-1225). A recent randomized trial evaluated the effects of tai chi, a balance-based exercise emphasizing slow mind-focused movements, in 195 patients with Parkinson disease (N Engl J Med. 2012;366:511-519).

Patients (mean age 69 years) with mild-to-moderate Parkinson disease were randomized to tai chi vs. resistance training vs. stretching for 60-minute sessions twice weekly for 24 weeks. The tai chi group received training in six movements specifically designed to improve balance and gait; the resistance training group participated in exercise to strengthen muscles involved in balance, posture and gait; and the stretching group performed low-intensity exercise in a group setting as an attention control.

At the end of treatment, the rate of falls was significantly lower in the tai chi group (62 total falls, corresponding to a rate of 0.22 falls per patient-month) than in either the resistance training group (133 falls, 0.51 falls per patient month, p=0.05 vs. tai chi), or the stretching group (186 falls, 0.62 falls per patient-month, p=0.005 vs. tai chi). Tai chi was also associated with significantly greater improvement in balance compared with both groups and significantly greater improvement in gait, strength, and motor scores compared with stretching.

There were no serious adverse events in any group.

© PHOTO RESEARCHERS, INC. / JOHN COLE

Evidence-Based Medicine

COMMENTARY Debra Clements Coats, RN, BSN, MSN, NP-C, is employed in internal medicine at New Stanton Primary Care in New Stanton, Pa.

Social media is here to stay I sit down at the kitchen table with my coffee and morning paper, Pittsburgh’s Tribune Review. The headline that catches my eye reads, “Coroner begins to post notices on Twitter, Facebook” (triblive .com/news/westmoreland/1094397-85/information-office-coroner-public-county-media-socialtwitter-via-facebook, accessed July 15, 2012). Apparently, Westmoreland County, Pennsylvania, is the first county in the state to release public information via social-media outlets. Companies, organizations, and individuals are utilizing social-media outlets in increasing numbers. The amount and variety of health-care information available to the public is staggering.

Keep in mind that what we post on social-media sites may be permanent and traceable back to us.

Merriam-webster.com defines social media as forms of electronic communication, such as websites for social networking and blogging, through which users create online communities to share information, ideas, personal messages, and other content such as videos. Social media includes not only social-networking sites such as Facebook.com and Twitter.com, but also YouTube.com (a videosharing website), Flickr.com (a photo-sharing website), Wikipedia.com (an information-sharing website), and many more.

The use of social media in health care has both benefits and drawbacks. One cannot deny the clear advantage of the speed at which information may be dispersed to many recipients simultaneously. Financial rewards also may be realized in the form of saved postage fees, reduced use of office supplies such as paper and ink, and even a need for fewer personnel.

Convenience is a huge advantage as well: You can access information from wherever you are through your cell phone, laptop computer, or tablet computer.

One disadvantage of social media for clinicians is that we must be very careful about what we “post” on these sites. You never want to disclose private health-care information about your patients; HIPAA violations are serious.

We must also be careful when posting personal information about ourselves. How much do we really want our patients to know about us? We

need to keep in mind that what we post may be permanent and traceable back to us.

We also must be careful about trusting the information we get from social-media sites. We have to let our patients know that just because something is out there on the Internet does not make it true. According to one article, “How America Searches Health and Wellness,” 34% of consumers use social media to search for health information (www.healthcareos.com/299 /healthcare-social-media-strategy/, accessed July 15, 2012). We need to guide our patients toward online sources that provide reliable health information such as the National Library of Medicine (www.nlm.nih.gov); MedlinePlus (www.medlineplus.gov), the CDC (www.cdc .gov), and the Mayo Clinic (www.mayoclinic .com). I personally get texts from the CDC containing health information that pertains to my age and gender.

Not only is social media here to stay, but continues to expand at a rapid pace. When patients come to the office with a medical complaint or a question about their medications, most have already searched the Internet—including social-media sites—for answers and often are ready to accept that information as the complete truth. The clinician should listen to what the patient has learned and steer him or her in the direction that best suits that patient’s personal health-care needs. ■

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PA WANTED

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

NP WANTED

CONFERENCES

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CLASSIFIEDS NP/PA WANTED

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

PA WANTED

PA WANTED

Sunmount DDSO is now hiring for: Neurosurgery Physician Assistant Private Office Central California

Nurse Practitioner Must have a certificate and current registration to practice as a Nurse Practitioner in NYS

Central California Faculty Medical Group (CCFMG), affiliated with the University of California San Francisco Fresno Medical Education Program has excellent opportunities for licensed Physician Assistants. The selected applicants should have Neurosurgery OR and clinic experience and will be involved in all levels of patient care in the Neurosurgery Department at Community Regional Medical Center (CRMC) in Fresno. Excellent salary and benefit package. Please mail or fax CV to: Diane O’Connor, Recruiting CCFMG, 4910 E. Clinton Avenue, #101 Fresno, CA 94727-1505 Fax #: (559) 443-2691 E-Mail: diane.oconnor@ccfmg.org

Physicians Assistant Must be registered as a Physician’s Assistant

by NYS Education Dept OR Possess a limited permit to practice as a Physician’s Assistant in NYS Excellent NYS benefit package.

Work in a therapeutic environment with Developmentally Disabled Individuals. The nationally recognized Sunmount Program, located within NYS Adirondack Park, provides active treatment to individuals with Forensic and Behavioral concerns.

Contact Arlene T Mace at the address below.

OFFICE OF HUMAN RESOURCES SERVICES SUNMOUNT DDSO 2445 STATE ROUTE 30 TUPPER LAKE, NY 12986 (518) 359-4155 Arlene.Mace@OPWDD.ny.gov AN AFFIRMATIVE ACTION/ EQUAL OPPORTUNITY EMPLOYER

Visit our website at: www.universitymds.com EOE

NP/PA WANTED

NP WANTED

Emergency Care Center – non-hospital, free standing Emergency Clinic, staffed by Board Certified Emergency Medicine Doctors, needs a full-time NP with Acute Care / Emergency Dept. experience to work full-time. Applicant must be highly motivated, driven by Quality Medicine, and have at least five year’s experience as a NP. We have a highly trained staff, ER nurse, and the full lab and imaging of an ER. You are our addition for growing patient volume to work autonomously beside the MD. Position will be Mon-Thurs, plus two Saturdays per month.

Silver Health CARE, a dynamic practice in southwestern New Mexico, is recruiting for THREE physician assistants/nurse practitioners in urgent care and primary care at its Silver City, Deming, and Las Cruces locations. Quality-driven and serviceoriented with an excellent reputation, established 38 years ago. Excellent salary and benefits. Enjoy mild weather, beautiful mountain scenery, easy access to outdoor recreational opportunities, four-year colleges with graduate programs, a vibrant arts scene, rich and diverse cultural heritage.

See more about us at: www.crucialcare.com and call Heather at: 904-854-7911 for application information.

MEDICAL EDUCATION

Please e-mail or fax CV to: Cindy Donatelli, Recruiter (575) 388-3373 cdonatelli@silverhealthcare.org

www.silverhealthcare.org

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