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While there are many diabetes complications,

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

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1

“If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that speciﬁc care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit www.aan.com/guidelines. Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other speciﬁed criteria. AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP01859A/291945-01

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

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difﬁculty with concentration/attention). Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufﬁcient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. 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

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

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

100–150

150

QD or BID

25–50

50–75

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 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”.

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

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CONTENTS APRIL 2012

NEWS AND COMMENT 16

■ A woman experienced puffy hands and depigmentation on her cuticles and the middle of her chest.

Newsline ■ Drug slows cognitive decline in severe Alzheimer disease ■ Rest no better than exercise for back pain ■ Soda linked with asthma and COPD ■ CKD predicts mortality in diabetes ■ Accuracy of rapid flu tests ■ Some sleeping pills raise risk of death

■ An irregular area of hair loss is noted in a new high-school student who was nervous about his grades.

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

Clinical Challenge Lab results that showed abnormal iron levels in an otherwise healthy man propmted clinicians to take a closer look at his family history.

Legal Advisor A woman’s arm pain following myocardial perfusion imaging was blamed on incorrect IV insertion.

CME/CE Dermatologic Look-Alikes Two cases of trunk rashes with central clearing—one on the buttocks of a woman following hip surgery, the other on the flank of a woman who had just been to the New Jersey shore.

Commentary

FEATURES 28

70 Donepezil for severe Alzheimer disease 16

Drug Update ■ Twice-daily tablet to control blood sugar ■ New option for actinic keratosis

CME/CE A new understanding of osteoarthritis New research and development holds promise for altering osteoarthritis, not just treating the symptoms.

CME/CE Dermatology Clinic

How to spot cases of elder abuse 40

Screening strategies for spotting elder abuse The primary-care provider may be the only contact homebound elders have outside of an abusive situation.

Continues on page 12

DEPARTMENTS 59

Stat Consult Find out the most recent information on diagnosing and treating individuals with hypertensive emergency/urgency.

MAKING CONTACT

Unexpected diagnosis following DNA test 77

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CONTENTS DEPARTMENTS, cont’d 90

CME/CE Posttest

Alternative Meds Update Saffron is used to treat depression, Alzheimer disease, and PMS.

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2012 Salary Survey

ADVISOR FORUM 48

Consultations ■ Vitamin D and post-fracture symptoms ■ Options for treating an anxious and depressed alcoholic ■ Urine drainage at the end of life ■ Gyecomastia in a patient on dialysis

A man on dialysis with breast enlargement 49

Clinical Pearls ■ Decreasing agitation in patients with dementia ■ Rectal foreign body removal ■ Antibiotic eye drop reminder Your Comments ■ Alternatives to triptans for migraine

in patients with CAD ■ Ensuring early detection of a

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Saffron holds promise against depression 94

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Nurse-initiated steroids improve pediatric asthma care Time to clinical improvement and discharge was shortened for children with asthma admitted to the pediatric emergency department.

Psoriasis variants and related conditions Psoriasis is a chronic autoimmune skin disease, marked by thick, red skin with flaky, silver-white scaly patches. Learn more about the different variants with this slideshow.

Gastroenteritis deaths doubled between 1999 and 2007 Mortality increased from 7,000 to more than 17,000 gastroenteritis-associated deaths per year from 1999 to 2007.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Leigh Montejo, MSN, FNP-BC Detecting vitamin D insufficiency A middle-aged woman presents with a two-year history of fatigue and mood changes. She attributes her symptoms to aging, but could it be a sign of a nutritional deficiency?

iPads improve resident efficiency Clinician’s in training who were given Apple iPads were more efficient at ordering tests and procedures for their patients, reporting about one hour saved each day.

Robyn Carlisle, MSN, CNM, WHNP Are you a concerned clinician, or do you scare your patients straight? When it comes to patient care, finding an appropriate balance between emphasizing the need for follow up and causing unnecessary alarm can be difficult.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments. ClinicalAdvisor.com/DermDx0412A Flat-topped, slightly violaceous papules A patient presents complaining of itchy papules that have been present for several months. He denies any preceding illnesses or medication changes. What’s your diagnosis?

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Sharon M. O’Brien, MPAS, PA-C What’s causing a patient’s overwhelming urge to sleep? A young man visits the sleep clinic concerned about being terminated because he cannot stay awake at work. Julee Waldrop, DNP, PNP, FNP Be an advocate for vaccinating boys against HPV Encouraging patients of both sexes to receive the HPV vaccine will help achieve higher herd immunity rates and offer greater protection. Leigh Montejo, MSN, FNP-BC Explaining kidney function to prevent CKD Patients often have trouble understanding health outcomes they cannot see. It is our job as health-care providers to help patients understand their bodies in efforts to improve treatment compliance for chronic conditions.

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

Newsline A P R I L 2 0 12

Rapid flu tests no good at ruling out illness page 20

Soda drinking tied to asthma and COPD page 19

Some sleep aids may increase mortality risk page 20

Drug slows cognitive decline in severe AD

DONEPEZIL (Aricept), widely used to treat mild to moderate Alzheimer disease (AD), has demonstrated benefit when patients continued to take the drug as their condition progressed. The study yielding this finding involved 295 community-dwelling patients in the United Kingdom who had been treated with donepezil for at least three months and who had moderate or severe AD. Donepezil, a cholinesterase inhibitor and the most commonly prescribed of the dementia drugs, is recommended for persons in the earliest stages of AD. Clinicians are advised to stop prescribing the drug once the patient has advanced to moderate to severe Alzheimer status; there had been no clear evidence that continuing treatment was of benefit to patients. In this study, however, patients assigned to continue receiving donepezil scored an average of 1.9

Brain MRI shows tissue atrophy in the temporal lobes.

points higher on the Standardized Mini-Mental State Examination (SMMSE) than did patients assigned to discontinue the drug, with the higher scores indicating better cognitive function. The donepezil group also scored 3.0 points lower on the Bristol Activities of Daily Living Scale (BADLS) than did the patients no longer taking the drug, which indicated less impairment. Investigators also assigned some patients to receive memantine (Namenda) either while taking donepezil or upon discontinuing donepezil. Memantine is an N-methyl-D-aspartate (NMDA)receptor antagonist prescribed to control AD. Compared with those assigned to receive a memantine placebo, memantine users scored an average of 1.2 points higher on the SMMSE, and 1.5 points lower on the BADLS.

The efficacy of each agent did not differ significantly in the presence or absence of the other, and combining donepezil and memantine use did not offer significant benefits over the use of donepezil alone (N Engl J Med. 2012;366:893-903). A separate study published in BMC Geriatrics (2012;12:3; available at www.biomedcentral.com/14712318/12/3, accessed March 15, 2012) described a 21-item questionnaire that can be used not only to help primary-care providers diagnose AD, but also to help them distinguish between normal memory loss and amnestic mild cognitive impairment (aMCI). The items are divided into five domains including memory, orientation, functional ability, visuospatial ability, and language. Six of the items are predictive of clinical AD, and four items—all memory-related—were found to be predictive of aMCI.

Causes of foodborne illness outbreaks Contamination by infected food handlers probably causes the most foodborne norovirus infections.

1% 4%

Norovirus Bacteria Chemicals

51%

Source: MMWR Morb Mortal Wkly Rep. 2011;60:1197-202.

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

38%

Other/Multiple Parasites

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 Rest no better than exercise for back pain of daily rest and the option of using a flexible lumbar belt, and 51 patients to exercise therapy once a week for 10 weeks. No statistically significant differences were found between the two groups on any outcome measure, including pain, disability, general health, and global assessment, after 10 weeks or one year. The study authors speculated that because LBP did not improve more with rest than exercise, Modic changes themselves might not be causing pain, two hours of rest per day might not have been enough, or some types of Modic changes might respond better than others to rest. Another project focusing on musculoskeletal pain indicated that cold-water baths reduced

The study concentrated on back pain with Modic changes.

the muscle soreness that commonly results after sports and exercise activity. However, the optimum method of cold-water immersion and the safety of this form of cryotherapy are not clear, wrote Chris Bleakley and colleagues in an online report for The Cochrane Library.

Soda linked with asthma and COPD HIGH LEVELS of soft-drink consumption were positively associated with asthma and chronic obstructive pulmonary disease (COPD) in a study of 16,907 persons age 16 years and older living in southern Australia. Overall, 13.3% of participants with asthma and 15.6% of those with COPD reported consuming more than a half-liter of such drinks as soda, lemonade, fl avored mineral water, or Gatorade per day. Comparing that group with persons who did not consume soft drinks, the odds ratio for asthma was 1.26

A healthy diet is important in preventing chronic diseases.

and the odds ratio for COPD was 1.79 (Respirology. 2012;17: 363-369). Smokers who had more than a half-liter of soft drinks per day were 6.6 times more likely to develop COPD than were nonsmokers who do not drink these beverages. The authors contend that the fi ndings emphasize the importance of healthy eating and drinking for the prevention of asthma, COPD, and other chronic diseases. This point was revisited by another recent study indicating that an excessive

intake of such cured meats as bacon, salami, and chorizo can increase hospital readmission for COPD patients. The research, conducted in Spain by Dr. Judith GarciaAymerich and colleagues and published online ahead of print in European Respiratory Journal, demonstrated that after hospitalization for COPD, patients who had more than one slice of ham per day or equivalent were twice as likely as other such patients to suffer another exacerbation that would require them to be readmitted.

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

TOP: © ISTOCKPHOTO.COM / CHRISTOPHER PATTBERG; BOTTOM: © PUNCHSTOCK

TWO TREATMENT approaches to persistent lower back pain (LBP)—“rest and reduced load” and “exercise and staying active” appeared to be equally effective in patients with Modic changes. Exercise therapy is the recommended treatment for chronic LBP (BMC Med. 2012;10:22). But for the subpopulation of LBP sufferers who also have Modic changes in the spine, in which the bone marrow is infi ltrated by serum, fatty deposits, or sclerosis, the underlying pathology of these changes may make rest a better option. To determine which treatment strategy would work best for people with persistent LBP and Modic changes, the investigators randomized 49 such patients to a 10-week course of two hours

Newsline

IN A REVIEW of 22 randomized controlled trials involving more than 90,000 adults with type 2 diabetes mellitus, chronic kidney disease (CKD)—as defined by higher serum creatinine or lower estimated glomerular fi ltration rate (eGFR) and/or the presence of proteinuria—was found to be an important predictor of death ( J Am Heart Assoc. 2012;1:8-15). The studies were categorized into four groups according to annual mortality rates: <1, ≥1 to <2, ≥2 to < 4, and ≥4 per 100 patient-years. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Although the mortality rates were higher in the trials enrolling participants with prior cardiovascular problems, the selection for CKD was associated with the highest mortality rates. Trials in which inclusion required elevated serum creatinine values (mostly >1.5 mg/dL) or eGFR <60, and/ or evident proteinuria, showed the highest mortality rates: 5.9 to 8.24 per 100 patient-years. Patients in the highest mortality category were more likely to be older, had diabetes for longer, and had higher BP. Hypertension was not associated with higher mortality rate. Furthermore, selection for hypertension specifically did not discriminate those at higher risk of death.

Accuracy of rapid flu tests RAPID INFLUENZA diagnostic tests can accurately identify the infection in adults and children presenting with flulike symptoms (fever, cough, sore throat), but are not as accurate at ruling it out, meaning a negative result should be followed up with a culture or reverse transcriptase–polymerase chain reaction (PT-PCR) test. Simple to use, RIDTs give results in 15 to 30 minutes. In some cases, they can be used at the point of care in a routine clinical setting, such as a primary-care office. However, cautioned an investigative team led by Caroline Chartrand, MD, MSc, RIDTs may have inconsistent accuracy, with reported sensitivity ranging from 10% to 80%. The researchers conducted a systematic review of 159 studies involving 26 RIDTs. The data yielded pooled sensitivity and specificity of 62.3% and 98.2%, respectively. The positive and negative likelihood ratios were 34.5 and 0.38, respectively.

Rapid flu tests were more sensitive for influenza A than for influenza B.

RIDTs were more sensitive for influenza A than for influenza B. The tests also were more sensitive in children than in adults (66.6% vs. 53.9%). “This is plausible because children have higher viral loads and longer viral shedding than adults,” affirmed Chartrand’s group in their early-release report for Annals of Internal Medicine. Considering their rapid turnaround time, “RIDTs fill a void at the point of care that no other test is likely to fi ll in the near future: as a first-line test to be confirmed (especially if negative) by more time-consuming, definitive testing,” concluded the authors. “As long as clinicians understand the limitations of RIDTs, namely that a negative result is unreliable and should be confirmed by using culture or RT-PCR, RIDTs could enable clinicians to institute prompt infection-control measures, begin antiviral treatment in high-risk populations, and make informed decisions about further diagnostic investigations.”

Some sleeping pills raise risk of death Hypnotic agents used to aid sleep may increase mortality risk by more than fourfold, according to the results of a large study. Data were evaluated for 10,529 pepole who received prescriptions for hypnotics, including such non-benzodiazepines as zolpidem (Ambien, Edluar, Intermezzo, Zolpimist), such benzodiazepines as temazepam (Restoril, Temazepam Gelthix), barbiturates, and sedative antihistamines. Patients with prescriptions for hypnotics

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

had approximately 4.6 times the hazard of dying over an average observation period of 2.5 years compared with 23,676 matched controls with no hypnotics prescriptions ( BMC Open. 2012;2:e000850). Those taking the most doses of hypnotics per year (>132) were five times more likely to die than were those prescribed none. Although these associations were found in every age group, they were strongest among persons aged 18 to 55 years. ■

CKD predicts mortality in diabetes

DrugUpdate New drug information from the publishers of MPR

Twice-daily tablet to control blood sugar Product: Jentadueto Companies: Boehringer

Ingelheim and Lilly Pharmacologic class: Dipeptidyl peptidase-4 inhibitor (DPP-4) + biguanide Active ingredients: Linagliptin, metformin HCl; 2.5 mg/500 mg, 2.5 mg/850 mg, 2.5 mg/1,000 mg; tablets. Indication: Adjunct to diet and exercise in type 2 diabetes when treatment with both linagliptin and metformin is appropriate. Pharmacology: Jentadueto is an antidiabetic product that combines linagliptin, a DPP-4 inhibitor, and extended-release metformin, a biguanide. Linagliptin slows the inactivation of incretin hormones, increasing their levels in the blood, leading to reduced fasting and postprandial glucose levels in a glucose-dependent manner. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing

peripheral glucose uptake and utilization. Clinical trials: The coadministration of linagliptin and metformin was studied in type 2 diabetes patients inadequately controlled on diet and exercise and in combination with sulfonylurea. There have been no clinical efficacy studies conducted with Jentadueto; however, bioequivalence of Jentadueto to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects. Adults: Individualize. Take b.i.d. with meals. Previously not on metformin: initially 2.5 mg/500 mg b.i.d.

Linagliptin and metformin in one tablet

Previously on metformin: Start with 2.5 mg linagliptin and current dose of metformin b.i.d. Previously on linagliptin and metformin: switch on mg/mg basis. Maximum 2.5 mg/1000mg b.i.d. Children: Not recommended. Contraindications: Renal impairment (serum creatinine ≥1.5 mg/dL [men], ≥1.4 mg/dL [women], or abnormal creatinine clearance). Metabolic acidosis, diabetic ketoacidosis. Warnings/Precautions: Not for treating type 1 diabetes. Confirm normal renal function before starting; monitor (especially in patients aged 80 years and older). Avoid in hepatic disease. Discontinue if lactic acidosis, shock, acute congestive heart failure or MI, sepsis, or hypoxemia occurs. Suspend therapy if dehydration occurs or before surgery. Monitor hepatic function, hematology (especially serum vitamin B12 in susceptible patients). Elderly, debilitated, uncompensated strenuous exercise, malnourished or deficient caloric intake, adrenal or pituitary insufficiency, or alcohol intoxication:

Ingenol mebutate 0.015%, 0.05%; topical gel Indication: Topical treatment of actinic keratosis (AK) Pharmacology: The mechanism of action by which ingenol mebutate induces cell death in treating actinic keratosis lesions is unknown. Clinical trials: In two double-blind, vehicle-controlled, clinical trials (Study 1 and Study 2), 547 adult subjects with AK on the face or scalp were randomized to treatment with either Picato gel, 0.015% or vehicle gel for three consecutive days, followed by an eight-week follow-up period. The studies enrolled subjects with four to eight clinically typical, visible, discrete AK lesions within a 25-cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded. On each dosing day, gel was applied to the entire treatment

Continued pg. 26

For more products, visit www.eMPR.com

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

New option for actinic keratosis Product: Picato Company: LEO Pharma Active ingredient:

DrugUpdate Jentadueto from pg. 22

increased risk of hypoglycemia. Concomitant intravascular iodinated contrast agents (suspend during and for 48 hours after use). Pregnancy (Category B). Nursing mothers: not recommended. Interactions: Antagonized by strong P-gp or CYP3A4 inducers (e.g., rifampin); consider alternatives to linagliptin if used in

Picato from pg. 22

area. Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. Partial clearance rate was defined as the proportion of subjects with ≥75% reduction in the number of AK lesions at baseline in the selected treatment area. In Study 1, the complete clearance rate for Picato was 37% and vehicle was 2%; partial clearance rate for Picato was 60% and vehicle was 7%. In Study 2, the complete clearance rate for Picato was 47% and vehicle was 5%; partial clearance rate for Picato was 68% and vehicle was 8%. In two other doubleblind, vehicle-controlled clinical trials (Study 3 and Study 4), 458 adults with AK on the trunk or

combination. Concomitant sulfonylurea: may need lower dose of sulfonylurea to reduce risk of hypoglycemia. Cationic drugs eliminated by renal tubular secretion (e.g., amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin): may increase metformin levels. Avoid excessive alcohol intake (potentiates

effects of metformin on lactate). Increased risk of lactic acidosis with topiramate, other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, dichlorphenamide). Diuretics, steroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, sympathomimetics, calcium channel blockers, isoniazid, nicotinic acid, others may cause hyperglycemia.

Concomitant insulin: not studied. Adverse reactions: Nasopharyngitis, diarrhea; hypoglycemia, hypersensitivity, cough, decreased appetite, nausea, vomiting, pruritus, pancreatitis. How supplied: Tabs—60, 180, 2,000

extremities were randomized to treatment with either Picato gel, 0.05% or vehicle gel for two consecutive days, followed by an eight-week follow-up period. The studies enrolled subjects with four to eight clinically typical, visible, discrete AK lesions within a 25-cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded. On each dosing day, gel was applied to the entire treatment area. In Study 3, at Day 57, the complete clearance rate for Picato was 28% and vehicle was 5%; partial clearance rate for Picato was 44% and vehicle was 7%. In Study 4, the complete clearance rate for Picato was 42% and vehicle was 5%; partial clearance rate for Picato was 55% and vehicle was 7%.

Subjects who achieved complete clearance at Day 57 in Study 1, 2, and 4 entered a 12-month follow-up period. Adults: For topical use only; not for oral, ophthalmic, or intravaginal use. Face and scalp: apply 0.015% gel to the affected area once daily for three consecutive days. Trunk and extremities: apply 0.05% gel to the affected area once daily for two consecutive days. Limit to one contiguous skin area of about 25 cm2 using one unit dose tube. Allow treated area to dry for 15 minutes after application. Wash hands immediately after application; avoid inadvertent transfer to other areas. Avoid washing and touching treated area for six hours after application; following this time, may wash with mild soap. Children: <18 years: not established.

Warnings/Precautions:

For more products, visit www.eMPR.com

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

For more information, call 800.243.0127 or visit www.Jentadueto.com.

Eye disorders (e.g., severe eye pain, eyelid edema, eyelid ptosis, periorbital edema) may occur after exposure. Avoid contact with the periocular area. Administration not recommended until skin is healed from previous drug or surgical treatment. Severe skin reactions. Pregnancy (Category C). Nursing mothers. Adverse reactions: Local skin reactions (e.g., erythema, crusting, swelling, vesiculation/pustulation, erosion/ ulceration), application site pain/pruritus/irritation/ infection, periorbital edema, nasopharyngitis, headache. How supplied: Singleuse tubes 0.015% —3 0.05% —2 For more information, call 877.494.4536 or visit www.Leo-pharma.us. ■

CME CE

PROGRAM OUTLINE APRIL 2012

0.5 CREDITS

Page 28 FEATURE A new understanding of osteoarthritis Linda Davis, MHS, PA-C Ms. Davis has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Name the single most common risk factor for osteoarthritis (OA). • Describe the physical finding that indicates a joint has minimal cartilage and is bone-on-bone. • Identify the oral analgesic of choice for mild to moderate OA pain. • Discuss indications for total joint replacement. 0.5 CREDITS

Page 65 DERMATOLOGY CLINIC Depigmentation on the chest and nail folds Emily Grauel and Julia R. Nunley, MD Ms. Grauel and Dr. Nunley have no relationships to disclose relating to the content of this article.

Recent-onset hair loss in a high-school student Kerri Robbins, MD Dr. Robbins 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 85 DERMATOLOGIC LOOK-ALIKES Trunk rashes with central clearing Esther Stern, NP-C Ms. Stern 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 90 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 April 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 • APRIL 2012 27

■ LEARNING OBJECTIVES :

CME CE FEATURE

• Name the single most common risk factor for osteoarthritis (OA). • Describe the physical finding that indicates a joint has minimal cartilage and is bone-on-bone. • Identify the oral analgesic of choice for mild to moderate OA pain. • Discuss indications for total joint replacement. ■ COMPLETE THE POSTTEST: Page 90 ■ ADDITIONAL CME/CE: Pages 65, 85 Turn to page 27 for additional information on this month’s CME/CE courses.

LINDA DAVIS, MHS, PA-C

A new understanding of osteoarthritis Ongoing research and new developments hold promise for altering osteoarthritis and go beyond simply treating the symptoms.

Hip x-ray shows advanced osteoarthritis, evidenced by severe narrowing of the joint space.

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

steoarthritis (OA) was once thought to be an inevitable stage in the aging process, but there are significant unmet needs in the early diagnosis, monitoring, and treatment of the disorder that could bring relief to suffering patients. Researchers are now taking a much closer look at OA and its underlying causes to find better ways to prevent and treat it. To clarify why this topic has begun to draw more interest from the scientific and medical community, a few facts should be considered. In the United States, the importance of treating OA can be tied to the economic burden it has placed on society at an annual cost of $128 billion in disability. Today, OA affects 50 million Americans, or one in five adults. In 20 years, the number of people affected will be 67 million, or about 25% of the population. OA affects 300,000 children. As a result of this disease, one in 20 Americans is forced to change jobs, stop working, or reduce the number of hours he or she can work. In addition, there are concomitant diseases associated with OA: 52% of adults with

diabetes have OA and 57% of adults with heart disease have OA. Each year, arthritis results in 44 million clinician visits and almost 1,000,000 hospitalizations, with an estimated 1 million joint replacements being performed in an even younger population than in previous years.1 According to one report, “Obesity and OA of the knee are robbing millions of older Americans of an average…3.5 years of life in which they might otherwise be feeling healthy.”2 Moreover, as a result of the most recent wartime casualties, 32% of veterans have OA, compared to 22% of nonveterans. This is a result of the generally more than 100 lb of equipment the troops carry regularly. Thus, the gear used to protect troops may also injure them, and the tremendous impact of strenuous physical forces placed upon them in the performance of their duties increases their risk of injury, resulting in an unfortunate occupational hazard.3 OA has become a public health issue. All medical providers should be cognizant of this disease and become familiar with the newest evidenced-based research that could lead the way to treating the underlying cause(s) of OA, not just the symptoms. Clinical research helps to answer questions about the efficacy of biologic and pharmaceutical treatment. Defining OA

At a 1994 workshop entitled “New Horizons in Osteoarthritis,” the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging, National Arthritis Foundation, and American Academy of Orthopaedic Surgeons (AAOS) developed a new defi nition of OA: “…[a] disease process that involves the entire joint-subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles. Ultimately, the articular cartilage degenerates with fibrillation, fissures, ulceration and full thickness loss of the joint surface.”4 Eyre defined OA as the clinical and pathologic outcome of a range of disorders resulting in structural and functional failure of synovial joints. OA occurs when the dynamic equilibrium between the breakdown and repair of joint tissues is overwhelmed.5 The most commonly used criteria for diagnosis were published by the American College of Rheumatology (ACR).6-8 Pathogenesis

OA is widely believed to be the result of local mechanical factors acting within the context of systemic susceptibility. The systemic factors that increase the vulnerability of the joint to OA include age, gender, bone density, nutritional factors, and genetic predisposition. In persons vulnerable

to the development of OA, such local biomechanical factors as malalignment, muscle weakness, or alterations in the structural integrity of the joint environment (e.g., meniscal damage or bone marrow lesions), facilitate the progression of disease.9 The affect of genetics

Genetic predisposition to OA, which has been evident from anecdotal studies, was confi rmed by Kellgren and coworkers, who reported that generalized nodal OA was twice as likely to occur in fi rst-degree relatives as in control individuals.10 Because OA is so prevalent in the general population, the role of genetics has been difficult to analyze. Asking the patient about family history of OA is key during the patient assessment. In addition, additive factors that may contribute to the development of OA can be contained within specific genes. Risk factors

Age is the single most strongly correlated risk factor associated with OA. Cohort studies have demonstrated a clear association between obesity and knee OA. Local mechanical factors, vulnerability of the knee joint, and joint loading are directly related to obesity and to occupation-related injury and physical trauma, whether from sports or accidents. An increase in mechanical forces across weight-bearing joints is probably the primary factor leading to joint degeneration.11 According to a recent statement from the CDC, “Obese adults with arthritis are 44% more likely to be physically inactive than obese people who do not suffer from this painful disease.”12 Joint malalignment and varus or valgus deformities are markers of disease severity associated with risk of OA progression. Patients with pes planus (flat feet) are more likely to experience knee OA. Female gender is a well-recognized risk factor, with a marked increase in OA prevalence after age 50 years, likely due to estrogen insufficiency. Common sites of OA

The most common sites of OA involvement and prevalence are the hand (70%), knee (30%), hip (10%), and spine (60%).13 As previously noted, classification criteria of OA in specific joints (i.e., the hip, knee, and hand) have been published by the ACR.6-8 Signs and symptoms

A combination of typical symptoms, physical findings, and radiographic changes helps to differentiate OA from other rheumatic diseases. Patients with early OA have localized

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

CME CE

OSTEOARTHRITIS

joint pain that worsens with activity but is relieved with rest. Patients with OA often describe a sensation of “giving way” or “buckling” in the knee or subluxation in the hand joints. Gel phenomenon is a condition that occurs when a joint has been too long at rest and the synovial fluid becomes thickened, much like motor oil in a car that has been sitting at cold temperatures. Physical findings of OA may include bony enlargement, crepitus, cool effusions, and decreased range of motion. The presence of crepitus, whether it is heard or felt, indicates that the joint has minimal, if any, cartilage and is bone-on-bone. A sensation of warmth may indicate inflammation or even infection. This symptom requires evaluation to determine the proper therapy, ie, an anti-inflammatory agent or steroids versus antibiotics. In some patients, there may be an inflammatory component to the OA. This can sometimes be misinterpreted as rheumatoid arthritis (RA). Joint swelling, deformity, or instability (laxity) of the joint may be seen. The distal phalanges of the hand may be affected with Heberden nodes (Figure 1), while the proximal phalanges may be affected with Bouchard nodes (Figure 2). X-rays (Figure 3) may show osteophytes, joint space narrowing, subchondral sclerosis, and cysts. Joint space narrowing can occur as the cartilage breaks down. Radiography is considered the gold standard for diagnosing OA, although other imaging modalities may be utilized, especially in the research arena.14 Laboratory or biologic markers for OA

Since OA is generally a noninflammatory disease, laboratory tests do not usually help with the diagnosis, although when there is readily apparent swelling of the joint, a lower erythrocyte sedimentation rate (ESR) may help differentiate OA from such other arthritides as RA. Ongoing research reveals promise for future laboratory studies that may show the AT A GLANCE ●

Age is single most strongly correlated risk factor associated with osteoarthritis (OA). Cohort studies have demonstrated a clear association between obesity and knee OA.

●

The most common sites of OA involvement and prevalence are the hand (70%), knee (30%), hip (10%), and spine (60%).

●

There are currently no prescriptive medications that prevent or decrease OA, so treatment is relegated to pain relief.

●

Knee-replacement surgeries have doubled over the past decade and more than tripled among the 45- to 64-year-old age group.

presence of specific markers, such as chondroitin sulfate epitope 846. Measurement of type II collagen in the blood or urine may help diagnose OA and monitor its progression. Another project is looking at finding and validating microRNAs, small noncoding nucleic acids, which could “yield information critical to clinical guidelines and treatment strategies for post-traumatic osteoarthritis.”15 MicroRNAs are also present in other diseases, such as cancer and heart disease. Clinical course

OA affects each person differently by limiting activities of daily living (ADLs), such as walking, bathing, dressing, climbing stairs, and doing household chores. In some patients, disease progression is very slow, while in others, progression occurs much more rapidly. In the early stages, the joints may ache after physical work or exercise. Later in the course of the disease, the joint may be painful even at rest. Symptoms vary from person to person and may be intermittent. X-rays may show dramatic degeneration of the joint, and yet the patient experiences little pain. The degeneration is generally asymmetric and noninflammatory. Differential diagnosis

Many diseases include joint pain as a symptom, and this is must be considered when making a diagnosis. Since the area of joint pain may fall under the “umbrella” of rheumatic diseases, such as rheumatoid or psoriatic arthritis, those disorders must be ruled out. Metabolic and endocrine diseases can predispose to OA. Other common causes of hip pain include trochanteric bursitis, iliopsoas tendinitis, referred pain from the lumbosacral spine, avascular necrosis, inguinal hernia, and hip fracture. Knee pain may be caused by pes anserine bursitis, iliotibial band syndrome, patella tendinitis, patellofemoral pain syndrome, prepatellar bursitis, and semimembranous bursitis. Hand pain occurs as a result of carpal tunnel syndrome, flexor tenosynovitis, ulnar nerve compression, and de Quervain disease. Treatment goals

The best way to determine treatment goals is to discuss with the patient how OA affects his or her quality of life, that is, how the patient’s symptoms interfere with performance of ADLs. The goal varies, depending on what the individual wants to accomplish. One report noted that compared to other adults, those with arthritis had a higher average number of physically unhealthy days per month, mentally unhealthy days, total unhealthy days, and activity-limited days. The five measures of health-related

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

quality of life included demographics; social factors; health care factors, such as access and cost barriers to obtaining care; health behaviors, such as smoking and alcohol use; and chronic health conditions, such as diabetes, weight, or hypertension.16 One resource patients can utilize is the Arthritis Foundation’s Programs for Better Living series (www.arthritis.org/programs.php), including aquatic exercise, self-help, Tai Chi, and walking. Physical therapists and aquatic specialists developed these programs to address the pain, fatigue, and decreased strength that often accompany OA. Treating OA

The algorithm for OA management includes nonpharmacologic therapies, pharmacologic agents, and surgery. The most important nonpharmacologic approach is patient education,17 followed by a self-management approach that includes personalized social support, weight loss,18 aerobic exercise, physical therapy, and muscle-strengthening exercises. These therapies can be self-directed or ordered by the appropriate provider to increase mobility. The mission of the Arthritis Foundation includes research, education, and prevention of joint diseases. The Foundation advocates movement as a therapy. The efficacy of its walking program has been validated by research data. Exercise increases aerobic capacity, muscle strength, and endurance and also facilitates weight loss. All persons capable of exercising should be encouraged to participate in a low-impact aerobic exercise program (walking, biking, swimming).19 Quadriceps-strengthening exercises have led to improvements in pain and function.20 Advise patients that if a joint is warm, red, or swollen, applying ice before starting to exercise may help. If a joint is painful and stiff, applying heat will help loosen the surrounding muscles and increase blood flow to the area. When using an exercise facility, dry heat could be utilized prior to any physical activity and tends to “soften” the body or get the muscles ready to exercise. The steam room, sauna, or hot tub can be used to help with sore or achy muscles. A double-blind randomized controlled trial from Korea showed that radiofrequency neurotomy is a therapeutic alternative for chronic pain associated with OA.21 Assistive devices are often used by people whose pain or instability limits physical activity, those who are not eligible for surgery, and those who do not want surgery or who want to delay it. These devices, which include canes, walkers, or wheelchairs, can help decrease pain and improve ability for ambulation. Their purpose is to provide rest to the joint

FIGURE 1. Heberden nodes are a complication of osteoarthritis.

during the performance of ADLs. Caution patients against prolonged use of assistive devices, as it can result in weakening of unused joints. Supports, braces, splints, and shoe orthotics are examples of external devices that can help stabilize joints, provide support, correct malalignment, or prevent further joint deformity.22 Some of these appliances, such as elastic or neoprene knee supports, are available OTC. Appropriate footwear provides protection and energy conservation and is important for balance and support of joints. Custom knee braces, splints, and shoe wedges are prescribed.23 These are typically fitted by physical therapists, occupational therapists, or orthotists and made from many types of materials, such as plastic, metal, leather, or moldable foam. Other assistive devices for ADLs are available, such as jar openers, reacher/grabbers, and key covers. Role of nutritional supplements

Use of oral glucosamine and chondroitin has been controversial over the years. Although these substances are widely recommended in Europe to help reduce joint pain, the most recent meta-analysis does not favor their use in treating OA.24 Glucosamine and chondroitin are found naturally within cartilage. There is certainly a placebo effect, as has been demonstrated in several double-blind, placebo-controlled studies.24 Since no regulatory agencies oversee production of nutritional supplements, advise patients to read the label to be sure they are purchasing a standardized extract, meaning that each capsule contains a consistent amount of each active ingredient listed on the

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OSTEOARTHRITIS

label. To determine whether glucosamine and chondroitin in combination is beneficial for pain relief, patients should follow directions on the label for one month. If they find the supplement helpful, then the general rule is to continue as directed on the label. Vitamin D is touted as having many almost miraculous benefits for treating and preventing disease, including relieving OA pain and repairing structural damage. Yet a two-year clinical trial funded by the National Institutes of Health found no such benefits of vitamin D therapy. Whatever its role in OA, vitamin D is important for the metabolism of calcium in patients who are at risk of or who have osteoporosis.25 Orthopedic surgeons may prescribe vitamin C and zinc to aid in healing and for overall nutrition, usually after a patient has had joint surgery. Pharmacologic agents

There are currently no prescriptive medications that prevent or decrease OA, so treatment is relegated to pain relief. Acetaminophen, which may be used in dosages up to 4 g/day, is the oral analgesic of choice for mild to moderate OA pain.26 Although the pain relief experienced may be limited, acetaminophen is indicated as first-line therapy. The Food and Drug Administration has been reviewing acetaminophen to determine its safety. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be added or substituted in patients who respond inadequately to acetaminophen. Aspirin, ibuprofen (Ibu-tab), naproxen (Anaprox, Naprosyn), and ketoprofen are OTC NSAIDs. Patients should be cautioned about side effects of NSAIDs, such as GI distress or bleeding. Results of a comprehensive metaanalysis of all randomized controlled trials of NSAIDs showed a two- to fourfold increased risk of cardiovascular impact.27 Tramadol (Conzip, Ryzolt, Ultram) is a narcoticlike medication that can provide stronger pain relief than other agents. Narcotic analgesics are useful alternatives for patients in whom NSAIDs are contraindicated, ineffective, and/or poorly tolerated. Codeine, oxycodone (Oxecta, Oxycontin, Roxicodone), and propoxyphene (recently taken off the market) are narcotic analgesics used in severe OA. However, long-term use may cause drug dependency and tolerance that can necessitate an increase in dose over time to maintain pain relief. Side effects should be reviewed with the patient, as these could be detrimental to overall health. Dizziness is common and could cause falls in patients with unstable hip or knee joints. Constipation is a common complaint, so patients should be advised to use such measures as OTC stool softeners or to drink prune juice as alternatives to offset this problem.

Topical formulations of NSAIDs, methyl salicylate creams (e.g., Biofreeze), and capsaicin have been shown to be helpful adjuncts to symptom management. These agents come in various forms, such as gels, patches, rubs, or sprays, that are applied on the skin over a painful joint. They contain combinations of salicylates, skin irritants, and local anesthetics. Note that using these topical agents with heat therapy can cause burns and serious injury, especially in diabetic patients. The newest addition to the pain armamentarium is a nasal formulation of toradol (Sprix) that can be used in patients who are unable to tolerate oral medications. Other pharmacologic options

Such COX-2 inhibitors as celecoxib (Celebrex) tend to be less toxic to the GI tract than NSAIDs. Celecoxib is currently undergoing structural changes in order to reduce its adverse effects—primarily cardiovascular in nature, such as strokes and MIs. The efficacy of this class of drugs has been compared with that of traditional NSAIDs, including ibuprofen, naproxen, and diclofenac (Cambia, Cataflam, Voltaren, Zipsor). All NSAIDs can cause occasional decline in renal function. Cyclooxygenase-inhibiting nitric oxide donators (CINOIDs), a new class of agents, increase vascular tone and mucosal blood flow.28 In addition, CINOIDs have the advantage of causing fewer adverse effects than NSAIDs, including renal injury and GI and liver effects, as well as hypertension. CINOIDs are similar in efficacy to naproxen but superior to placebo Combination drugs are common in treating hypertension and dyslipidemia but had not yet been used for OA. One

CME CE

FIGURE 2. Bouchard nodes occur at the middle joint of the fingers.

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

Surgical options

combination now available for OA is Vimovo. This drug combines naproxen and a proton pump inhibitor (PPI), which helps to reduce GI toxicity. Vivomo has similar efficacy and tolerability to celecoxib but is associated with a greater number of heartburn-free days. Another combination drug recently approved by the FDA is Duexis, which combines 800 mg of ibuprofen with 26.6 mg of famotidine (proton pump inhibitor). Hyaluronic acid therapy involves injecting the knee joint directly with hyaluronans, a substance found naturally in joint fluid that helps provide lubrication and cushioning. Viscosupplementation utilizing hyaluronans seems to have a large placebo effect, as demonstrated in a systematic review and other studies.29,30 Intra-articular steroids may help with acute exacerbations of pain in patients who have signs of local inflammation with joint effusion but are of limited benefit (less than a week) for pain and function.31 FIGURE 3. Lateral x-ray shows severe osteoarthritis of the knee.

The need for surgery is best determined by an orthopedic surgeon with a specialty in the involved joint. The most common orthopedic interventions for OA are arthroscopic debridement and lavage (cleaning and vacuuming of the joint), osteotomy (corrects misalignment by cutting and resetting bone), cartilage transplant (from stem cells or patient’s own cells), arthroplasty (rebuilding of a joint), and joint replacement. The incomplete, temporary improvement seen with arthroscopic knee surgery is a placebo effect. 32

Acupuncture and OA

Acupuncture is the use of fine needles inserted into the skin at precise points. Stimulation of these points can help block pain. There is some evidence that acupuncture may be useful to ease the pain of OA, but the data are generally equivocal.35 Additional clinical studies are under way to determine if acupuncture is an effective treatment for OA of the knee. Evidenced-based research

Indications for total joint replacement

Night pain that is unresponsive to anti-infl ammatory agents, major inability or difficulty to perform ADLs, or unacceptable reduction in the ability to walk or work are indications for total joint replacement. With proper patient selection, good to excellent results can be achieved in 95% of joint replacement procedures; the expected 15-year survival rate of the implant is also 95%. 33 In a May 2011 report on joint replacements, research showed that younger people are more commonly having joint replacement. Knee replacement surgeries have doubled over the past decade and more than tripled in the 45- to 64-year-old age-group. Hips are trending that way too. According to Nicholas Di Nubile, MD, spokesperson for the AAOS, “The baby boomers are the fi rst generation trying to stay active in droves on an aging frame. They are less willing to use a cane or put up with pain or stiffness, as their grandparents did.”34

While biologic therapy has been available to treat rheumatoid arthritis for more than 10 years, such therapy has not been available for OA. Tanezumab, a new monoclonal antibody, may be a treatment option for OA knee pain. Tanezumab has been shown to be efficacious when taken for 24 weeks in both phase 2 and phase 3 clinical trials. The antibody acts differently depending on the tissue. In OA and other diseases, the target is nerve growth factor. One key trial was halted when patients’ OA damage worsened, although their pain was lessened. Some trial participants had to have hip replacement surgery.36 Future of OA

The years 2002-2012 were declared to be the International Bone and Joint Decade, the intent of which was to increase awareness of OA. As a result of data concerning the staggering costs of this disease, NIH has provided support for outstanding, investigator-initiated research in the form of

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

CME CE

OSTEOARTHRITIS

Chondrocytes act as sensors, and the possibility exists that these cells could serve as novel targets for disease-modifying osteoarthritis drugs. additional grant dollars. NIH initiated and participated in natural history studies of OA. It has lent its support and participated in meetings and processes to reach consensus with regard to diagnostic criteria, acceptable outcome measures, and recommendations for treatments. Backing from NIH led to the creation of the Osteoarthritis Initiative (OAI), which has as its goal the design, development, and support of a research project to identify, test, and validate biomarkers as surrogate end points for clinical trials in OA. The OAI is a public-private partnership that includes funding from the pharmaceutical industry and several of the National Institutes, including NIAMS. OAI comprises a public data set of clinical, functional, and imaging data on 4,800 subjects, aged 45 to 79 years, with eight years of follow-up. It is a unique resource for investigators, many of whom use the data source to explore research questions. For example, bone marrow lesions (BMLs), defi ned as increased signal areas on MRI, have been shown occur less frequently in patients treated with bisphosphonates, the class of drugs most often used to treat osteoporosis. Additional associations with cartilage loss and joint space loss in OA have also been reported. Evidence that OA is not just a “wear-and-tear” disease has been demonstrated through the OAI. A similar research grant provided support for the Multicenter Osteoarthritis Study (MOST) involving 3,000 subjects, aged 45 to 79 years, with risk factors for OA and six years of follow-up as of 2011. The Health, Aging, and Body Composition Study (Health ABC) included 3,075 subjects, aged 70 to 79 years at the start of the study, with more than six years of follow-up. Results indicated that genetics plus additive risk factors puts larger joints at higher risk of OA than smaller joints.37 Stem cell research has been quite controversial across the globe. In OA, stem cells have been injected into joints to grow new cartilage and bone. Autologous supplementation involves the removal of cartilage cells from the patient. These cells are then grown in culture and reinjected into the joint several weeks later. In the future, mesenchymal cells, progenitors of new growth in cartilage, may become injectable. Research is being conducted in the area of genetics and the impact it has on OA. According to emerging data from evidenced-based research, the impact of genetics is likely greater than previously thought. One study done

by the ACR looked at possible therapeutic approaches to activating particular gene pathways in order to reduce the progression of OA.38 Public research is being conducted with the help of the Arthritis Foundation Innovative Research Grant. One study has revealed a strong connection between key regulatory proteins referred to as “nuclear factors of activated T cells (NFATs)” and severe OA symptoms. Researchers found that a lack of certain NFAT proteins results in serious joint degradation. Additional studies should also reveal more details about how an enzyme called HtrA1 degrades proteins in joint cartilage.39 At the 2011 European League Against Rheumatism (EULAR) Annual Congress, two posters discussed randomized controlled trials with therapy supporting efficacy in knee OA. The first poster, by Abou-Raya and colleague, was a two-arm study of 188 outpatients, aged 65 years and older, who had symptomatic and radiographic OA and took the antidepressant duloxetine 60 mg or placebo for 16 weeks. The outcome measure was reduction in knee pain and stiffness. Results in this study supported efficacy of duloxetine in knee OA.40 The second poster, by Laslett and colleagues, was a randomized controlled trial of the bisphosphonate zoledronic acid (5 mg/mL) versus placebo in 59 patients ranging in age from 50 to 80 years who had knee pain from OA and BMLs on MRI. Pain and radiographic data were assessed at baseline, 6 months, and 12 months with pain scales and T2-weighted MRI images. This study asked the question: Can patients with knee OA be treated with bisphosphonates and reduce the symptom of pain? Validation of this treatment will require repetition of the study using a larger number of subjects.41 Chondrocytes may be the most exciting area of research to date. Data have suggested that chondrocytes act as sensors, and the possibility exists that these cells could serve as novel targets for disease-modifying OA drugs. Inhibition of cartilage degradation and stimulation of cartilage growth and repair are the two additional areas of research to date. More insight is being gained as various targets are revealed through scientific research. In addition, the etiology of pain is still poorly understood. What local structural factor is most responsible for pain and functional impairment in OA? Much remains to be done in this complex area.

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

Conclusion

14. Felson DT, Zhang Y. An update on the epidemiology of knee and

The direction of current and future treatment of OA is to modify the disease itself, instead of just treating the symptoms. Clinicians should be cognizant of the availability of emerging research, so that they can help be part of the solution to decreasing the public burden of this disease. ■

hip osteoarthritis with a view to prevention. Arthritis and Rheumatism. 1998;41:1343-1355. 15. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Hunt for microRNA biomarkers of post-traumatic osteoarthritis underway. Available at www.niams.nih.gov/Recovery/Chronicles/microrna_biomarkers.asp.

Ms. Davis is a physician assistant with VIP Care Housecalls in Arlington, Tex.

16. Preidt R. Study highlights arthritis’ toll on quality of life. April 28, 2011. Available at consumer.healthday.com/Article.asp?AID=652315. 17. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interven-

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on varus gonarthrosis. J Bone Joint Surg Am. 1999;81:539-548.

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23. Maillefert JF, Hudry C, Baron G, et al. Laterally elevated wedged insoles

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9. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights.

24. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroi-

Part 1: the disease and its risk factors. Ann Intern Med. 2000;133:635-646.

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28. Baerwald C, Verdecchia P, Duquesroix B, et al. Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: a randomized, double-blind, parallel-group, multicenter study. Available at onlinelibrary.wiley.com/doi/10.1002/art.27694/full. 29. Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA. 2003;290:3115-3121. Available at jama.ama-assn.org/content /290/23/3115.long. 30. Jüni P, Reichenbach S, Trelle S, et al. Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: a randomized controlled trial. Arthritis Rheum. 2007;56:3610-3619. Available at onlinelibrary. wiley.com/doi/10.1002/art.23026/full. 31. Bellamy N, Campbell J, Robinson V, et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;2:CD005328.

“Gee, I thought you’d be happy to be the presumptive front-runner.”

32. Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002; 347:81-88. Available at www.nejm.org/doi/full/10.1056/NEJMoa013259. 33. Callahan CM, Drake BG, et al. Patient outcomes following tricompartmental total knee replacement. A meta-analysis. JAMA. 1994;271:1349-1357. 34. Baby boomers fueling jump in hip, knee replacement. USA Today, May 23, 2011. Available at yourlife.usatoday.com/health/story/2011/05/Babyboomers-fueling-boom-in-knee-hip-surgeries/47353154/1. 35. Berman BM, Lao L, Langenberg P, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med. 2004;141:901-910. 36. ClinicalTrials.gov. Tanezumab In Osteoarthritis Of The Hip Or Knee. Available at clinicaltrials.gov/ct2/show/NCT00985621. Osteoarthritis initiative. Available at www.niams.nih.gov/Funding/Funded_

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Research/Osteoarthritis_Initiative/oaepipappen_a.asp. 38. Terkeltaub, Robert, Yang, et al. Potential role of the LKB1-AMPK and CaMKKb-AMPK pathways in controlling the progression of OA. [abstract]. Arthritis Rheum. 2010;62 Suppl 10:1494. 39. Polur I, Lee PL, Servais JM, et al. Role of HTRA1, a serine protease, in the progression of articular cartilage degeneration. Histol Histopathol. 2010;25:599-608. Available at www.ncbi.nlm.nih.gov/pubmed/20238298. 40. Abou-Raya S, Abou-Raya A. Duloxetine for the management of pain in older adults with knee osteoarthritis: randomized placebo-controlled trial. Poster present at the European League Against Rheumatism Annual Congress; May 25-28, 2011; London, UK. 41. Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces bone marrow lesions and knee pain over one year. Poster presented at the European League Against Rheumatism Annual Congress; May 25-28, 2011; London, UK. All electronic documents accessed March 15, 2012.

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

“Today’s meeting will be endless, with a half-hour break for lunch.”

37. National Institute of Arthritis and Musculoskeletal and Skin Diseases.

FEATURE: WANDA BONNEL, PHD, GNP-BC

Screening strategies for spotting elder abuse The primary-care provider may be the only contact homebound elders have outside the abusive situation. Knowing what to listen for is key.

lder abuse is a topic often avoided but important to consider. Frail, elderly individuals with increased vulnerability and limited reserves to rebound are most impacted. Primarycare providers (PCPs), who have access to these patients via office visits, are in a position to identify and intervene if necessary. Recognizing patients who are at risk for elder abuse or those who have experienced elder abuse can guide plans to promote patient safety. This article identifies approaches for primary-care screening, including strategies to identify and minimize the risk of elder abuse for homebound patients.

Extent and impact of the problem

Elder abuse can be psychological and emotional as well as physical.

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

Elder abuse is considered a growing form of family violence. Each year, an estimated 1 to 2 million older adults are impacted and the number of abuse cases increases.1 Actual numbers of cases may be underestimated, since elder abuse is thought to be underreported. Because the most frail and vulnerable are impacted, including elders with dementia, patients’ ability to report abuse may be limited. PCPs may also miss reporting opportunities because presentations of abuse are subtle and many have limited familiarity with the provider’s responsibilities. The impact of abuse on elders may be magnified related to physical aging changes, leading to increased illness, loss of independence, or death.2 In addition to physical injury, psychological trauma and loss of self-esteem occur. Current societal trends support the need for increased attention to the problem of elder

ELDER ABUSE

abuse. A growing older adult population is resulting in larger numbers of frail elders and their increasing needs for family caregiving. Spouses or adult children are the typical caregivers, providing an estimated 80% of all home-care services.3 Since elder abuse often occurs in the home setting among family members, the PCP may be the main person to see the patient and offer help.

POLL POSITION

Do you feel prepared to identify and effectively handle cases of elder abuse? n=79

Yes

44%

Forms of elder abuse

Elder abuse is considered a form of violence against older adults and can occur in any setting. Abuse can take multiple forms, with overlap between the forms. Definitions for the various aspects of elder abuse from the National Center on Elder Abuse (NCEA) provide a starting point in understanding its breadth.4 Physical abuse. Elder abuse may involve the use of force that threatens or physically injures an elder who is vulnerable. This includes rough handling or actual violent behavior resulting in injuries. Sexual activity forced on a vulnerable elder who is unable to grant consent is also considered abuse. Neglect. Failure or refusal on the part of the caregiver to provide necessities that impact an elder’s safety or physical or emotional needs constitutes neglect. It is more subtle than elder abuse and the most commonly reported form of elder mistreatment. The caregiver is one who is considered to owe a duty of care to the patient, and the neglect can be considered active or passive depending on the intent. Selfneglect is a related concept focusing on a patient’s lack of self-care, distinguished by the absence of a caregiver.5 Psychological/emotional abuse. Psychological abuse in the elderly can be subtle and challenging to pinpoint and describe. Verbal abuse or ignoring, rejecting, belittling, threatening, or isolating the elder are common indicators. Victims may exhibit distress, pain, and mental anguish. AT A GLANCE ●

Elder abuse is considered a growing form of family violence and thought to be underreported.

●

Spouses or adult children are the typical caregivers, providing an estimated 80% of all home-care services.

●

Elder abuse includes physical abuse, neglect, psychological/ emotional abuse, and financial exploitation.

●

Strategies for supporting elders and their families include identifying stressful situations and making needed patient referrals to social service agencies as well as appropriate reporting.

52%

Other

4% 0

For more polls, visit www.ClinicalAdvisor/polls

Financial exploitation. While PCPs focus primarily on a patient’s physical and mental health, financial abuse also occurs and may come to the attention of providers or office staff. This form of abuse involves undue influence to gain control over an older person’s money or property and includes theft, fraud, or misuse of authority. Barriers to addressing abuse

Elder abuse becomes a hidden problem for several reasons: Victims often do not wish to report the abuse, abuse can be hard to detect, and providers may lack awareness of the abuse or knowledge on how to report. Most older adults want to stay in their homes as long as possible. The decision not to report abuse is often related to the victim’s perceived comfort of home, family loyalty, fear of the unknown, or even concerns of retaliation. In addition, the ability of elders to report may be limited because of frailties. In complex elder abuse situations, the abused patient may be ambivalent rather than angry toward the abusing caregiver. Detection of physical abuse can be challenging. Some symptoms look like chronic illness or changes associated with advanced physical aging, including cognitive decline. Increased weakness, greater risk of falling, or limited functional abilities also make abuse difficult to detect. Older patients who are frail and have physical and or mental deficits are most at risk. Elder abuse is thought to be underreported by clinicians. PCPs note limited education and experience with elder abuse.6,7 Abuse codes in the International Classification of Diseases (ICD) system are rarely used, suggesting that

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

ELDER ABUSE

providers tend to code an injury or condition as the primary diagnosis rather than the abuse. There may be a lack of awareness or reluctance to use abuse codes.8 Barriers to identifying and reporting abuse by PCPs focus on issues of time; lack of access to screening tools; limited knowledge of risk factors and symptoms; insufficient observation time with the older adult; and various issues relating to the act of reporting, including limited understanding of reporting mechanisms.2 A sense of discomfort with the problem and lack of clinician education are suggested as causes of underreporting, as is an absence of professional protocols guiding documentation and justification.9 Role of the provider

Providers have a key role in screening for elder abuse. This is especially important for their patients living at home; in some cases, the provider may be the only contact a patient has outside the abuse situation. Starting points for screening and assisting patients are highlighted in Table 1 and include TABLE 1. Provider roles in screening for elder abuse and promoting patient safety Know the risk factors for elder abuse (both patients and potential abusers); increase vigilance with those patients presenting with risk factors. Extend the traditional history and physical examination to screen for elder abuse indicators; listen for consistency in patient and caregiver accounts and search for further details on subtle physical presentations. Consider team-based patient support strategies and referrals to minimize risk for abuse; educate caregivers about resources available to minimize caregiver stress. Keep patients safe via needed referrals to social service agencies and report to adult protective services as indicated.

TABLE 2. Resources for family and staff education on elder abuse National Center on Elder Abuse www.ncea.aoa.gov National Committee for the Prevention of Elder Abuse www.preventelderabuse.org Centers for Disease Control & Prevention www.cdc.gov/features/elderabuse US Administration on Aging www.aoa.gov/AoARoot/AoA_Programs/Elder_Rights?EA_Prevention/ index.aspx National Institute of Justice: Elder Abuse www.nij.gov/topics/crime/elder-abuse/welcome.htm

knowing the risk factors, extending the history and physical examination to identify indicators, and understanding the providerâ&#x20AC;&#x2122;s role in promoting patient care and safety. Know the risk factors. Certain indicators suggest a higher risk of being abused. Risk factors for abuse of older adults center around patient frailty. Those at risk to carry out the abuse are most often caregivers of the frail; diverse psychosocial factors are also related to abuser roles. Patient risk factors for abuse. Frail, elderly patients are most at risk for elder abuse. Common descriptors of patient frailty include multiple comorbidities, decreased strength, fall risks, polypharmacy, and functional deficits.10 Physical variables specific to increased risk for elder abuse include female gender, poor health, and cognitive impairment. Other issues include dependency on care and requiring assistance with activities of daily living. Social factors related to abuse risk include isolation and a history of family violence or of drug and/or alcohol abuse.11 Caregiver risk factors to abuse. Elder abuse involves at least one person besides the victim, with most abusers being family caregivers. Typically, family members are not paid for their care services, and they take on numerous supportive tasks for patients. Caregiving increases the stressors on complex family situations, with ongoing stressors building and new acute stressors adding their impact. In addition to providing care for frail patients, factors that lead to abuse include family and job stressors; limited fi nances; poor relationship quality; perceived caregiving burden; little social support; depression; and history of family violence, including child or spousal abuse. Additionally, abuse of substances and caregiver psychopathology are considered. The caregiver who is fi nancially dependent on the elder, such as an adult child, is another person considered to be at high risk for abusing.12 Screening for abuse. All elders are considered at risk for abuse. Addressing questions to the elder in a manner that conveys respect and maintains patient dignity and selfesteem is indicated. This applies particularly to the elder who may already be suffering emotionally from the impact of abuse. Use of funnel-type questions that start broad and then become more detailed is recommended.14 Such an approach is only minimally obtrusive and helps guide a more focused examination with an awareness of the potential for elder abuse.2 PCPs build on all information available to them. In addition to observing and speaking with the older adult patient, providers have the opportunity to focus on those caregivers who present with the patient and to ask questions about

44 THE CLINICAL ADVISOR â&#x20AC;˘ APRIL 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

the caregiving situation. This includes asking about and synthesizing the health problems, living arrangements, and support systems that comprise a patient’s situation. Gaining the history—what to listen for. Extending traditional history questions and observations provides an opportunity to consider potential abuse in all older adults. Listening for clues to problems provides a good starting point for all patients and allows opportunity for a further brief screen that most individuals would not find objectionable. In addition to traditional health history questions, PCPs can be specific and ask: Is someone hurting you? And if injury is present, Did someone do this to you? 2 Speaking with potential victims in a private, safe place allows them an opportunity to express any feelings or fears they might have about the caregiving situation. This means separating the patient and caregiver for portions of the interview or examination. The health history allows opportunity to complete the following: • Assess the quality of interactions with patients and caregivers. A mismatch of verbal and nonverbal communication behaviors often provides clues to problems. • Listen for meanings and inconsistencies. Descriptions from the patient and the caregiver of how an injury occurred should match. Clues that suggest a need for further information include reluctance on the part of the caregiver to leave the patient alone and discrepancy between objective data and what the caregiver says. Other clues include reports of frequent visits to the emergency department, clinician’s office, or hospital; seeking care from different providers; or delays in seeking medical care.12 Build from the physical examination findings. While images of major physical injury may come to mind, elder abuse symptoms often are more subtle. Challenges already exist in the physical examination of the older adult relative to age-associated physical changes and chronic illnesses; elders often present with fewer physical and psychosocial reserves. With patients who are already frail and at risk for falls and injuries, elder abuse can be masked. For all elders, a watchful, screening approach is indicated, including increased vigilance for those presenting with risk factors.

PEER PERSPECTIVES

CLINICAL SLIDESHOW Alzheimer disease affects approximately one in eight older Americans. For more information, view the slideshow at ClinicalAdvisor.com/AlzheimerSlideshow.

Patients who present with risk factors for abuse warrant a more focused examination. This includes a comprehensive functional approach to the examination, inquiring about social supports, specifics about the patient’s environment, and other resources, with particular attention to cognition and function or dependency.13 Physical indicators of abuse vary. Common physical symptoms that should raise suspicion include:9,12 • Repeated or unexplained injuries; evidence of old injuries not previously documented • Wounds or bruises in various stages of healing or in unusual locations. Differentiating accidental bruising or tears in age-sensitive skin versus nonaccidental bruising is indicated. • Pattern injuries indicating objects used to inflict the injuries, such as signs of cigarette burns or restraints • Untreated health problems; poor nutrition; patients lacking necessities, such as eyeglasses, dentures, or hearing aids • Withdrawn or passive behaviors; indicators of depression. Document thoroughly. Clear documentation of findings provides baseline data and legally substantiates information gained.2 Documenting a thorough skin assessment is indicated, particularly in highly suspected abuse. Recommendations include taking pictures of wounds for the health record.10 Information can also be recorded from the functional assessment that includes the informal support system, environment, and social resources. Detailed documentation of follow-up plans and referrals is key.11 A more detailed assessment and further documentation of elder abuse can be gained with specific elder abuse assessment tools. These tools have been developed for both research and clinical practice. Appropriate follow-up tools depend on the

“Thank you for reinforcing the importance of the primary-care assessment in a home caregiving situation. Empowering elders to report abuse or to make changes if it is occurring can often be difficult.” Bobbe Mansfield, ARNP, Topeka, Kan. (via ClinicalAdvisor.com)

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

ELDER ABUSE

population and setting. The Elder Assessment Instrument is one example; it has 41 items that further address elder abuse risk within general assessment and broad screening categories.15 These screening tools can be administered as part of office protocol, in at-risk situations, or to further process and document concerns. Selected tool summaries are provided by the University of Iowa Department of Family Medicine (www .uihealthcare.com/depts/med/familymedicine/research/ eldermistreatment/screeninginstruments/index.html. Accessed March 15, 2012).

TABLE 3. Support services and resources for assisting family caregivers Eldercare Locator, Administration on Aging www.eldercare.gov/Eldercare.NET/Public/Index.aspx Caregiving Resources, The National Family Caregivers Association www.nfcacares.org/caregiving_resources/ National Association of Area Agencies on Aging www.n4a.org/answers-on-aging/ State Directory of Helplines, Hotlines, and Elder Abuse Prevention Resources www.ncea.aoa.gov/ncearoot/Main_Site/Find_Help/State_Resources.aspx

Education, communication, and referral roles

PCPs can establish a practice philosophy and put in place protocols to guide all staff members in being advocates for frail elders. To enhance screening efforts, front-office staff should receive education that includes awareness of the potential for elder abuse and indicators that should raise suspicions. This includes staff members involved in admitting and fielding family/patient phone calls. As noted, watchful screening and speculation is indicated for all patients. Information acquired by office staff and their concerns can be conveyed to the provider, raising awareness that further screening is indicated. Education. A proactive team approach to minimize risk for elder abuse includes focus on the caregiver. Information can be shared routinely with all caregivers regarding how to minimize stress and how to reach out for help when it is needed. This includes support for minimizing high-stress/abusive environments. Typically, caregivers do not receive training for this role, and assisting caregivers to access support or respite is often indicated. Many resources exist to assist in dealing with this important problem (Table 2). The resources provide helpful teaching materials for caregivers as well as office staff. Information includes access to abuse hotlines and resources for minimizing caregiving stress. Assisting caregivers and potential victims. Communicating potential concerns or information about high-risk situations to appropriate team members is central to keeping patients safe. Interdisciplinary dialogue and referrals to appropriate teams/agencies are often indicated.16 Team members might be broadly described to include social workers and various allied health disciplines. Some primary-

MAKING CONTACT

care settings identify an individual to fill the role of either an informal or formal case manager for high-risk families, helping to screen for problems and identify resources. Sample approaches to support caregivers and decrease stressors leading to abuse include: • Communicate with patients and informal caregivers regarding their stressors; seek early awareness of stressful situations. • Provide information on caregiver support groups and resources for caregiving respite. Online support communities exist for caregivers with limited ability to leave home. • Involve the stressed caregiver in planning, and refer to informal or formal agencies designed to support or assist in caregiving. Sample approaches to support potential victims include: • Develop or support team plans to keep elders socially involved. Social ties and networks can decrease isolation and create access to assistance. • Seek telephone contact resources for homebound patients, such as volunteer programs providing daily phone checks. Recommend that emergency call systems be in place for urgent situations. • Promote regular health-care checkups that also serve as contact for elder abuse risk.10 Resource protocols. Protocols can be in place not only for appropriate screening, but to refer for available community services. Informal and formal resources are available to help meet caregiver stress situations and follow up on elder abuse concerns. Community resources exist, such as senior centers, adult day-care programs, or respite services within assisted

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living settings. A national network of resources includes the Area Agencies on Aging at the local level. Online resources, such as Elder Locator, are identified in Table 3. Reporting cases of suspected abuse. For potential or actual victims, the goal is patient safety. Patient followup by an interprofessional team is indicated in suspected abuse. An office social worker or staff designee could assist in further planning and ongoing sensitive communication needs. Team management approaches include counseling, protective services, relocation, and legal actions.16 Adult protective service agencies are mandated in all jurisdictions in the United States. In working with these agencies, the role of the PCP is to identify events and report before any events escalate. In addition to documenting findings, providers work with agencies to assist with medical issues and determine patients’ capacity for self-care and selfprotection. In some cases, patient relocation or legal actions will be required.16 Elders have the right to refuse services unless they no longer have the mental capacity for making their own decisions. All ethical codes support respect of the human condition and protecting vulnerable patients. Health-care providers have a duty to report and, in most cases, are legally required to do so. Reporting to adult protective services is indicated if there is a reasonable suspicion of elder abuse as summarized in the following: • If there is any evidence of mistreatment without sufficient clinical explanation • Whenever there is a subjective complaint by the elder of elder abuse • Whenever the clinician believes there is high risk or probable abuse.15

References 1. Bonnie RJ, Wallace RB. Elder mistreatment: Abuse, neglect, and exploitation in an aging America. Panel to Review Risk and Prevalence of Elder Abuse and Neglect. Washington, DC: The National Academies Press; 2003. Available at www.nap.edu/openbook.php?isbn=0309084342. 2. Halphen JM, Varas GM, Sadowsky JM. Recognizing and reporting elder abuse and neglect. Geriatrics. 2009;64:13-18. 3. National Family Caregivers Association. What is family caregiving? Available at www.nfcacares.org/who_are_family_caregivers/what_is_family_caregiving.cfm. 4. National Center on Elder Abuse. What is abuse? Available at www.ncea.aoa.gov/Ncearoot/Main_Site/pdf/publication/NCEA_ WhatIsAbuse-2010.pdf. 5. Mosqueda L, Dong X. Elder abuse and self-neglect: “I don’t care anything about going to the doctor, to be honest...”. JAMA. 2011;306:532-540. 6. Taylor DK, Bachuwa G, Evans J, Jackson-Johnson V. Assessing barriers to the identification of elder abuse and neglect: a communitywide survey of primary care physicians. J Natl Med Assoc. 2006;98:403-404. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2576103/. 7. Kennedy RD. Elder abuse and neglect: the experience, knowledge, and attitudes of primary care physicians. Fam Med. 2005;37:481-485. 8. Wood E; for the National Center on Elder Abuse. The Availability and Utility of Interdisciplinary Data on Elder Abuse: A White Paper. Available at www.ncea.aoa.gov/Main_Site/pdf/publication/WhitePaper060404.pdf. 9. Ahmad M, Lachs M. Elder abuse and neglect: what physicians can and should do. Cleve Clin J Med. 2002;69:801-808. Available at www.ccjm.org/ content/69/10/801.long. 10. Ham RJ, Sloane, PD, Warshaw GA, et al. Primary Care Geriatrics: A Case-Based Approach. 5th ed. St. Louis, Mo.: Mosby; 2006. 11. Lantz MS. Domestic violence in an older couple. Clin Geriatr. 2009;17:710. Available at www.clinicalgeriatrics.com/node/3441. 12. Hirsch CH, Stratton S, Loewy R. The primary care of elder mistreatment. West J Med. 1999;170:353-358. Available at www.ncbi.nlm.nih.gov/

Summary

pmc/articles/PMC1305693/pdf/westjmed00321-0035.pdf.

PCPs have a screening role in identifying elder abuse as well as stressful situations that may lead to abuse. This includes knowing the risk factors for elder abuse and extending the history and physical examination as a screening tool. Opportunities exist for communicating with patients and families about elder abuse risks as well as resources to assist in stressful situations. Team-based strategies for supporting elders and families include needed patient referrals to social service agencies and appropriate reporting. Listening, observing, and synthesizing the patient’s complex story leads to opportunities to promote patient safety. ■

13. Bonnel W. Screening for functional deficits in older adults. Clinical Advisor. 2011;14:55-60. Available at www.clinicaladvisor.com/screening-forfunctional-deficits-in-older-adults/article/211565/. 14. Reuben DB. Geriatrics at Your Fingertips 2011. 13th ed. Belle Meade, NJ: Excerpta Medica; 2011. 15. Fulmer T. Elder mistreatment assessment. Best Practices in Nursing Care to Older Adults. Available at consultgerirn.org/uploads/File/trythis/ try_this_15.pdf. 16. Halphen JM. Geriatric gems and palliative pearls: intervention in cases of suspected elder abuse, neglect and exploitation. The University of Texas Health Science Center at Houston. Available at www.uth.tmc.edu/ reynolds/soundbytes/intervention.html.

Dr. Bonnel is an associate professor at the University of Kansas School of Nursing, Kansas City.

All electronic documents accessed March 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 47

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 APRIL 2012

Consultations Vitamin D and post-fracture symptoms . . . . . . . . . . . . . . . . . . . .48 Options for treating an anxious and depressed alcoholic . . . . . . . . . .48 Urine drainage at the end of live. . . . .49 Gynecomastia in a patient on dialysis . .49

Clinical Pearls Decreasing agitation in patients with dementia . . . . . . . . . . . . . . . . .50 Rectal foreign body removal . . . . . . . . . 50 Antibiotic eye drop reminder . . . . . . .50

Your Comments Alternatives to triptans for migraine in patients with CAD. . . . . . . . . . . .50

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.

Ensuring early detection of a breast lump . . . . . . . . . . . . . . . . . . .55

CONSULTATIONS VITAMIN D AND POST-FRACTURE SYMPTOMS What role does vitamin D deficiency play in such postfracture symptoms as pain, particularly in northern regions?—ERIN RYSAVY, PA-C, MPH, Sartell, Minn. Nutritional osteomalacia (bone demineralization) can be the result of low vitamin D levels (<10 ng/mL) and causes bone pain, achiness, and increased risk of fracture. The condition is often associated with such malabsorption conditions as celiac disease, intestinal bypass surgery, and Crohn’s disease; it can also be attributable to such endocrine conditions as hypophosphatemia and renal disease. Osteomalacia is diffi cult to diagnose and can be mistaken for osteopenia, osteoarthritis, Paget’s disease, and somatization. With regard to post-fracture pain, it would be helpful to know if the patient had been experiencing generalized bone pain or achiness prior to the fracture, which could be a sign that osteomalacia was the cause of both fracture and pain.—Rebecca H. Bryan, APRN, CNP (162-1)

OPTIONS FOR TREATING AN ANXIOUS AND DEPRESSED ALCOHOLIC I am treating a woman aged 50 years for major depression, alcoholism, and general anxiety disorder. Her previous

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.

48 THE CLINICAL ADVISOR • APRIL 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.

provider had her venlafaxine (Effexor) 300 mg for quite some time. I added L-methylfolate (Deplin) to the venlafaxine because her depression was not improving. I also started her on buspirone (Buspar) 7.5 mgs b.i.d. for anxiety. The patient’s alcoholism prevents her from taking benzodiazepines. After landing in the emergency department with symptom-related anxiety, she was started on gabapentin (Neurontin) and titrated to 800 mg/day. Early on in the treatment, I tried the mood stabilizer aripiprazole (Abilify), with no success. The patient remains significantly anxious and has been encouraged to take up yoga class or tai chi to control her breathing and palpitations. What else do you suggest?— DEBRA WOODARD, CRNP, Sykesville, Md.

likely will involve multiple medications. Exercise, including yoga and tai chi, can be part of the treatment plan for patients who are depressed and anxious.—Eileen F. Campbell, MSN, CRNP (162-2)

The patient and treatments described sound quite complicated. The maximum recommended daily dose of venlafaxine is 225 mg/day. While physicians and psychiatrists may prescribe in excess of that dose, nurse practitioners should avoid off-label prescribing. If the woman’s depression was not controlled on venlafaxine, consider a selective serotonin reuptake inhibitor (SSRI), such as sertraline (Zoloft) or citalopram (Celexa) and titrate the dose as needed. If her depression was not controlled on a maximum dose of an SSRI, adding the dopamine-norepinephrine reuptake inhibitor buproprion (Wellbutrin) works well. Limited studies show that the antiseizure medication gabapentin may be beneficial in patients with bipolar and ADHD disorders, alcohol withdrawal, restless leg syndrome, migraine, and other pain disorders. Gabapentin does not have an indication for the treatment of anxiety or major depression. Such atypical antipsychotics as aripiprazole are quite expensive and would not be a first-line choice. There are reports of using L-methylfolate, a medicinal food, for treatment-resistant depression. Cognitive behavior therapy can be quite helpful in patients with anxiety disorders. At this point, I would refer this patient to psychiatry to confirm the diagnosis, and work with her on an effective treatment plan that

While the Indiana pouch may drain spontaneously, it does not empty completely and requires intermittent straight catheterization. Indwelling catheters are not recommended because a very small catheter is used, and the mucous production often quickly occludes the tube, causing urine to back up to the kidneys. The patient described here may need to visit a urologist for an alternative urine-drainage system, such as an ileal conduit, which drains continuously and does not store the urine. This may not be as complicated as it seems since the Indiana pouch also uses a piece of the ileum. The pouch or neobladder lies between the ureters and the conduit. A simple ileal conduit may allow the pouch to be removed.—Marie Mangino, MSN, GNP-BC, Vincent Healthcare, Inc., Clinical and Educational Specialists, Erdenheim, Pa. (162-3)

URINE DRAINAGE AT THE END OF LIFE A patient at the end of life is no longer able to self catheterize with a continent urinary diversion (i.e., Indiana Pouch Reservoir). No reliable caregivers are available. Can the catheter be left in to drain into a urostomy pouch? Should it be secured with or without a balloon?—ANNE WALSH, APRN-BC, Long Beach, N.Y.

GYNECOMASTIA IN A PATIENT ON DIALYSIS A man aged 69 years has coronary artery disease, type 2 diabetes mellitus, hypertension, multiple myeloma, and end-stage renal disease. He started dialysis last year and did

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 of the Department of Cardiothoracic Surgery, Lenox Hill 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 • APRIL 2012 49

Advisor Forum

CT scan to rule out a pituitary tumor and a mammogram to rule out breast cancer before referral to endocrinology and/or surgery.— Kim Zuber, PA-C, Chair National Kidney Foundation Council of Advanced Practitioners, Alexandria, Va. (162-4)

CLINICAL PEARLS

Gynecomastia is usually caused by high levels of estrogen in the blood.

very well. About three months after starting dialysis, he complained of painful nipples bilaterally (especially the right nipple). The pain eventually spread to the entire breast. A mammogram and ultrasound showed tissue growing in both breasts and a mass in the right. The patient was referred to a breast surgeon and an endocrinologist. Is there any association between gynecomastia and hemodialysis.—EILEEN SCARINCI, DNP, APN ACRN, Scotch Plains, N.J. Gynecomastia is extremely common in dialysis patients. In one study, almost 50% of the patients on hemodialysis had gynecomastia ( J Nephrol. 2012;25:31-42). The cause is multifactorial. Leydig-cell dysfunction will cause disruption of the pituitary-testicular axis in men (N Engl J Med. 1977;296:1245-1249). Certain medications commonly used in renal patients can also cause gynecomastia, including spironolactone (Aldactone), cimetidine (Tagamet), amiodarone (Cordarone, Pacerone), omeprazole (Losec, Omesec, Prilosec), cyclosporine (Gengraf, Neoral, Sandimmune, Sangcya), ACE inhibitors and angiotensin receptor blockers, calcium channel blockers, and highly active antiretroviral therapy. Discontinuation of the offending medication will often reverse the breast enlargement. The third factor causing gynecomastia in dialysis patients is high serum prolactin levels (Greenberg A. Primer on Kidney Diseases, 5th ed. Philadelphia, Pa.: Saunders Elsivier; 2009:515). The mechanism for the hyperprolactinemia is a decrease in the metabolic clearance of prolactin along with a three-fold increase in production, which can mean a prolactin level six times higher than normal in your standard dialysis patient. These prolactin levels will drop to normal after renal transplant. When presented with gynecomastia in a dialysis patient, adjust any offending medications, and order a

DECREASING AGITATION IN PATIENTS WITH DEMENTIA Distressed elderly patients—especially those with dementia— frequently have a paradoxical reaction to benzodiazepines, causing extremely agitated states. Men with type A personalities are at greatest risk. Administering risperidone (Risperdal), quetiapine (Seroquel), or haloperidol (Haldol) will control agitation. If sedation is required, a benzodiazepine can be safely added 30 to 45 minutes later.—LESLIE de la FLOR, NP, Anaheim, Calif. (162-5)

RECTAL FOREIGN BODY REMOVAL When retrieving a foreign body from the rectum, pass a Foley catheter past the item, inflate the balloon, and pull the Foley toward you to bring the item closer to the rectum. This maneuver will also break the suction in the rectum, which can make retrieval difficult.—JODY COLLETTO, FNP, Bremerton, Wash. (162-6)

ANTIBIOTIC EYE DROP REMINDER A treatment regimen that requires frequent antibiotic eye drops can result in dropped applications. Women often wear clothes with no pockets, so carrying the small bottle in their bra helps remind them to put the drops in as ordered. As an added bonus, this storage strategy ensures that the temperature of the drops will be exactly right. The drops should be put in the pocket of the eye, not directly onto the eye itself. Finally, many drops should not be applied while wearing contact lenses.—BONNIE FAHERTY, PhD, APRN-BC, Northridge, Calif. (162-7)

YOUR COMMENTS ALTERNATIVES TO TRIPTANS FOR MIGRAINE IN PATIENTS WITH CAD Contrary to what Dr. Kidner advocated with regard to migraine relief, all of the triptans are contraindicated in

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

Advisor Forum patients with known coronary artery disease (CAD) (Item 159-2) and are to be used cautiously in patients with CAD risk factors. A more appropriate recommendation for abortive therapy would be nonsteroidal anti-inflammatory drugs, barbituates, or opioids. Another approach would be to titrate beta-blocker therapy to an effective dose to prevent migraine headache from occurring in the fi rst place.—KELLEY KORONA, MSN, NP-C, Detroit

ENSURING EARLY DETECTION OF A BREAST LUMP The Legal Advisor about a young woman with a cystic mass in her left breast (“A suspicious lump is of real concern,” February 2012) was most interesting. Even though the case was eventually dismissed, additional steps may have prevented legal action altogether. With the young patient’s palpable finding and a history of breast cancer in her mother, the least invasive option would have been to perform a breast ultrasound. This modality would have documented the size and shape of the mass and helped determine whether it solid or cystic, which is something that cannot be detected by fingers alone. A certified letter sent to the patient’s home serves as a written reminder that a follow-up appointment is due and explains what consequences may be at stake if the re-evaluation is delayed. At the very least, such a document provides written evidence that attempts were made to contact the patient directly.—CATHY J.F. COLE, NP, MPH, CHES, Thousand Oaks, Calif. (162-9) ■

“I just worry that it’s affecting our work.”

“You seem calm above the surface, but underneath I feel as if you’re paddling like hell away from me.”

“Run for your lives! It’s the full ‘Ring’ cycle!”

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

CAD incorporates a wide range of illness that includes nonobstructive, mild, severe three-vessel, and vasospastic disease. Development of a treatment plan requires an understanding of the disease process and risk-benefit ratios. For significant ischemic CAD with multiple stents, triptans would not be advisable. However, in mild disease that has been stable and a patient with a low risk of endothelial dysfunction, treating debilitating migraines with a triptan can be considered under supervision. If the provider is uncomfortable with this approach, refer the patient or ask for help. Furthermore, treating migraines with a narcotic is not supported by the literature and should only be tried if all other means have failed. Guidelines provide a framework for clinical decisions, but a complex patient with multiple pathologies requires consideration of severity, quality of life, risks, and potential outcomes before the final plan is established. Educating the patient on treatment options, risks, and benefits and encouraging active participation in the creation of the plan is always beneficial.—Maria Kidner, DNP, FNP-C (162-8)

Stat Consult

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

Description

Hypertensive emergency/ hypertensive urgency

• Hypertensive emergency is def ined as BP > 180/120 mm Hg with end-organ dysfunction. • Hypertensive urgency is defi ned as severe BP elevation without evidence of end-organ dysfunction. Also called

• Hypertensive crisis • Malignant hypertension ICD-9 codes

• 401.0 malignant essential hypertension • 405.0 malignant secondary hypertension Epidemiology

BY BRIAN RANDALL, MD

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

• 1% -2% of patients with hypertension • More common in — Elderly — Blacks — Men Causes

• New onset or complication of essential or secondary hypertension — Medication nonadherence — Use of monoamine oxidase inhibitor — Recreational drug use — Acute postoperative hypertension

Risk factors

Hypertensive emergency can lead to complications such as acute renal failure, encephalopathy, and intracerebral hemorrhage.

• Ineffective outpatient BP control • Patient noncompliance with hypertension treatment • Lack of primary-care provider Complications

• End-organ damage may include — Encephalopathy — Intracerebral hemorrhage — Acute myocardial infarction — Unstable angina — Acute heart failure Continues on page 63

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

Stat Consult — Pulmonary edema — Dissecting aortic aneurysm — Acute renal failure — Preeclampsia/eclampsia • Hypotension may be a complication of aggressive treatment. History

• Patient may complain of — Chest pain — Dyspnea — Neurologic deficit — Faintness — Paresthesia — Headache — Vertigo — Vomiting — Agitation — Epistaxis • Most patients have persistently elevated BP for years before presenting with hypertensive emergency. • Review medications, adherence, and time from last dose • Ask about recreational drug use (e.g., amphetamines, cocaine, phencyclidine [PCP]). Physical Exam • Confirm BP on both arms using a properly sized BP cuff. • Check pulses in all extremities. • Perform physical exam to evaluate for end-organ damage and to differentiate between hypertensive emergency and hypertensive urgency (no end-organ dysfunction). — Funduscopic exam (assess for arteriolar changes, hemorrhages, exudates, papilledema) — Cardiac exam (assess for murmurs and gallops) — Lung exam (assess for pulmonary edema) — Abdominal exam (assess for bruits, aortic aneurysm) — Neurologic exam (check mental status, lateralizing signs may suggest vascular event) Making the diagnosis

• Hypertensive emergency—BP >180/120 mm Hg with evidence of end organ dysfunction • Hypertensive urgency—severe BP elevation without evidence of end-organ dysfunction Rule out

• Subarachnoid hemorrhage—consider in patients with sudden onset of severe headache

• Stroke—consider if focal neurologic findings, especially lateralizing signs Testing to consider

• Blood chemistries (electrolytes, blood urea nitrogen, creatinine) • Complete blood count • Urinalysis • Electrocardiogram • Consider cardiac biomarkers if cardiac ischemia suspected • Consider toxicology screen • Imaging based on clinical picture for specific conditions (e.g. chest x-ray, if dyspnea or chest pain) Treatment

• Hypertensive urgency (no evidence of end organ damage) — Observe for several hours following administration of antihypertensives — Medication options include ■ Nicardipine 5 mg/hour orally, should be increased by 2 mg/hour every 15 minutes, maximum dose 15 mg/hour ■ Captopril 25 mg orally two to three times daily ■ Clonidine » Adults—initial dose 0.1-0.2 mg orally, then 0.05-0.2 mg every hour up to total dose of 0.5-0.7 mg as needed » Children aged 1-17 years—initial dose 0.050.1 mg orally, repeat up to maximum 0.8 mg ■ Labetalol dose options include » Initial dose 20-80 mg IV, then additional 4080 mg dose (range 20-80 mg) at 10-minute intervals until desired BP achieved » Initial dose 0.5-2 mg IV infusion, adjust as required » Initial dose 200 mg oral, then additional 200400 mg dose after six to 12 hours as needed • Hypertensive emergency (end-organ damage) — Admit to intensive care unit and treat with IV antihypertensives. — Continuous BP monitoring (consider intra-arterial blood pressure monitoring) — Give IV saline if volume depleted. — In most cases, lower diastolic pressure by 10% -15% over the fi rst hour. — Choosing BP lowering medications and BP goal depends on target organ with dysfunction. Continues on page 64

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 63

Stat Consult Options include nicardipine, fenoldopam, clevidipine. — Preeclampsia/eclampsia ■ Initiate antihypertensive treatment when diastolic blood pressure is ≥105-110 mm Hg. ■ Maintain systolic BP 130-160 mm Hg and diastolic BP 80-110 mm Hg. ■ Options include labetalol, hydralazine, nifedipine. ■ Treatment usually also includes magnesium sulfate for seizure prevention. — Sympathetic crisis (e.g., cocaine overdose) ■ Avoid beta-blockers, which might lead to increased BP. ■ Options include nicardipine, diltiazem, phentolamine, verapamil [Calan, Covera, Isoptin, Verelan]. ■ Consider treatment with benzodiazepine in addition to antihypertensive medication. — Acute postoperative hypertension ■ Usually starts less than two hours after surgery and lasts six hours or more. ■ No consensus regarding treatment threshold (except cardiac surgery patients where treatment recommended for BP >140/90 mm Hg or MAP ≥105 mm Hg) ■ Options include esmolol, nicardipine, clevidipine, labetalol, nitroprusside. — Transition to oral therapy as soon as possible after BP stabilization ■

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

■

— Acute aortic dissection ■ Lower systolic pressure to <120 mm Hg rapidly (i.e., five to 10 minutes) ■ Options include beta blockers (esmolol [Brevibloc], metoprolol [Lopressor, Toprol]) and vasodilators (nicardipine [Cardene], nitroprusside, fenoldopam [Corlopam]) — Ischemic stroke ■ For thrombolysis candidates » IV therapy is indicated for patients if systolic pressure is >185 mm Hg or diastolic pressure is >110 mm Hg. » BP should be maintained at <180/105 mm Hg for at least first 24 hours after thrombolysis. » Options include labetalol [Normodyne, Trandate], nicardipine, or nitroglycerin topical ointment. ■ For patients not able to have thrombolysis » Lowering BP (by 15% -25% in first 24 hours) is indicated if systolic pressure is >220 mm Hg or diastolic pressure is >120 mm Hg. » Options include labetalol, nicardipine. — Acute hemorrhagic stroke ■ The goal of BP lowering depends on how elevated BP is and whether there is elevated intracranial pressure. ■ Options include enalaprilat [Vasotec], esmolol, hydralazine [Apresoline], labetalol, nitroglycerin, nicardipine. — Hypertensive encephalopathy ■ Treat promptly, as delay can lead to seizures and neurologic deficits. ■ Lower mean arterial pressure by 20% -25% in the first hour ■ Targets are then systolic pressure of 160 mm Hg and diastolic pressure of 90-100 mm Hg. ■ If patient is tolerating treatment, gradually lower BP further over next 24 hours. ■ Options include IV labetalol or nicardipine. ■ Avoid nitroprusside, which might increase intracranial pressure. — Acute myocardial ischemia ■ Nitroglycerin drug of choice ■ Treatment alternatives include labetalol, esmolol, clevidipine [Cleviprex], nicardipine. — Acute pulmonary edema ■ Options include nitroglycerin, nitroprusside, furosemide [Delone, Furocot, Lasix, Lo-Aqua]. — Acute renal failure

“Can we do now later?”

CME CE

Dermatology Clinic ■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 90

■ ADDITIONAL CME/CE: Pages 28, 85

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

CASE #1

Depigmentation on the chest and nail folds EMILY GRAUEL AND JULIA R. NUNLEY, MD

A woman, aged 38 years, complained of color loss on her cuticles and upper chest. Examination revealed bilateral puffy hands with depigmentation and dilated capillary loops of all proximal nail folds. A sclerotic depigmented patch with circular islands of normal color was present over her mid-chest. Review of systems revealed Raynaud’s phenomenon as well as recent onset of dyspnea on exertion. A biopsy was taken from the patch on her chest. Further studies demonstrated the presence of anti-DNA topoisomerase I (Scl-70) antibodies and a low diffusion capacity on pulmonary function testing. What is your diagnosis? Turn to page 66

CASE #2

Recent-onset hair loss in a high-school student KERRI ROBBINS, MD

A teenaged boy was referred to the dermatology clinic with a chief complaint of alopecia. His mother first noticed hair loss approximately six months ago. The teenager had just entered high school and was nervous about doing well academically, according to his mother. No pain or pruritus was associated with the area of alopecia, and no OTC treatments had been tried. There was no family history of alopecia, and there are no pets in the household. Physical examination revealed an irregularly shaped area of alopecia with broken hairs throughout. What is your diagnosis? Turn to page 67 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 65

CME CE

CASE #1

Dermatology Clinic

Scleroderma

The biopsy showed a normal epidermis, thickened and closely packed collagen bundles in the reticular dermis spreading up into the papillary dermis, and atrophy of the eccrine glands; a paucity of vessels was evident. Subcutaneous fat was partially replaced by collagen bundles. Silver staining for melanocytes was negative. The diagnosis was consistent with scleroderma with vitiligolike pigmentary changes. The term scleroderma encompasses a spectrum of disorders caused by excessive collagen deposition. The skin is the most commonly affected organ; however, the spectrum of disease can range from an isolated skin lesion to a multiorgan systemic disease. When only localized cutaneous plaques exist, the condition is called morphea. Morphea rarely has systemic manifestations. The term systemic sclerosis (SSc) is the preferred nomenclature when systemic manifestations exist. A very small percentage of patients may have systemic disease without cutaneous changes, which is classified as sclerosis sine scleroderma. Systemic sclerosis is divided into two main subsets that are defined by the extent of skin involvement: diffuse systemic sclerosis (dSSc) and limited systemic sclerosis (lSSc).1 In dSSc, skin involvement is widespread, affecting the extremities, chest, abdomen, and shoulders. In comparison, skin changes in lSSc are typically limited to the hands, face, feet, and forearms. Collagen deposition results in skin thickening and hardening, which is frequently preceded or accompanied by edema and erythema. Overtime the more classic sclerodactyly with skin tightening (sclerosis) is observed. Nail fold telangiectases are common but not pathognomonic for SSc, since they can also be seen in systemic lupus and dermatomyositis. The presence of Raynaud’s with or without digital infarcts is highly suggestive of the diagnosis of SSc. Cutaneous calcification is variable. CREST syndrome (Calcinosis, Raynaud’s syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) is a form of lSSc. Pruritus is common in patients with advanced skin disease, and pigmentary alteration can also be seen in SSc. More common in women, with a peak onset between age 30 and 50 years, SSc has an annual incidence of 0.6-122.0 per million persons.2 The presentation of SSc varies according to the organ of involvement and disease severity. In

addition to the skin, other frequently affected organ systems include the musculoskeletal, renal, pulmonary, cardiac, and GI tract. The most frequent constitutional symptoms of individuals with SSc are fatigue, weakness, and insomnia; other symptoms reflect the organs affected and include stiffness, decreased strength, joint pain, palpitations, chest pain, shortness of breath, cough, bloating, abdominal pain, and swallowing difficulties. The depigmentation seen in association with SSc is very uncommon. It can be morphologically identical to idiopathic vitiligo and is often mistaken for vitiligo. Although islands

Systemic sclerosis is divided into two main subsets that are defined by the extent of skin involvement. of normal color can be seen within patches of vitiligo (due to repigmentation), areas of pigmentary retention are uniformly seen in SSc-associated depigmentation. Anatomic sites most commonly affected are the hands, arms, upper chest, neck, and face. Unlike vitiligo, which commonly affects the lips and mucosa, mucosal depigmentation has not been reported in SSc. A biopsy of a depigmented area will demonstrate an absence of melanocytes, frequently associated with a lymphocytic infiltrate and dermal fibrosis.3 The areas where color persists in SSc are around hair follicles. This follicular sparing has been attributed to better blood circulation around hair follicles. The underlying pathology of SSc is not fully understood but is believed to be a combination of immune system activation and vascular damage inciting existing fibroblasts to excessively produce collagen. Although the pathogenesis of SSc color loss is also poorly understood, it is thought to be similar to the pathogenesis of vitiligo. According to the autoimmune theory for vitiligo, activation of the immune system and the subsequent development of autoantibodies lead to the destruction of melanocytes. The absence of melanocytes in biopsy samples and the presence of various autoantibodies in both vitiligo and vitiligolike macules of SSc support this theory. When evaluating patients with skin complaints, consider a diagnosis of SSc. Although systemic involvement is more common in advanced dSSc, those with lSSc or early onset of dSSc may have serious organ involvement, as seen in this patient. Despite minimal cutaneous findings at presentation,

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

further evaluation demonstrated the presence of significant pulmonary disease. The diagnosis is usually made by a combination of clinical, pathologic, and serologic tests, led by the patient’s review of systems. Treatment for SSc is based on the underlying organ of involvement. A recent meta-analysis created recommendations by organ system.4 The drug of choice for interstitial lung disease is usually cyclophosphamide (Cytoxan), despite its toxicity. This patient was referred to the pulmonary team for further management. Due to the risk of infertility and the mild status of her lung disease, she opted not to take this medication. Although few studies specifically address the treatment of depigmentation in SSc the treatments chosen are the same as those for vitiligo. Options include topical or systemic steroids, topical calcineurin inhibitors, vitamin D3 analogs, phototherapy, laser therapy, and photochemotherapy. 5 Success rates vary widely based on patient demographics and the location and extent of disease. The best responses to therapy are seen in younger patients; those with recent onset of disease; those with darker skin types; and for lesions on the face, neck, and trunk. Topical fluocinonide resulted in 50% repigmentation of the area on this patient’s chest. Her nailfolds showed no response. Laser treatment was too costly for the patient to pursue this option. ■ Ms. Grauel is a third-year medical student at Virginia Commonwealth University School of Medicine in Richmond. Dr. Nunley is professor of dermatology at Medical College of Virginia Hospitals, also in Richmond. References 1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989-2003. 2. Chifflot H, Fautrel B, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223-235. 3. De Villiers WJ, Jordaan HF, Bates W. Systemic sclerosis sine scleroderma presenting with vitiligo-like depigmentation and interstitial pulmonary fibrosis. Clin Exp Dermatol. 1992;17:127-131. 4. Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68:620-628. 5. Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.

CASE #2

Trichotillomania

Trichotillomania is derived from three Greek words: thrix (hair), tillein (pulling out), and mania (madness). The disorder is characterized by the irresistible urge to pull out hair from various regions of the body. The scalp, pubic regions, eyebrows, and even eyelashes are primary targets for patients with trichotillomania. The American Psychiatric Association (APA) classified trichotillomania as an impulse disorder; however, some in the psychiatry community have classified it as an obsessive-compulsive disorder.1 In the dermatologic world, trichotillomania is simply defined as self-induced plucking or breakage of the hair. Trichotillomania may be caused by either a learned habit or psychiatric disorder. About 20% of people who have chronic hair-pulling issues do not fall into the APA classification, and these individuals have developed a learned behavior. Episodes of hair pulling occur throughout such activities as watching television, writing, and reading. Parents and teachers may be present during this time and distract the individual, which will cause cessation of the hair pulling activity. A successful episode of hair pulling will often occur just before the individual falls asleep. This is primarily attributable to the fact that a parent is not present to stop the episode and is often unaware that the child has developed the behavior. From the psychiatric perspective, people with trichotillomania may be anxious and tense. Patients have reported feeling a great sense of tension just before the start of a hair-pulling episode. Afterward, they feel a pleasure sensation and a sense of calm. They may also be suffering from poor impulse control and unresolved subconscious anger. Patients with long-term trichotillomania may also have such behavioral disorders as thumb sucking, nail biting, cheek biting, acne picking, nose picking, poor social skills, poor family relations, and a poor academic record.2 Some research shows the disorder to be very prevalent; as many as 1 in 200 persons have the disorder by age 18 years. Trichotillomania affects both sexes, although the female-to-male ratio is 5:1.3 Children are affected more commonly than adults, with the average age of onset for boys being 8 years and 12 years for girls.4 The most commonly affected area is the scalp, which results in a patchy alopecia. Within the scalp, the most commonly affected regions are the frontal, frontotemporal, and

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

CME CE

Dermatology Clinic

frontoparietal areas. The occipital scalp tends to be spared, even in the most severe cases. Whether the alopecia is seen on the left or right side of the scalp depends on whether the individual is right or left handed, as the pattern is usually contralateral.5,6 Hence, if the patient is right-handed, he or she will likely pull hair from the left side. A common technique an individual might use is to wrap multiple hairs around the finger in a twisting motion and pull them out simultaneously. The patient will usually start pulling hair in irregular patterns, centrifugally from a single starting point. The borders of the alopecia will be undefined and have unusual shapes. The plucking will most likely be incomplete, resulting in short and roughly fractured hair fibers. Other areas of the body susceptible to hair plucking are the eyebrows, eyelashes, beard, and pubic areas.7 When examining someone with trichotillomania, ask what he or she does with the plucked hair. Some patients have been known to consume the hair (trichophagy). This ingestion can cause intestinal obstruction, which may lead to severe illness and death. Deformed and broken hair shafts are the histological hallmark of trichotillomania. Pigmented hair casts are another hallmark and are derived from the bulbar or hair-shaft melanin.7 The total number of hairs should remain normal, but the number of terminal catagen and/or telogen hairs will increase. A horizontal view of the biopsy will show distortion in the area where the rim of outer root sheath epithelium remains after the hair was forcefully pulled out. The follicle may be seen as partially avulsed rather than tightly anchored to the inner root sheath. On vertical sections, the hair canal will be seen as distorted in a spiral configuration. This distortion is likely caused by the twisting of the hair. No significant inflammation will be appreciated. Diagnosing trichotillomania is fairly straightforward. If the disorder is suspected by visual observation of irregular alopecia, ask if the is pulling out the hair. If dealing with a child who does not admit to pulling out the hair, parents are recommended to observe the child during various time of the day. Some good times for observation are during reading time, while watching television, and when eating. Parents may also check their child’s bedroom, particularly under the pillow or mattress for clumps of hidden hair. Other disorders

that may be confused with trichotillomania are tinea capitis, alopecia areata, and other nonscarring alopecias.2 Tinea capitis can be eliminated from the list by microscopic examination of the hair stubs and skin culture and biopsy.5 If the clinician is concerned about alopecia areata, history, physical examination, and scalp biopsy may help confirm the diagnosis. Treatment of trichotillomania is difficult due to the fact that 80% of patients may have an underlying psychiatric disorder, such as depression, anxiety, or obsessive-compulsive disorder.2,5 Because of embarrassment of the disorder, the patient often does not seek treatment or delays treatment. Treatment should be a combination of tactics that individually target the different aspects of the disorder. Psychotherapy should target the obsessive-compulsive portion, while behavioral therapy should aim to break the habit and unlearn the behavior of pulling out the hair.6 Pharmacologic therapy has been tried and includes such medications as clomipramine (Anafranil) or a selective serotonin reuptake inhibitor. Typically, the earlier the onset, the more likley the child will outgrow the behavior. Early detection is key, because it will stop the progression of the alopecia. If the onset of trichotillomania occurs in adulthood, the disorder is more likely to be chronic. Secondary infections caused by scratching, twisting, and pulling the hair are very rare but may occur. Support groups are available for patients who suffer with trichotillomania. This patient was referred for behavioral therapy and successfully broke the habit of pulling his hair. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. References 1. Stein DJ, Simeon D, Cohen LJ, Hollander E. Trichotillomania and obsessive-compulsive disorder. J Clin Psychiatry. 1995;56 Suppl 4:28-34. 2. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2006:159-163. 3. Greenberg H, Sarner C. Trichotillomania – symptom and syndrome. Arch Gen Psychiatry. 1965;12:482. 4. Messinger ML, Cheng TL. Trichotillomania. Pediatr Rev. 1999;20:249-50. 5. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:111-112, 990-992. 6. Habif TP. Skin Disease: Diagnosis and Treatment. 2nd ed., Philadelphia,

MORE DERMATOLOGY ON THE WEB

Pa.: Elsevier Mosby; 2005:524, 526-527.

Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

7. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:145. 8. Christenson GA, Crow SJ. The characterization and treatment of trichotillomania. J Clin Psychiatry. 1996;57 Suppl 8:42-47.

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

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“So your biggest concern is my pronunciation of the word ‘crevasse?’” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 69

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.

Flat-topped, slightly violaceous papules An otherwise healthy black man presented with numerous pruritic papules that had been present for several months. No preceding illnesses or medication changes were reported. WHAT IS YOUR DIAGNOSIS?

• • • • •

Lichen planus Scabies Psoriasis Lupus erythematosus Syphilis

● See the full case at ClinicalAdvisor.com/DermDx0412A

Itchy pink patches on the back and trunk A man, aged 38 years, presented complaining of large and itchy erythematous patches on his back and trunk after the lesions did not respond to treatment with clotrimazole antifungal cream. WHAT IS YOUR DIAGNOSIS?

• • • •

Psoriasis Tinea corporis Tinea versicolor Contact dermatitis

● See the full case at ClinicalAdvisor.com/DermDx0412B

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. Papules on the penis

70 THE CLINICAL ADVISOR • APRIL 2012 • www.clinicaladvisor.com

Perioral rash for one year

Clinical Challenge A routine check-up reveals a significant genetic abnormality JILL BEYER BLODGET, FNP

A corrections officer simply wanted to get his employer-paid medical incentive, but he received so much more.

As a part of his employer’s incentive pay program, Mr. B came in for a routine physical. He was a seemingly healthy 37-year-old white man with no medical complaints to report. Mr. B worked as a correctional officer and, as such, was encouraged to keep his health records current. His annual exam was supposed to be pro forma, but it revealed silent traits that even he was astonished to find.

CASE

1. HISTORY Mr. B appeared in robust health and had an unremarkable medical history. His family history was positive for diabetes (a paternal grandfather), and hypertension (his father). Mr. B had stable, though stressful, employment, with no evident signs of depression. Married with two children, Mr. B mentioned that he exercised regularly— often daily. He engaged in both aerobic activity and weight training and reported no nicotine habits and minimal alcohol intake (three beers per week). Mr. B also noted that approximately once a month he used ibuprofen for muscle aches. His immunizations, including hepatitis B vaccine series, were up to date. His tuberculin skin test, done within the past year, was negative. Except for occasional mild muscle aches or pains, which he associated with his physical activity, Mr. B showed no symptoms of disease.

2. EXAMINATION AND LABORATORY TESTS

Minor muscle aches and pains were more than they appeared to be.

Mr. B’s vital signs on physical examination were good: BP 134/80 mm Hg; pulse rate 98 beats per minute; temperature 98.4° F; and oxygen saturation 98%. Mr. B was 5 ft 8 in tall and weighed 162 lbs, with a BMI of 24.63. His complete physical was essentially normal. Mr. B had not had laboratory work done in more than three years. At this visit, routine lab work was ordered, including a fasting lipid panel, fasting blood sugar, alanine transaminase (ALT) test, creatinine, and a complete blood count.All results www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 77

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers... Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®. WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage. • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials. • Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk. Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs. Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®. DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk. Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

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Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

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IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel. Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk. USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother. Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups. Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk. • For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®. Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable. ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications. The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%. Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

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Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information]. B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions]. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions]. INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information]. Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage. A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions]. Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions]. Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning]. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours. Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions]. 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 clinical practice. During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3). Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study. Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. 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. Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure. Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk. • Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed. • Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed. • Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition. • Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%. • Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively. Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

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Janssen Pharmaceuticals, Inc.

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort). Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban. NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions]. Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions]. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions]. Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug. Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day). Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information]. Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information]. Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed. Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions]. OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information]. Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

Clinical Challenge were within normal range except for a mildly elevated ALT at 45 U/L (normal <36 U/L). Additional tests were done to further evaluate the elevated ALT. Hepatitis screening for A, B and C, and antinuclear antibody (ANA) test results were negative. Ceruloplasmin, albumin, alkaline phosphatase, aspartate aminotransferase (AST), alpha-1 antitrypsin, and hemoglobin electrophoresis tests were all within normal range. Iron study results, however, were abnormal, with results as follows: 205 iron μg/dL (normal range: 41-96 μg/dL), total iron-binding capacity (TIBC) 295 μg/dL (baseline range: 236404 μg/dL), transferrin saturation 69% (normal:15%-60%), and ferritin 363 ng/mL (normal is 22-322 ng/mL). (Table 1 lists tests and disorders associated with elevated ALT.)

3. DIAGNOSIS AND DISCUSSION Mr. B acknowledged that his father did indeed have “an iron disease,” which he forgot to mention. DNA testing was done and Mr. B was found to have a C282Y/H63D compound

heterozygous mutation, indicative of hemochromatosis. Mr. B was referred to a hematologist, who confirmed the diagnosis of hereditary hemochromatosis (HH). Hereditary hemochromatosis is a recessively inherited disorder of iron metabolism, leading to abnormal increase in body iron stores. It is considered the most common genetic disorder in populations of Northern European ancestry1,2 with a genetic incidence in white populations in the United States of approximately 0.4% for homozygotes and 9.6% for heterozygotes.1 Approximately 10% of patients with clinical manifestations of HH are heterozygous, carrying a single copy each of the C282Y and H63D mutations, and 70%-100% of patients with a clinical diagnosis of HH are homozygous for the C282Y mutation.1 However, not all patients with genetic markers for HH develop iron overload. In fact, recent studies have shown rates of development of clinical iron overload even in those homozygous for the C282Y mutation as low as 50%.1,3 The genetic and environmental factors for the differences are not well defined, but they may be linked to modifying genes.1,4,5 Continues on page 81

TABLE 1. Additional tests for screening with elevated ALT Test

Screening for; diagnosis to consider:

Abnormality

Alpha 1 antitrypsin *

Alpha -1 antitrypsin deficiency

Decreased

Ceruloplasmin * (check in patients <40)

Wilson’s disease

Decreased

Hepatitis B *

Acute/chronic hepatitis B

Anti-HBs; HbsAg; Anti-HBc positive

Hepatitis C antibody*

Hepatitis C

Positive Further testing for quantitative and qualitative values to determine if active infection

Iron studies *

Hemochromatosis

Increased transferrin saturation, ferritin and iron; decreased TIBC

Protein electrophoresis *

Biliary cirrhosis, hepatic diseases, autoimmune hepatitis

Elevated globulins

Alkaline phosphatase **

Cholestasis, viral hepatitis, infectious mononucleosis, cirrhosis

Increased

Amylase **

Pancreatitis, hepatitis, cirrhosis

Increased

ANA **

Autoimmune disease

Positive

Anti-tissue transglutaminase (AtTG) **

Celiac disease

Positive

AST **

Liver disease; alcohol abuse, NASH, celiac disease, Wilson’s, hemochromatosis

Elevated

AST/ALT ratio **

Alcoholic liver disease, cirrhosis, intra/extrahepatic cholestasis, extrahepatic biliary obstruction, acute pancreatitis

Increased

Bilirubin, direct, conjugated **

Hepatocellular disease, biliary tract obstruction (including gallstones), Cholestasis from drugs, Dubin-Johnson syndrome, Rotor’s syndrome

Increased

*Initial follow-up tests for further evaluation of elevated ALT 7, 8 ** Additional tests to consider depending on history and physical 7, 8

78 THE CLINICAL ADVISOR • APRIL 2012 • www.ClinicalAdvisor.com

Clinical Challenge Most dietary iron absorption and regulation occurs in the duodenum. In patients with HH, duodenal absorption is increased, which leads to iron overload, especially in the liver, heart, and endocrine tissues. Humans have no mechanism for the excretion of excess absorbed iron, and chronic accumulation progresses to end organ dysfunction and damage. Accumulation of excess iron occurs slowly. Clinical symptoms are not usually noted until the fourth or fifth decade of life for men, and about a decade later for women, after menopause. Early clinical symptoms are subtle—fatigue, lethargy, weakness, depression, joint pain, weight loss, abdominal pain, and decreased libido.1, 3 More advanced disease, showing end organ damage, can include skin hyperpigmentation, cutaneous atrophy, flattening of the nails, loss of body hair, diabetes mellitus (iron accumulation in pancreatic B cells decreases insulin production and iron impairs insulin sensitivity), impotence in males, amenorrhea (secondary to cirrhosis), osteoporosis, congestive heart failure, arrhythmias (such as atrial fibrillation or sick sinus syndrome), hypogonadism, hypothyroidism, cirrhosis, and hepatocellular cancer.1,3,6 Some risk factors for acceleration of liver fibrosis in HH patients include chronic hepatitis C and alcohol use.4 Additional causes of iron overload include chronic viral hepatitis B and C, alcoholic liver disease, chronic inflammatory disorders, certain cancers, porphyria cutanea, thalassemia major, sideroblastic anemias, and nonalcoholic steatohepatitis.3,4 Transferrin saturation is the best screening test for iron overload1,2, with higher sensitivity (approximately 92%) and specificity (approximately 93%) than serum ferritin.1 Ferritin can be elevated due to other causes, such as inflammatory diseases, other chronic liver diseases, or malignancies, and does not necessarily indicate iron overload.4 Other laboratory abnormalities often seen in patients with clinical HH include elevated aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Hyperglycemia may be found as well as endocrine abnormalities, such as decreased testosterone, luteinizing hormone, follicle-stimulating hormone,2 or increased thyroid-stimulating hormone. With the 1996 identification of an HFE gene mutation as the cause of HH—in addition to sensitive screening tests for iron overload—the majority of HH patients are now identified while still asymptomatic.The life expectancy for patients identified, diagnosed, and treated before the development of end organ damage, such as cirrhosis, is the same as those without the disease. Although treatment cannot reverse end organ damage, it can slow the progression. Treatment of HH is usually venesection, or therapeutic phlebotomy, of 500 mL of whole blood, which equates to approximately 200-250 mg of iron depending on the iron concentration. Phlebotomy is individualized and should be continued until

the transferrin saturation is less than 50% and the ferritin level is less than 50 ng/mL.2, 3 Therapeutic phlebotomy usually starts with a frequency of once a week; then patients can usually be maintained with venesection at every two to three months,2 or just a couple of times per year. Iron chelation therapy is an option for patients unable to tolerate phlebotomy.2, 3 Patients should be advised to avoid iron supplements, multiple vitamins with iron, iron-fortified foods, or the use of iron cookware.They should also be warned not to drink alcohol, as it can increase the chance for liver damage. HH is easily treatable, and should be suspected in anyone with elevated liver enzymes with increased iron levels. It should also be considered for patients with unexplained liver, heart, or endocrine problems.1

4. PATIENT OUTCOME Mr. B started treatment with therapeutic phlebotomy every three weeks and, to date, is tolerating it well. His prognosis is good, as the HH was discovered early enough to thwart liver or heart damage. He will have to continue phlebotomy on a regular basis until his iron levels come down within normal range. Aside from minor muscle pain, Mr. B was one of those hemochromatosis patients who rarely experience any symptoms—even with the onset of middle age.Anecdotally, we were informed by Mr. B that in addition to the gift he received by serendipitously coming in for a routine work up, he also cashed in and managed to get his employer’s incentive pay. ■ Ms. Beyer Blodget is a family nurse practitioner at Kaiser Permanente Medical Center in Sacramento, Calif. References 1. Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: Current concepts and progress. The American Journal of Medicine. 2006;119:391-399. 2. Ferri FF. Ferri’s Clinical Advisor 2012. Philadelphia, Pa.: Mosby, 2012. 3. Bacon BR. Goldman’s Cecil Medicine, 24th ed. Philadelphia, Pa.: Saunders, 2011. 4. Harrison SA, Bacon BR. Relation of hemochromatosis with hepatocellular carcinoma: Epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Medical Clinics of North America. 2005;89:391-409. 5. F leming RE, Britton RS, Waheed A, et al. Pathogenesis of hereditary hemochromatosis. Clinics in Liver Disease. 2006;8:755-773. 6. Bacon BR, Britton RS. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases, 9th ed. Philadelphia, PA: Saunders, 2010:1239-12347. 7. Bakerman S. Bakerman’s ABC’s of Interpretive Laboratory Data, 4th ed. Scottsdale, Ariz.: Interpretive Laboratory Data, 2002. 8. Pagana KD, Pagana TJ. Mosby’s Diagnostic and Laboratory Test Reference, 4th ed. St. Louis, Mo.: Mosby, 1999.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2012 81

LEGAL ADVISOR CASE

A patient undergoing myocardial perfusion imaging claims the IV led to nerve damage.

BY ANN W. LATNER, JD

Shock did not begin to describe Ms. R’s feelings when she was served with papers informing her that a patient was suing her. Ms. R, 53, had been a nurse practitioner for a quarter of a century, and had never before been party to a lawsuit. She was proud of her spotless record, and the fact that she was always careful in everything she did, unlike, she felt, many of her younger contemporaries. She always strove to be professional and businesslike, and her attitude had been noted and praised by the cardiologists with whom she worked. The practice Ms. R worked for included five cardiologists and five NPs, as well as two office managers and a revolving set of interns and junior staff members. Ms. R had been with the practice for the bulk of her career and was highly regarded by the owners. Ms. R was by no means vivacious, but she was practical and highly skilled, and her willingness to work tirelessly allowed her to rise to the level of top NP in the practice. One of the cardiologists in the clinic had been conducting an outpatient myocardial

A seasoned and well-respected NP seeks counsel when she is accused of mishandling an IV insertion during a routine cardiac procedure.

82 THE CLINICAL ADVISOR • APRIL 2012 • www.ClinicalAdvisor.com

perfusion study, and requested that Ms. R be assigned to the project. Ms. R’s job was to administer adenosine intravenously to patients. Mrs. U, at 73, an older patient in the study, was hard to forget, as she incessantly asked questions in a demanding and querulous manner. After years of experience dealing with these types of patients, Ms. R didn’t let the older woman’s tone bother her, and she simply answered Mrs. U’s questions in a businesslike manner. Mrs. R inserted a butterfly needle into the vein of Mrs. U’s right arm just above the elbow to administer the radioactive tracer. “Ouch!” yelled the patient. “Nurse, that hurts! Can’t you be more careful?” “We’ll be done in a moment,” replied Ms. R. Everything seemed routine and Ms. R knew that some patients complained more than others, so she ignored Mrs. U’s grumblings. Still, Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR Mrs. U adamantly protested that she had substantial arm pain after the needle insertion. When Mrs. U’s test was finished, Ms. R thought that was the end of it. She was wrong. Six months later, Ms. R was served with papers notifying her that she was being sued for negligence. According to the papers, Mrs. U alleged that Ms. R negligently inserted the IV, causing median nerve injury, which had caused constant pain in her arm, shoulder, and fingers since. Ms. R could not understand how this had happened. She went over the entire process in her mind. Her technique was book perfect, and she’d inserted butterfly needles thousands of times during the course of her career with no ill result. The physicians in her practice were sympathetic and advised Ms. R to meet with the defense attorney provided by the practice’s insurance.

Defense experts testified that there was no way the median nerve could have been injured by Ms. R’s actions. The defense counsel obtained copies of the patient’s records, and retained an expert physician who met with both Ms. R and himself. The expert asked Ms. R to demonstrate the procedure she used to insert the IV, and he concluded that she had done so flawlessly. “I would suggest that you have Ms. R explain and demonstrate to the jury the process she uses to insert the needle,” said the expert. “I can see no way that a median nerve injury could have occurred based on her technique, or from anything in the patient’s chart.” “It may not even come to that,” said the attorney. “I’m going to make a motion to dismiss this case. I don’t think there is enough evidence to support a malpractice lawsuit.” The defense attorney did make a motion to dismiss, and the court held a hearing to establish whether there was enough evidence to proceed to a trial. At the hearing, Mrs. U testified about the lingering pain in her shoulder, arm, and hand, and how Ms. R had not heeded her protests. The plaintiff ’s attorney introduced two experts, a nurse, and a neurologist, who both opined that Ms. R must have done something wrong, since the patient reported pain afterwards. “There is no reason that a patient would have pain unless the needle was inserted incorrectly,” stated one of the plaintiff ’s experts.

Despite the stress of having to testify in court, Ms. R calmly and professionally explained the process she used to insert the small, short needle into a superficial vein. She testified that she had done the procedure thousands of times and that none of her patients had ever suffered any problems. Ms. R then showed the judge the butterfly needle and demonstrated how it was used. After her testimony, the defense expert testified that there was no way the median nerve could have been injured by Ms. R’s actions. The court agreed and dismissed the patient’s lawsuit. Legal background

The court ruled that the testimony of the plaintiff’s experts (the nurse and neurologist) was conclusory and thus insufficient to support a malpractice suit. Essentially, the judge stated, the expert witnesses jumped to the conclusion that Ms. R must have done something wrong simply because the patient reported pain afterwards. In the absence of an explanation showing how an injury might have occurred, a negative outcome reported by a patient does not prove negligence. While the judge was impressed by Ms. R’s careful documentation of the IV process, he did note that she had, perhaps, been lacking in other ways. “Ms. R allegedly failed to explain to the patient what she was doing, and failed to follow up when the patient complained of pain,” said the judge. “However, even if this amounted to less-than-optimal nursing practice, this court does not see how it could have caused injury to the patient.” Protecting yourself

As Ms. R surmised, some patients are naturally more sensitive and anxious. While Ms. R was not found liable in this case, she might have been able to avoid the lawsuit completely by simply taking the time and effort to walk the patient through the procedure step-by-step and then address the patient’s claims of pain when they occurred. Explaining to a patient what you are going to do, and how you are going to do it—before beginning—is an effective deterrent. Patients who know what to expect are less likely to have issues with their care. And if a patient does complain of pain, even in a situation where you are aware that this particular patient has a tendency to overreact, the best practice is to immediately address the situation. Taking the time to show compassion can often prevent a lawsuit. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 90

■ ADDITIONAL CME/CE: Pages 28, 65

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

Trunk rashes with central clearing ESTHER STERN, NP-C

CASE #1

CASE #2

A woman, aged 69 years, presented with a mildly pruritic rash on her buttocks and lower back that had appeared two weeks earlier. The woman, who had recently undergone a hip replacement, did not recall starting any new medication and had applied no topical medications to the affected area. Examination of the skin revealed several oval-shaped plaques with a distinct erythematous rim and central clearing. In addition, a fi ne scale was present at the inner periphery. No other lesions were noted.

A woman, aged 26 years, noticed a slowly enlarging and itchy rash on her right flank. She denied taking any new medications and had not treated the rash with topical medications. History was remarkable only for hypothyroidism controlled with levothyroxine. The patient had spent time outdoors on the New Jersey shore a few weeks earlier. No fever, malaise or flulike symptoms were reported. Physical exam revealed a 5-cm annular, slightly indurated, and scaling rash with central clearing. There was no associated tenderness or warmth.

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CME CE

CASE #1

Dermatologic Look-Alikes

Erythema annulare centrifugum

Although it is the most prevalent of the figurate or gyrate erythemas, erythema annulare centrifugum (EAC) is a rare condition. The gyrate erythemas represent a group of rashes that are believed to be a cutaneous response to several agents, including medications, infection, systemic malignancy, and stress. These rashes can be classified as a superficial or deep gyrate erythema.1 There is much controversy in the literature regarding classification, but the common presentation of EAC is typically classified as a superficial gyrate erythema.2 EAC presents with several erythematous annular, polycyclic, or oval lesions that slowly enlarge centrifugally at an estimated rate of 2 to 4 mm per day. The lesions simultaneously clear centrally. The characteristic sign and diagnostic clue of EAC is a faint trailing scale present at the inner periphery of the lesions. Occasionally, particularly in the deep form of EAC, the scale is not present. EAC typically appears on the trunk and extremities, with greatest incidence on the thighs. The palms, soles, and mucus membranes are usually spared. Middle-aged adults are most often affected, but EAC has been described in neonates and children, too. There does not appear to be any racial or sex preference. The pathogenesis of EAC remains unknown, but an increasing number of studies supports the theory of EAC representing a hypersensitivity reaction to a variety of causes. Although many cases are idiopathic, underlying causes must be ruled out. A concurrent dermatophytosis is likely the most common etiology. One study that found 48% of patients with EAC had an associated cutaneous fungal infection.3 Tinea pedis is the most common of the dermatophytoses. Such medications as penicillin, finasteride (Propecia, Proscar), hydroxychloroquine (Plaquenil, Quineprox), amitriptyline (Elavil, Endep, Vanatrip), and spironolactone (Aldactone) have been implicated. When associated with medications, EAC typically appears within a few weeks of starting the prescription.

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

Herpes zoster and HIV infection are also reported to occur with EAC. Ingestion of molds and tomatoes has been reported as a possible etiology as well. Systemic diseases associated with EAC include hepatic disease, lupus, thyroid disorder, and Sjogren’s syndrome. EAC may occur in pregnancy and subsequently resolve postpartum. Underlying malignancy has been reported to trigger EAC and must be investigated and ruled out. In most studies, a causal relationship is rarely established, primarily because the temporal relationship between EAC and the underlying disorder is variable, with EAC appearing before, during, or after diagnosis. With malignancy, however, the course of EAC tends to parallel that of the underlying cancer, with rash resolution occurring with tumor suppression and recurring with relapse. The differential diagnosis of EAC includes subacute cutaneous lupus, discoid lupus, erythema migrans, pityriasis rosea, tinea corporis, and erythema multiforme. A skin punch biopsy is often performed to confirm the diagnosis. In the superficial type of EAC, a nonspecific perivascular lymphohistiocytic infi ltrate is seen around the dermal vasculature in a tight “coat sleeve” pattern, along with papillary dermal edema. Epidermal changes of parakeratosis and spongiosis are often seen. A thorough physical exam should be performed. Laboratory workup should be done based on the exam findings. An extensive workup searching for malignancy is unnecessary, given that the association with EAC is not definite. Very often, no cause is identified, and the rash resolves spontaneously. EAC is mostly self-limiting, with a mean duration of 11 months and a range of duration from four weeks to 34 years. For many patients, however, EAC may be a chronic and relapsing disorder. Treatment must be directed at the underlying cause (if discernible). A topical medium potency steroid, such as triamcinolone acetonide 0.1%, may be prescribed for localized pruritus. Although this cream may lead to resolution of the treated lesions, it does not prevent the appearance of new lesions. If pruritus is severe, a short course of oral prednisone may be prescribed. Case reports have shown success with treatment with calcipotriol, hyaluronic acid, metronidazole, and etanercept (Enbrel). The patient in this case underwent a skin biopsy, which confirmed the diagnosis of EAC. She was referred to her internist for a complete physical exam and routine, age-appropriate labwork. The rash resolved spontaneously within approximately six months. Although no underlying cause was definitively indentified, consideration was given to a new medication given during hospitalization for her hip surgery.

86 THE CLINICAL ADVISOR • APRIL 2012 • www.ClinicalAdvisor.com

CASE #2

Erythema migrans

Histopathologic fi nding of a dermal hypersensitivity reaction, along with the characteristic clinical appearance, confi rmed the diagnosis of erythema migrans (EM). Introduced in 1909, EM was described as an expanding ring-like lesion and thought to be the resultof a bite of an Ixodes (deer) tick. Studies have correlated the rash of EM with early, localized Lyme disease, which is a systemic infection with the spirochete Borrelia burgdorferi. Lyme disease is transmitted via an infected tick’s salivary glands to the individual at the site of the inoculation. From there, the spirochete can either be eliminated by the host’s immune system, remain localized at the site of the bite, or spread to surrounding and distant tissue. EM is often referred to as the “bull’s-eye rash” because of its clinical appearance. The rash typically starts as a red inflammatory papule that expands in a circular or oval shape over several days or weeks to an average size of 16 cm. Central clearing occurs simultaneously. At times, the primary papule or proximal redness remains, contributing to the “bulls-eye” or “target” appearance. Several similar lesions can erupt elsewhere on the body. Although the lesions are usually macular, papular and scaly variations exist. The rash may be asymptomatic or cause mild itching or burning. Up to 50% of patients describe such mild flulike symptoms as malaise, poor appetite, and myalgia. EM typically appears at the site of the tick bite but may start anywhere else on the body. The rash can appear one day to one month after a tick bite, with an average onset of seven to 14 days post-bite. EM typically persists for two to four weeks, and in some patients it recurs intermittently if left untreated. Unfortunately, many patients may have no evidence of the rash, and Lyme disease only presents in the later stages with extracutaneous manifestations. Symptoms of Lyme disease result from both infection with the spirochete and from the body’s immune responses to the infection. The multiple lesions of EM, when present, are most likely the results of the body’s immune response. Clinical manifestations are generally divided into three groups: early localized, early disseminated, and chronic disseminated. EM is the primary manifestation of earlylocalized disease. (A detailed description of the symptoms

of and treatment for disseminated disease is lengthy and beyond the scope of this article.) While the classic appearance of the rash will assist in the diagnosis, it is important to consider the epidemiological context (i.e., geography, season, and history of outdoor exposure). Further workup and monitoring is only indicated for those who exhibit extracutaneous manifestations and those who do not show prompt resolution of the rash with recommended treatment. For the latter group, consider such alternative diagnoses as cellulitis or contact dermatitis, as well as co-infection with such other tick-borne illnesses as relapsing fever, tularemia, babesiosis, Rocky Mountain spotted fever, and Colorado tick fever.4 Individuals presenting with an inflammatory erythematous papule at the inoculation site that appeared while the tick was still attached or within hours of the bite most likely do not have EM, but rather are showing a hypersensitivity reaction to the tick. Patients presenting with EM and a positive history of exposure to a tick-infested area do not need serologic testing for a diagnosis of Lyme disease, and antibiotic therapy should be initiated. Empiric antibiotic therapy is also reasonable, even

Clinical manifestations of EM are divided into three groups: early localized, early disseminated, and chronic disseminated. if the clinical diagnosis of EM is moderately probable and not certain. For other Lyme disease symptoms, such laboratory studies as B. burgdorferi antibody titers are necessary. Testing early in the course of Lyme disease is often still negative and may cause a dangerous delay in treatment. EM generally responds and improves within a few days of starting antibiotic therapy. Controversy exists regarding optimum duration of treatment, with recommendations ranging from 10 to 30 days. Doxycycline 100 mg b.i.d. is the preferred drug for oral treatment in nonpregnant adults and children older than age 8 years. Amoxicillin 500 mg t.i.d. is the drug of choice for pregnant and pediatric patients. Second-line drugs include erythromycin, azithromycin (Zithromax, Zmax), and cefuroxime (Ceftin) and are reserved for patient intolerant of first-line agents. With appropriate treatment, the prognosis for EM is excellent. Early removal of ticks will lower the risk of contracting Lyme disease. Ticks need to be attached for at least 24 hours before disease transmission can occur. Individuals

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CME CE

Dermatologic Look-Alikes

presenting with ticks that are not engorged do not need any treatment. Prophylactic treatment with a single dose of doxycycline 200 mg for nonpregnant adults and children older than age 8 years is recommended for such cases. Removal of the tick should be done carefully, using tweezers to grasp the tick close to the skin and pulling gently outward to detach. Patients with EM should be educated regarding disease transmission as well as prevention strategies to avoid a repeat episode (e.g., cover exposed skin and tuck pants into the shoes when walking in wooded, brushy, or grassy areas). Applying insect repellants containing DEET (N,Ndiethyl-m-toluamide) will help repel ticks, however the American Academy of Pediatrics advises that children should not be exposed to products with greater than 10% concentration of DEET. Wearing light colored clothing will aid in identifying lingering insects. It is imperative to inspect the entire skin for evidence of ticks immediately after returning from outdoor exposures,5 paying special attention to body folds and the scalp. When a tick initially attaches to the human skin, it may be as small as a pinhead and difficult to see without a careful inspection. As the tick remains attached and feeds, it will become more engorged and more noticeable but may have already introduced infection by this time. This patient was treated with doxycycline 100 mg b.i.d. for 14 days and reported resolution of the rash one week later. ■

“Would you like to hear about our retirement plan?”

Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Bressler GS, Jones RE Jr. Erythema annulare centrifugum. J Am Acad Dermatol. 1981;4:597-602. 2. Weyers W, Diaz-Cascajo C, Weyers I. Erythema annulare centrifugum: results of a clinicopathologic study of 73 patients. Am J Dermatopathol. 2003;25:451-462. 3. Kim KJ, Chang SE, Choi JH, et al. Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J Dermatol. 2002;29:61-67. 4. McGinley-Smith DE, Tsao SS. Dermatoses from ticks. J Am Acad Dermatol. 2003;49:363-392. 5. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43:1089-1134. Available at cid. oxfordjournals.org/content/43/9/1089.long. All electronic documents accessed March 15, 2012.

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“Can’t you crunch bones with your mouth closed?”

POSTTEST Expiration date: April 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

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 28

page 65

page 85

A new understanding of osteoarthritis

Case #1: Scleroderma

1. What is the single most common risk factor for osteoarthritis (OA)? a. Obesity b. Gender c. Age d. Family history 2. The presence of which physical finding indicates that the joint has minimal cartilage and is bone-on-bone? a. Decreased range of motion b. Crepitus c. Bony enlargement d. Sensation of warmth 3. What is the oral analgesic of choice for mild to moderate OA pain? a. Ibuprofen b. Naproxen c. Acetaminophen d. Aspirin 4. What is an indication for total joint replacement? a. Night pain that is unresponsive to anti-inflammatory agents b. Major inability or difficulty to perform activities of daily living c. Unacceptable reduction in the ability to walk or work d. All of the above

Case #1: Erythema annulare centrifugum 1. What is a frequent constitutional symptom of systemic sclerosis (SSc)? 5. Where is the greatest incidence of erythema annulare centrifugum (EAC)? a. Fatigue a. Thighs c. Palms b. Weakness b. Mucous membranes d. Scalp c. Insomnia d. All of the above 6. Which medication has been implicated in EAC? 2. What is the drug of choice for a. Fluoxetine (Prozac, Rapiflux, interstitial lung disease in SSc? Sarafem, Selfemra) a. Azathioprine (Azasan, Imuran) b. Atenolol (Senormin, Tenormin) b. Cyclosporine (Gengraf, Neoral, c. Finasteride (Propecia, Proscar) Sandimmune, Sangcya) d. Acyclovir (Zovirax) c. Cyclophosphamide (Cytoxan) d. Methotrexate (Rheumatrex, Case #2: Erythema migrans Trexall) 7. How is the rash of erythema migrans Case #2: Trichotillomania (EM) described? a. A well-demarcated area of erythema 3. Which area of the scalp is with exudative lesions spared in trichotillomania, b. A red inflammatory papule that even in severe cases? expands in a circular or oval shape a. Frontal c. An erythematous annular patch with b. Occipital distinct borders c. Frontotemporal d. A macule with a halo of tender d. Frontoparietal inflammation and hemorrhage 4. Which medication has been used in 8. What is the preferred drug for oral the treatment of trichotillomania? treatment of EM in nonpregnant adults a. Clomipramine (Anafranil) and children older than age 8 years? b. Lorazepam (Ativan) a. Azithromycin (Zithromax, Zmax) c. Clozapine (Clozaril, FazaClo) b. Cefuroxime (Ceftin) d. Haloperidol (Haldol) c. Amoxicillin d. Doxycycline

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureApr2012

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TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermApr2012

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.

Saffron

Most of us know saffron as that wonderfully, intense (and expensive) spice used to make risotto, pilaf, and paella. Saffron is extracted from the dried stigma of the crocus flower (Crocus sativus).1 The saffron crocus is a sterile plant, as it cannot independently pollinate and reproduce.2 The plant is extremely difficult to cultivate, which is part of what makes the spice so expensive. Each crocus stalk grows 8-10 inches in height and produces up to four individual purple flowers. The flower has only three stigmas that yield the crimson powder that we know as saffron.2

Background

Science

Harvesting these stigmas is a very labor intensive effort, and it is estimated that 225,000 stigmas or 75,000 blossoms are needed to produce a single pound of saffron spice.2 Saffron’s use as a spice, dye, and medicinal plant dates back to ancient Greece and southwestern Asia.1 Pictorial records produced 50,000 years ago, show colorful depictions of burntorange saffron strands being harvested from rich purple plants.1 And a seventh-century Assyrian ruler compiled a botanical reference list for saffron in which he cited more than 90 illnesses that saffron was used to treat in classical times.2 Today, Iran produces over 90% of the world’s supply of the spice.2 As a spice, saffron is known not only for its intense, yellow-orange coloration, but hay-like, sweet taste.1 Saffron, unbeknown to most, contains more than 50% of the USDA’s recommended daily allowance of vitamin C, iron, and magnesium, and more than 30 % of the recommended daily phosphorus and potassium.3

Saffron’s standardized strength-of-evidence ratings are strongest for depression, Alzheimer’s disease, and premenstrual syndrome (PMS). The active ingredient in saffron that is believed to be responsible for health benefits is crocetin, a potent antioxidant and carotenoid.1 This compound has chameleon-like properties in that it acts different ways to meet the needs of differing conditions. In Alzheimer’s disease, crocetin appears to inhibit beta-amyloid (Abeta) protein fibrillogenesis, a hallmark of Alzheimer’s destructive pathology.1 In inflammatory conditions, crocetin down-regulates the production and modifies the expression of pro-inflammatory cytokines and inducible nitric oxide-synthase levels. Crocetin also demonstrates possible antinociceptive activity.1 In a clinical trial comparing saffron to placebo in patients with mild-to-moderate depression, the saffron group outperformed the placebo group. The results, based on pre-and post-study scores on the Hamilton Depression Rating Scale,

94 THE CLINICAL ADVISOR • APRIL 2012 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE yielded a statistically significant level (p<0.001).4 Another study examined 40 adults with DSM-IV criteria, suggesting a major depressive episode. Patients were randomly assigned to receive either saffron or fluoxetine (Prozac) for an eight-week treatment period. At the end of the trial, both groups exhibited similar results, with each group demonstrating a symptom remission rate of 25% for both treatments.5 In Alzheimer’s disease, researchers have shown that the continuous cognitive decline is due, at least in part, to the abnormal deposition of Abeta protein in the brain cells. Research suggests that saffron may inhibit Abeta deposition. In a study of 46 patients diagnosed with mild-to-moderate Alzheimer’s disease, randomized treatment with saffron or placebo was given for a 16-week period. At the end of the trial, participants receiving saffron treatment showed significant improvement over baseline testing on standardized cognitive tasks.6 In a randomized, double-blind trial of 50 women with diagnoses of consecutive, cyclical PMS, saffron vs. placebo was tested to see which would better alleviate symptoms. Cyclical PMS was defined by scores on the Total Premenstrual Daily Symptoms Scale and the Hamilton Depression Rating Scale.7 After a two cycle run-in period where symptom scores were collected and validated, the women were randomized to either 15 mg twice daily of saffron or placebo for another two cycles.7 For the purpose of the study, a ‘responder’ was considered a participant who showed a 50% or greater reduction in severity of symptoms.7 Using that definition, 19 of the 25 women in the saffron group were classed as responders compared to two in the placebo cohort.7

Dosage and cost Most trials used daily doses of 15-30 mg per day without any significant adverse affects. Saffron is supplied in powder-filled capsules, spice, or as a tea. The cost ranges from $50 to $300/oz.1

Summary

Saffron shows exciting possibilities for alleviating depression.

The active ingredient in saffron that is believed to be responsible for health benefits is crocetin, a potent antioxidant and carotenoid.

There is no question that saffron is an expensive herb, but studies show its potential beneficial effects. Current methods of cultivation, however, make it cost prohibitive. And while much more extensive research needs to be done on the medicinal properties of the Crocus sativus, there are exciting possibilities for treating depression and inflammatory disorders. ■ References 1. Herb Supplements: Saffron (Crocus sativus) monograph page. Natural Standard website. Available at www.naturalstandard.com/monographs/herbsupplements .saffron.asp. 2. Ghorbani, M. The efficiency of saffron’s marketing channel in Iran. World Appl Sci J. 2008;6:523-527. 3. Center for Nutrition Policy and Promotion’s Dietary Guidelines for Americans page. United States Department of Agriculture website. Available at www.cnpp.usda.gov / DietaryGuidelines.htm. 4. Moshiri E, Basti AA, Noorbala, AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a double-blind randomized and placebo-controlled trial. Phytomedicine. 2006;13:607-611. 5. Akhondzadeh BA, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L., and fluoxetine in the treatment of depressed outpatients: A pilot doubleblind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:439-442. 6. Akhondzadeh, S. Saffron in the treatment of

Saffron is considered a safe supplement with no known contraindications in pregnant or lactating women, or in infants.1 The potential for allergic response is always present, and, as with any botanical product, care should be exercised when using. Patients using warfarin and other medications that rely heavily on the cytochrome P-450 hepatic enzyme chain for metabolism can have an adverse reaction to saffron ingestion. 96 THE CLINICAL ADVISOR • APRIL 2012 • www.ClinicalAdvisor.com

patients with mild-to-moderate Alzheimer’s disease: A 165-week, randomized and placebo-controllled trial. Int J Clin Pharmacol Ther. 2010;35:581-588. 7. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: A double-blind, randomized and placebocontrolled trial. BJOG. 2008;115:515-519. All electronic documents were accessed on March 15, 2012.

Safety, interactions

COMMENTARY Peg Ackerman, DNP, APRN, is Director of Education at Commonwealth Care Alliance (Charlestown, Mass.), and an assistant professor at U Mass Worcester Graduate School of Nursing.

“Safe at home:” to die in peace A physician colleague of mine was unable to discharge a patient to home with hospice care because the nurse case manager at the hospital thought the patient would not be “safe at home,” despite the fact that as a quadriplegic, he had been living on a respirator at home for some time with the assistance of his personal care attendants (PCAs). Because the case manager had failed to communicate to the contracted hospices the full scope of care that the patient was receiving at home from his PCAs, the patient was rejected by all of them. The one hospice that was willing to accept him was not contracted with his insurance company, although the insurance company did review the case for four days.

They ended up battling with a case manager, an insurance company, and hospice providers to have their patient’s voice heard.

The Patient Self-Determination Act (PSDA) became effective in 1990, a federal mandate affording people the right to determine how they will die. The PSDA requires institutions to provide patients the opportunity to put their wishes in writing. In 1995, the SUPPORT study found that practitioners were not adequately trained in communication techniques regarding end-of-life care ( JAMA. 1995;274:1591-1598). This landmark study incited the palliative-care movement and standards that hospitals are now required to meet for Joint Commission on Accreditation of Healthcare Organizations ( JCAHO) accreditation. We have, however, a layer of bureaucracy in health care: insurance regulators determining where a patient will die based on information from well-intentioned but inexperienced case managers. We also have the artful subliminal messages of the extreme right and the media blitz of “death panels/offi ng granny/pulling the plug.” In the midst of this noise, the most important voice is lost—that of the patient who lies in an ICU, losing precious days at home, where he or she wants to die in peace. A year before he was appointed head of the Centers for Medicare and Medicaid Services, Donald Berwick proposed the following definition for patient-centered care: “The experience (to the extent the informed, individual patient desires it) of transparency, individualization, recognition, respect, dignity, and choice in all matters, without

exception, related to one’s person, circumstances, and relationships in health care” (Health Affairs (Millwood). 2009;28:w555-w565; available at content.healthaffairs.org/content/28/4/w555 .long, accessed March 15, 2012). Misguided compassion of inexperienced clinicians coupled with the noise of zealots has set us back in the pursuit of peaceful death, failing to achieve the basic goals of patient-centered care. Fragmented, bureaucratic health-care delivery in which insurance reviewers spend precious days and thousands of dollars going over a case further marginalizes our patients, making the goal of peaceful death more elusive. In this case, the primary nurse practitioner, Mary, had a longstanding relationship with the patient, and Mary and the patient’s primary-care physician collaborated to communicate with him in a patient-centric way, yet they ended up battling with a case manager, an insurance company, and a network of hospice providers to have their patient’s voice heard. If not for the patient-centered philosophy of one hospice that was able to say, “Yes, we will provide hospice care to a man on a respirator,” the patient would have died in the ICU, his wish to die at home surrounded by family and friends denied. Ironically, as a quadriplegic, the patient fought so hard to stay alive for so long, and in the end, he fought to die in peace. Dying in peace should not be such a struggle. ■

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