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A F O R U M F O R N U R S E P R A C T I T I O N E R S | M AY 2 012 | www.ClinicalAdvisor.com

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Access downloadable resources for managing Fibromyalgia and learn more about LYRICA at www.FMMGMT.com

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

LYRICA is indicated for the management of Fibromyalgia in adults 18 years and older.

Selected safety information:

LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema

with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebo-treated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED.

The most common adverse reactions across all LYRICA clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision,

weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention).

Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function.

Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution

when using LYRICA in patients who have had a previous episode of angioedema.

Patients with a history of drug or alcohol abuse may have a higher chance of misuse or abuse of LYRICA.

Withdraw LYRICA gradually over a minimum of 1 week. Discontinue LYRICA immediately in patients with symptoms of hypersensitivity or angioedema.

For more info, scan this QR code with your smartphone.

For Full Prescribing Information and Medication Guide, please visit www.FMMGMT.com.Please see Brief Summary of Prescribing Information on adjacent pages.

© 2012 Pfizer Inc. All rights reserved. April 2012 PBP455517-01

02-08912D_R1_LYR_FM_HUG_JA.indd 1-2 4/4/12 8:58 PM

LYRICA® (pregabalin) CAPSULESBRIEF SUMMARY: For full prescribing information, see package insert.INDICATION AND USAGELYRICA is indicated for:

• Management of neuropathic pain associated with diabetic peripheral neuropathyDOSAGE AND ADMINISTRATIONLYRICA 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 ImpairmentIn 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:

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 renaladjusted 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 FunctionCreatinine Clearance Total Pregabalin Daily Dose Dose Regimen(CLcr) (mL/min) (mg/day)*

≥60 150 300 450 600 BID or TID

30–60 75 150 225 300 BID or TID

15–30 25–50 75 100–150 150 QD or BID

<15 25 25–50 50–75 75 QD

Supplementary dosage following hemodialysis (mg)†

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mgPatients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mgPatients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mgPatients 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.CONTRAINDICATIONSLYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedemaand hypersensitivity reactions have occurred in patients receiving pregabalin therapy.WARNINGS AND PRECAUTIONSAngioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment withLYRICA. 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 patientswho have had a previous episode of angioedema. In addition, patients who are taking other drugs associated withangioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developingangioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiationof 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 withall AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizuredisorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and IdeationAntiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking thesedrugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening ofdepression, 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 ofthe AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviorcompared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, theestimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking orbehavior 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 ofsuicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs andpersisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts orbehavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varyingmechanisms 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 relativerisk by indication for all evaluated AEDs.

Table 2 Risk by indication for antiepileptic drugs in the pooled analysisIndication Placebo Patients Drug Patients Relative Risk: Risk Difference:

with Events Per with Events Per Incidence of Events Additional Drug Patients1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per

in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4Psychiatric 5.7 8.5 1.5 2.9Other 1.0 1.8 1.9 0.9Total 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 psychiatricor other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyoneconsidering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk ofuntreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated withmorbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavioremerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patientmay be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDsincrease the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worseningof 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. PeripheralEdema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heartor peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascularcomplications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratorychanges suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheraledema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICApatients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheraledema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patientstaking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety databasewere participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edemawas reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patientswho were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedioneantidiabetic 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 drugscan 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 NewYork 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 dizzinessand somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlledtrials, dizziness was experienced by 31% of LYRICA-treated patients compared to 9% of placebo-treated patients;somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizzinessand somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higherdoses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) fromcontrolled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizzinesspersisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICAtreatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baselineweight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated withLYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to doseand duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was notlimited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was notassociated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovasculareffects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained anaverage 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. Whilethe effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlledand longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated withloss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapiddiscontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. TaperLYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential Instandard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcomawas identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment ofFertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing developmentprovides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patientpopulations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumorswere reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations nottreated 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 blurredvision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Lessthan 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectivelyplanned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopicexamination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treatedwith LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12%of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treatedpatients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify theirphysician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequentassessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICAtreatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximumvalue were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiplepatient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least threetimes the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketingclinical trials. The relationship between these myopathy events and LYRICA is not completely understood because thecases had documented factors that may have caused or contributed to these events. Instruct patients to promptly reportunexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaiseor fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinaselevels 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 103/µL, compared to 11 x 103/µL in placebopatients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced apotentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 103/µL. A singleLYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomizedcontrolled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR IntervalProlongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, themean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associatedwith 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 notidentify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PRprolonging medications. However, these analyses cannot be considered definitive because of the limited number of patientsin these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and maynot reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations duringthe premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patientswere treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients weretreated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies Inpremarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treatedwith placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactionsmost frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patientswithdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuationfrom 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 allpatient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinkingabnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICAthan by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral NeuropathyAdverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabeticperipheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinuedprematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation dueto adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due todizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICAgroup than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawalin approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patientswith neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence wasgreater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinicalstudies had adverse reactions with a maximum intensity of “mild” or “moderate”.

CLCr = (x 0.85 for female patients)[140 - age (years)] x weight (kg)

72 x serum creatinine (mg/dL)

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associatedwith Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at leastnumerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* PlaceboBody 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 0Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1Metabolic 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 0Incoordination 1 0 2 2 2 0Thinking abnormal† 1 0 1 3 2 0Tremor 1 1 1 2 1 0Abnormal gait 1 0 1 3 1 0Amnesia 3 1 0 2 1 0Nervousness 0 1 1 1 1 0Respiratory systemDyspnea 3 0 2 2 2 1Special sensesBlurry vision‡ 3 1 3 6 4 2Abnormal vision 1 0 1 1 1 0

*PGB: pregabalin† Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes eventsrelated 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 adversereactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those eventsalready listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, thoseevents which were so general as to be uninformative, and those events reported only once which did not have a substantialprobability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasingfrequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasionsin at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions arethose occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings andPrecautions 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:Deepthrombophlebitis, 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. Hemicand 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-Barrésyndrome, 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, Skinatrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent:Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eyehemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Cornealulcer, 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, Urinaryretention, 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 INTERACTIONSSince LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of adose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to beaffected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showedthat LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are nopharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid,lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expectedto occur between LYRICA and commonly used antiepileptic drugs. PharmacodynamicsMultiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Althoughno pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen whenLYRICA 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 ofdevelopmental 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 plasmapregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. Whenpregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidencesof 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 alldoses. 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-fetaldevelopmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orallythroughout 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 developmentaltoxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at theMRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestationand lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. Theeffect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspringwere tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose forpre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times humanexposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancyonly if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in uteroexposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North AmericanAntiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, andmust 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 areunknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50times 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 inanimal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance ofthe 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 locomotoractivity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturationand decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acousticstartle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals testedafter cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmentalneurotoxicity 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 wasnot established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabeticperipheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlledclinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years ofage, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed betweenthese patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 yearsof age or older. Although the adverse reaction profile was similar between the two age groups, the following neurologicaladverse 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 iseliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.DRUG ABUSE AND DEPENDENCEControlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sitesassociated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse andobserve 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-treatedpatients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting ratewas higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation ofLYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings andPrecautions, 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 ofLYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, andthere were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote foroverdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observeusual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vitalsigns and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-dateinformation on the management of overdose with LYRICA. Although hemodialysis has not been performed in the fewknown 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidenceof 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 dosethat 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 ofcarcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years atdoses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposuresin males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. MutagenesisPregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems invitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility Infertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating withuntreated females, a number of adverse reproductive and developmental effects were observed. These included decreasedsperm 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 spermand fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductivetoxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 timeshuman exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductiveorgan (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) ingeneral toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathologyin rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In afertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating andearly gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, andembryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9times 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, 30healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one completesperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motilitywas <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductiveparameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seenin repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At themaximum 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 plasmaAUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesionswas observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss ofphotoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies inWistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humansgiven the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similarlesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.LAB-0294-21.0June 2011

PBP01873/291898-01 © 2011 Pfizer Inc. All rights reserved.

4 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

EditorJoe Kopcha, [email protected] editorMarina GalanakisSenior editorDelicia Yard Web editorNicole Blazek Contributing editorsBruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-CArt directorAndrew BassGroup art director, Haymarket MedicalJennifer DvoretzProduction directorLeslie CarsmanCirculation managerPaul SilverAudience development director John CreweNational accounts managerAlison McCauley, [email protected] publisherThomas P. Hennessy, [email protected] directorTanya GregoryVice president, medical magazines and digital productsJim BurkeCEO, Haymarket Media Inc.Lee Maniscalco

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

PBP01859A/291945-01 © 2011 Pfi zer Inc. All rights reserved. September 2011

While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNOREHelp manage your patients’ painful DiabeticPeripheral Neuropathy with LYRICA

“ 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 specifi c 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 specifi ed 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.

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. Specifi c symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebo-treated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED.The most common adverse reactions across all LYRICA

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily diffi culty 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 suffi cient 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.

LYRICA® (pregabalin) CAPSULESBRIEF SUMMARY: For full prescribing information, see package insert.INDICATION AND USAGELYRICA is indicated for:

• Management of neuropathic pain associated with diabetic peripheral neuropathyDOSAGE AND ADMINISTRATIONLYRICA 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 ImpairmentIn 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 inmL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

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 renaladjusted 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 dailydose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal FunctionCreatinine Clearance Total Pregabalin Daily Dose Dose Regimen

(CLcr) (mL/min) (mg/day)*≥60 150 300 450 600 BID or TID

30–60 75 150 225 300 BID or TID

15–30 25–50 75 100–150 150 QD or BID

<15 25 25–50 50–75 75 QD

Supplementary dosage following hemodialysis (mg)†

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mgPatients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mgPatients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mgPatients 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.

CONTRAINDICATIONSLYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedemaand hypersensitivity reactions have occurred in patients receiving pregabalin therapy.WARNINGS AND PRECAUTIONSAngioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatmentwith LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat andlarynx). 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 patientswho have had a previous episode of angioedema. In addition, patients who are taking other drugs associated withangioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developingangioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly afterinitiation 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) Aswith all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients withseizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behaviorand Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patientstaking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence orworsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analysesof 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patientsrandomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidalthinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment durationof 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one caseof suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in thetrials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect onsuicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after startingdrug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in theanalysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not beassessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. Thefinding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that therisk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinicaltrials 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 analysisIndication Placebo Patients Drug Patients Relative Risk: Risk Difference:

with Events Per with Events Per Incidence of Events Additional Drug Patients1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per

in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4Psychiatric 5.7 8.5 1.5 2.9Other 1.0 1.8 1.9 0.9Total 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 forpsychiatric 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 withthe risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associatedwith morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts andbehavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in anygiven patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICAand other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for theemergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or theemergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately tohealthcare 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 peripheraledema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was notassociated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trialsthe incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlledclinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequenciesof weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabeticagent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agentsin the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. Inthis population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabeticagents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were onboth LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients onthiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As thethiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating orleading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limiteddata on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercisecaution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness andsomnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform taskssuch as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICA-treated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treatedpatients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after theinitiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adversereactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reportingthese adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolencepersisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICAcontrolled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlledtrials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did notappear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [seeWarnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically importantchanges in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associatedweight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabeticpatients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term openlabel 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, somepatients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimumof 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetimecarcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two differentstrains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinicalsignificance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides nodirect 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 werereported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations nottreated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected bytreatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reportedblurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continueddosing. 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 dilatedfunduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% ofpatients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% ofplacebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patientsto notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Considermore frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine KinaseElevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase frombaseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In allcontrolled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had avalue of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reportedas rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is notcompletely 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 musclesymptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed orsuspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment wasassociated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in plateletcount of 20 x 103/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% ofplacebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, definedas 20% below baseline value and <150 x 103/µL. A single LYRICA treated subject developed severe thrombocytopeniawith a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increasein bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR intervalprolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300mg/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 ofsecond or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patientswith baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannotbe 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 reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patientpopulations 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 Inpremarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patientstreated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adversereactions 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 todiscontinuation 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 ofall patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinkingabnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated withLYRICA 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 NeuropathyAdverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabeticperipheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinuedprematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuationdue to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrewdue to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency inthe LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events ledto withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patientswith neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence wasgreater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinicalstudies had adverse reactions with a maximum intensity of “mild” or “moderate”.

CLCr = (x 0.85 for female patients)[140 - age (years)] x weight (kg)

72 x serum creatinine (mg/dL)

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associatedwith Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at leastnumerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* PlaceboBody 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 0Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1Metabolic 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 0Incoordination 1 0 2 2 2 0Thinking abnormal† 1 0 1 3 2 0Tremor 1 1 1 2 1 0Abnormal gait 1 0 1 3 1 0Amnesia 3 1 0 2 1 0Nervousness 0 1 1 1 1 0

Respiratory systemDyspnea 3 0 2 2 2 1

Special sensesBlurry vision‡ 3 1 3 6 4 2Abnormal 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 tocognition 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 adversereactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events alreadylisted in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events whichwere so general as to be uninformative, and those events reported only once which did not have a substantial probabilityof being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency accordingto the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurringin 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, Hangovereffect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heartfailure, 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, Tongueedema; 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 andNutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent:Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. NervousSystem – 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, Lungfibrosis, 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: Abnormalityof accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Tasteperversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis,Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. UrogenitalSystem – 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 reliablyestimate 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 INTERACTIONSSince LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of adose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to beaffected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studiesshowed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are nopharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid,lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expectedto occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although nopharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA wasco-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 ofdevelopmental toxicity, including lethality, growth retardation, and nervous and reproductive system functionalimpairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that producedplasma 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 jugaland nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification wereincreased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associatedwith 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 1250mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletalmalformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose fordevelopmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposureat the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestationand lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effecton offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring weretested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg andreproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnataldevelopmental 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 potentialbenefit 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 patientsthemselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor andDelivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study inrats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalinis excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, andbecause of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing orto discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacyof pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orallyadministered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioralabnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding andhabituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) wereobserved at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotoractivity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were consideredto represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenilerats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at themaximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinicalstudies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years ofage, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associatedwith postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. Nooverall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinicalstudies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile wassimilar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 yearsof 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 inpatients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderlypatients with renal impairment.DRUG ABUSE AND DEPENDENCEControlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sitesassociated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse andobserve 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, singledose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patientsoverall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higherand 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 orRapid Discontinuation], suggestive of physical dependence.OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose ofLYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, andthere were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote foroverdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observeusual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vitalsigns and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-dateinformation on the management of overdose with LYRICA. Although hemodialysis has not been performed in the fewknown 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidenceof 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 dosethat 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 ofcarcinogenicity 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 inmales and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalinwas 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 inwhich 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 andsperm 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 parameterswere 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 maximumrecommended 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 fourweeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associatedwith a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats weregiven pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicityand an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. Thelow dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effectdose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinicaltrial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baselineof 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 inrepeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximumrecommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The moresevere dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) ofapproximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observedin 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. Thesefindings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximumrecommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were notobserved in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.LAB-0294-21.0June 2011

PBP01873/291898-01 © 2011 Pfizer Inc. All rights reserved.

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A TRIO OF studies adds support to earlier fi ndings that aspirin reduces cancer risk and, in some cases, metastasis.

Previous work by Peter M. Rothwell, FMedSci, who led all three of the current studies (two published online ahead of print by The Lancet and one published online ahead of print by The Lancet Oncology), established that daily aspirin reduces the long-term risk of death from cancer. One of the new Lancet studies clarifi ed this effect by demonstrat-ing that in 34 trials of low-dose aspirin for primary prevention of vascular events, involving 69,224 participants, persons allocated to aspirin had a risk of cancer death 15% lower than that of controls. The subset of patients who had been on aspirin therapy for at least fi ve years was 27% less likely than the control group to die from cancer.

The same analysis revealed that in six trials of daily low-dose aspirin for primary prevention, using aspirin for at least three years reduced cancer incidence by 24% in women and by 23% in men, compared with controls.

In the other Lancet study, Rothwell’s team collected new data on the metastasis of cancers that had been diagnosed during all fi ve large randomized trials in the United Kingdom evaluating daily aspirin (>75 mg/day) vs. con-trol for the prevention of vascular events. During a mean follow-up of 6.5 years, people who had been allocated to aspirin therapy had a 36% lower risk of cancer with distant metastasis, a 46% lower risk of adenocarcinoma (such common solid cancers as colon, lung, and prostate cancers), and an 18% lower risk of such other solid cancers as bladder and kidney cancers.

The study also showed aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis by 31% and the risk of metastasis on follow-up in patients without initial metastasis by 55%—particu-larly in patients with colorectal cancer (by 74%) and in patients who remained on trial treatment up to or after diagnosis (by 69%).

The Lancet Oncology paper described a review of studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. Observational studies showed a 38% reduced risk of colorectal cancer, which corre-sponded with the effect of daily aspirin use on 20-year risk of death from colorectal cancer from the randomized trials (42%). Similarly consistent reductions were seen in risks for esophageal, gastric, biliary, and breast cancers.

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Distribution of BMI categories in adults age 20 and older

Men were less likely than women to have a healthy weight, according to the Agency for Healthcare Research and Quality (AHRQ).

Source: Center for Financing, Access, and Cost Trends, AHRQ, Medical Expenditure Panel Survey, 2009

Daily aspirin

has been shown

to reduce the

risk of death

from cancer.

Aspirin appears to keep cancer at bay

Underweight

Healthy weight

Overweight

Obese

Extremely obese

Male

3.0% 0.7%

Female

5.9% 2.2%

42.6%

27.4%26.3% 38.6%

29.4%

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older revealed that 985 Medicare patients had babesiosis in 2006 and 851 in 2007, but 1,223 had the disease in 2008 (Emerg Infect Dis. 2012;18:128-131).

The highest rates of babesiosis were found in persons aged 65 years and older who were liv-ing in New York, Connecticut, Rhode Island, or Massachusetts. The infections appear to be on the rise in the District of Columbia, Maryland, and Virginia.

Ticks are also causing anoth-er problem in the Northeast: According to disease ecologist Richard S. Ostfeld, PhD, of the Cary Institute of Ecosystem Studies in Millbrook, N.Y., this region can expect a surge in Lyme disease this spring.

The problem began with a cycli-cal scarcity of acorns. A dearth of

SOME PATIENTS who are experiencing fl ulike symptoms—particularly elderly individuals—might actually be affl icted with babesiosis, a malaria-like disease caused by infection of red blood cells by a protozoan called Babesia. This parasite is spread by ticks, with the peak transmission period being May through September.

Babesia are related to the para-sites that cause malaria. Although infections can be asymptomatic, they can also cause mild fever, chills, and aches as well as other fl ulike symptoms. Severe com-plications, including multiorgan failure and death, mostly occur in the elderly, newborns, and persons who are immunocompromised or do not have a spleen.

A recent analysis of clinical babe-siosis in persons aged 65 years and

acorns reduces the population of white-footed mice, which are the preferred hosts of black-legged ticks. These ticks carry Borrelia burgdorferi, the bacterium that causes Lyme disease. With fewer mice off of which to feed, the ticks will be biting more humans, predicted Ostfeld.

NINE PHYSICIAN organiza-tions have teamed up to identify specifi c tests or procedures com-monly but not always practically used in their respective fi elds.

The Amer ican Board of Internal Medicine Foundation has brought together the American Academy of Family Physicians (AAFP), the American College of Physicians, the American College of Cardiology, the American College of Nuclear Cardiology, the Amer ican Academy of Allergy, Asthma & Immunology, the American Gastroenterological Association,

the American Society of Clinical Oncology, the American College of Radiology, and the American Society of Nephrology. Each group has posted a list of “Five things Physicians and Patients Should Question” at the website www.ChoosingWisely.org.

For example, the fi ve “don’ts” specifi ed by the AAFP are: (1) don’t do imaging for low back pain within the fi rst six weeks unless red fl ags are present; (2) don’t routinely prescribe antibiotics for acute mild-to-moderate sinusitis unless symptoms last for seven or more days or symptoms worsen

after initial clinical improvement; (3) don’t use DEXA screening for osteoporosis in women young-er than age 65 years or in men younger than age 70 years with no risk factors; (4) don’t order annual ECGs or any other cardiac screening for low-risk patients without symptoms; and (5) don’t perform Pap smears on women who are younger than age 21 years or who have had a hysterectomy for noncancer disease.

Each organization included additional details to explain when a particular test or treatment may be appropriate.

Tick-borne disease looks like the fl u

Check this list before ordering that test

Pap smears on women younger than age 21 are not necessary.

Babesiosis is

caused by the

protozoan

Babesia (red).

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Viral vs. bacterial sinusitisALTHOUGH THE vast majority of sinus infections are caused by viruses, bacteria are likely to be the culprits in specifi c circum-stances, and in those instances, antibiotics should be used.

This information comes from a new guideline issued by the Infectious Diseases Society of America (IDSA) focusing on acute bacterial rhinosinusitis in children and adults. Authored by a team led by Anthony W. Chow, MD, the guideline is available at www.idsociety.org and provides specifi c characteristics of the illness to help distinguish between viral and bac-terial sinus infections.

According to the guideline, a sinus infection is likely to be caused by bacteria rather than a virus if any of the three fol-lowing conditions is present: (1) symptoms last for at least 10 days without any evidence of clinical improvement; (2) symptoms are severe, including fever of 102°F or higher, and nasal discharge and facial pain enduring for at least

three to four consecutive days at the beginning of illness; and (3) symptoms or signs worsen, as characterized by new fever or headache developing or nasal dis-charge increasing, typically after a viral upper respiratory infection that lasted fi ve or six days and initially seemed to improve.

The IDSA guideline also sug-gests that a fi ve- to seven-day course of antibiotics is long enough to treat the infection in adults without encouraging anti-biotic resistance. Children, how-ever, should undergo antibiotic treatment for 10 to 14 days.

Topical and oral decongestants and antihistamines should be avoided in patients with acute bacterial rhinosinusitis due to scant evidence that they hasten recovery; they may even induce infl ammation in the nasal cav-ity, according to the guideline. Symptoms should be managed by means of hydration, analgesics, antipyretics, saline irrigation, and intranasal corticosteroids.

Be sure patients can identify nutsWHEN USING dietary avoid-ance to treat nut allergies, be sure that the patient can properly iden-tify peanuts and tree nuts.

In a recent study, persons aged 6 years and older were asked to iden-tify peanuts and nine tree nuts—including almonds, Brazil nuts, cashews, hazelnuts, Macadamia nuts, pecans, pine nuts, pistachios, and walnuts—displayed in 19 dif-ferent forms. The 649 adults and 459 children who completed the study identifi ed an average of 8.4 nuts (44.2%). Children aged 6 to 18 years were only able to identify a mean 4.6 nuts (24.2%), com-pared with 11.1 (58.4%) for adults older than age 18 years.

Half of people with a peanut or tree-nut allergy correctly identi-fi ed all forms of nuts to which they were allergic, but these respondents performed no bet-ter than nonallergic subjects on the test. Furthermore, parents of children with nut allergies did no better than parents of nonallergic children.

“Overall, both children and adults are unreliable at visually identifying most nuts,” conclud-ed Todd L. Hostetler, MD, and colleagues (Ann Allergy Asthma Immunol. 2012;108:25-29).

The most commonly identifi ed items were peanuts in the shell and out of the shell. Hazelnuts both in the shell and out of the shell were the least commonly identifi ed tree nut. ■

Symptoms that last for at least 10 days may indicate a bacterial infection.

The CDC’s Advisory Committee on Immunization Practices (ACIP) expanded its tetanus, diphtheria, and acellular pertus-sis (Tdap) vaccination recommendation to include persons aged 65 years and older.

Prior to this change, the shot was recom-mended only for adults aged 19 through 64 years. Vaccination in adults aged 65 years and older was generally recommended only for those who had close contact with an infant younger than age 12 months.

Now, the ACIP believes that providers should not miss an opportunity to admin-ister the Tdap vaccine to persons aged 65 years and older.

In its updated guidance, ACIP calls for adults aged 19 years and older to receive a single dose of Tdap if they have never had the vaccine and recommends that Tdap be administered regardless of the interval since the last tetanus or diphtheria toxoid-containing vaccine was received.

Tdap vaccination now okay for seniors, too

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 21

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0.5 CREDITS Page 23 FEATUREHAART meds: Implications for the older adult patientTeri Capriotti, DO, MSN, CRNP, and Sarah SheerinDr. Capriotti and Ms. Sheerin have no relationships to disclose relating to the content of this article.

LEARNING OBJECTIVES: ■Name the medication that boosts the activity of some protease inhibitors (PIs) • when added to a highly active antiretroviral therapy (HAART) regimen.Describe the most common adverse effect associated with HAART.• Identify the HAART medication associated with reductions in bone mineral density. • Name the medication that is contraindicated in a patient taking PIs.•

Page 59 DERMATOLOGY CLINIC

Macules spread from abdomen to extremities Kerri Robbins, MDDr. Robbins has no relationships to disclose relating to the content of this article.

Pink nodule on the crown of the headEsther Stern, NP-CMs. Stern 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 65 DERMATOLOGIC LOOK-ALIKESBimalar facial rashesJoe Monroe, MPAS, PAMr. Monroe 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 70 POSTTEST

0.5 CREDITS

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

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 May 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.

MAY 2012

PROGRAM OUTLINECMECE


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HAART medications can impact a patient’s digestion, increase insulin resistance, and decrease bone density.

HAART meds: Implications for the older adult patientPatients infected with HIV are living longer, which means they have more age-related comorbidities that require other medications as well.

TERI CAPRIOTTI, DO, MSN, CRNP, AND SARAH SHEERIN

■ LEARNING OBJECTIVES:Name the medication that boosts the activity of some protease inhibitors (PIs) when • added to a highly active antiretroviral therapy (HAART) regimen.

Describe the most common adverse effect associated with HAART.•

Identify the HAART medication associated with reductions in bone mineral density. •

Name the medication that is contraindicated in a patient taking PIs.•

■ COMPLETE THE POSTTEST: Page 70

■ ADDITIONAL CME/CE: Pages 59, 65

Turn to page 22 for additional information on this month’s CME/CE courses.

CMECE

FEATURE


T he introduction of highly active antiretro-viral therapy (HAART) has transformed HIV infection from a rapidly progressive

life-threatening illness to a chronic manageable condition. More and more persons are growing older with HIV infection. The CDC estimates that more than 1 million people are living with HIV infection in the United States. Approximately 29% of those infected with HIV are older than age 50 years, and the number of older Americans with HIV infection is on the rise. In the next fi ve years, the number of Americans older than age 50 years is projected to constitute 50% of those infected with HIV.1,2 The demographic shift in those affected by HIV is attributed to the aging of the baby boom generation and to medical advancements in antiretroviral therapy that are allowing HIV-infected adults to remain productive longer. Older individuals with HIV are dealing with the effects of age while on HAART and will endure unique side effects because of their age, comorbidities, and other prescribed medications.3,4 According to

some data, up to 75% of deaths among HIV-infected adults taking antiretroviral medications are due to comorbidities, not AIDs-defi ning conditions.5

Comorbidities of the HIV-positive older adultWith age comes physiologic changes as well as susceptibility to certain chronic diseases. Approximately 80% of older adults have at least one chronic health condition, and 50% have two or more. Cardiovascular conditions (e.g., hypertension, coronary artery disease, and stroke) are the most common causes of morbidity and mortality in the older age group. Diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), and osteoporosis are also common in older adults. These conditions usually require prescrip-tion medications. Older adults commonly take four to fi ve prescription medications in addition to OTC medications daily.6 For many HIV-positive older adults, HAART is added to a regimen of other medications. Researchers are attempting to answer questions about how HAART will affect the aging adult, infl uence comorbid conditions, and interact with other medications.

HAART medications and their mechanisms of actionThe multidrug combinations of HAART can suppress the HIV viral load to undetectable levels and stop the destruction of CD4 T lymphocytes. There are six categories of HAART agents: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), fusion inhibitors (FIs), and chemokine coreceptor 5 (CCR5) antagonists. The drugs in each category attempt to interrupt the life cycle of HIV at a different point, and when used together, there is an additive effect (Figure 1).7,8

Reverse transcriptase inhibitors (RTIs) block the activ-ity of reverse transcriptase, an enzyme used by the virus to build new DNA from its RNA. PIs inhibit the activity of viral enzymes that cleave new proteins for fi nal assembly into new HIV virions. Entry inhibitors, which include FIs and CCR5 antagonists, block entry of HIV into the cell membrane, preventing infection of uninfected cells.

Achieving viral suppression requires use of HAART regimens with three drugs from two or three different cat-egories. Some HAART agents are available as fi xed-dose combinations in order to reduce the number of pills the patient must take. The current standard for formulating a HAART regimen recommends the use of either a PI or an NNRTI in combination with two NRTIs.9 The activity

of some PIs is “boosted” by the addition of the PI ritonavir (Norvir) to the regimen. In this therapeutic strategy, a small dose of ritonavir is given concurrently with another PI to pharmacologically enhance the PI effect. For many of the PIs, ritonavir-boosting results in improved drug levels that can increase effi cacy. However, increased exposure to PIs carries with it the potential for increased toxicity.10 Guidelines for the use of antiretroviral agents in adults infected with HIV-1 can be found at the AIDSinfo Web site.8

How does HAART affect the older adult?As with many other medications, nausea and vomiting are common side effects associated with HAART. However, these symptoms are transient and can be alleviated by adjusting the patient’s mealtimes relative to medication administration. Allergy, a possible side effect of any medica-tion, may also be experienced early in the HAART regi-men. Different agents can be substituted when a patient is exhibiting signs of allergy.

The most common adverse effects associated with HAART involve metabolic abnormalities.11 Some HAART medica-tions have direct effects on lipid metabolism, insulin uti-lization, and bone formation. Specifi c types of HAART medications are known to increase risk of cardiovascular disease (CVD), diabetes, and osteoporosis. Hepatotoxicity


FIGURE 1. Different points in the HIV life cycle at which HAART medications work

New HIV isreleased here.

Protease inhibitors work here to stop

HIV protein assembly.

CCR5 antagonists work here.

Fusion inhibitors work here.

Integrase strand transfer inhibitors

work here to stop HIV DNA from integrating

into CD4 DNA.

Reverse transcriptase inhibitors work here

to stop HIV RNA from turning into DNA.

CD4 T cell

CD4 Receptor

CD4 T cell under attack by HIV

CMECE HAART MEDICATIONS

has been shown to occur with HAART, mainly in patients with concomitant hepatitis B or hepatitis C. In some stud-ies, nephrotoxicity is associated with HAART, but renal problems are often reversible with discontinuation of the drugs. HAART has also been linked to esophagitis and gastroesophageal refl ux disease (GERD).12

Cardiovascular side effects. Patients on HAART are at increased risk of developing an unfavorable lipid profi le. PIs and NNRTIs have been associated with dyslipidemia (elevated serum triglyceride, total cholesterol, and LDL levels and reduced HDL levels). The clinician needs to educate patients about cardioprotective nutrition and exercise.

A condition known as lipodystrophy affects 40% to 80% of persons with HIV who are being treated with HAART.13-16 Lipodystrophy is a disturbance in the way the body produces, uses, and stores fat. There are two different kinds of lipo-dystrophy: lipoatrophy and lipohypertrophy. In lipoatrophy, fat is lost from particular areas of the body, particularly the arms, legs, face, and buttocks. In lipohypertrophy, also known as hyperadiposity, fat accumulates in particular parts of the body, especially the abdomen, breasts, and back of the neck. Lipodystrophy is often accompanied by insulin resistance, hyperinsulinemia, and hyperglycemia. The metabolic dis-turbances and central fat accumulation are the same as those seen in metabolic syndrome, a condition that predisposes a person to CVD and diabetes.11,17,18

Insulin resistance and diabetes. The prevalence of hyperglycemia and diabetes mellitus is signifi cantly higher in persons treated with HAART than in the general population. Insulin resistance was one of the fi rst metabolic complications reported with HAART. Specifi c antiretrovirals can increase insulin resistance through two principal mechanisms: either directly, by interfering with insulin signaling at the cellular level; or indirectly, as a consequence of lipodystrophy and associated metabolic syndrome.19 Although PIs are the drug class usually implicated in insulin resistance, some studies have shown an association between increased risk of diabetes and cumulative exposure to NRTIs.20 Given the current epidemics of obesity and diabetes in this country, PIs and NRTIs should be used with caution in patients at risk of diabetes. Periodic measurement of body weight and lipid and glucose levels is necessary. Insulin resistance can result in hyperglycemia.

Effects on bone. Osteopenia and osteoporosis resulting from decreased bone mineral density (BMD) have been found in patients taking HAART. Results of a recent investigation of 670 adults on HAART who were followed for fi ve years showed that osteopenia developed in 18% and osteoporosis

developed in 29%. Factors associated with bone loss were age, male sex, low BMI, and use of specifi c HAART agents (PIs, NRTIs, and NNRTIs).21 Some of the strongest data regarding the association of HAART with BMD reductions have been observed with the NRTI tenofovir (Viread). Tenofovir treatment has been shown not only to decrease BMD but to increase urinary calcium excretion as well.22,23

Hip fracture is more common in HIV-positive adults on HAART than in the general population. Bisphosphonates (such as alendronate [Fosamax]), calcium, and vitamin D have been shown to prevent bone loss.24 In addition, the patient should be encouraged to undergo annual dual-energy x-ray absorptiometry to measure BMD, and weight-bearing exercises should be prescribed to enhance bone strength.

GI effects. HAART has also been associated with gastroesophageal refl ux and esophagitis. A recent research investigation reviewed endoscopies of 706 HIV-infected patients; 467 of the patients were on HAART and 239 were not. Signifi cant increases were seen over time in the frequencies of refl ux symptoms, GERD, infl ammatory gastropathy, gastric ulcer, and Helicobacter pylori infection in those treated with HAART.12

Esophagitis, gastritis, and GERD are common in patients older than age 50 years. Individuals often take OTC medica-tions, such as histamine2-receptor blockers (e.g., cimetidine [Tagamet]) or proton pump inhibitors (e.g., lansoprazole [Prevacid]). HAART-treated individuals may take these OTC drugs without understanding that signifi cant drug-drug interactions can occur. Taking a gastric acid-reducing agent can lower blood concentrations of HAART, which may lead to inadequate viral suppression or adverse events. Studies indicate that the PIs atazanavir (Reyataz) and nelfi navir (Viracept) are contraindicated with many acid-suppressive drugs. Educating patients about the importance of reporting the use of any acid-reducing agents, whether prescription or OTC, is essential to optimizing the treat-ment of HIV disease.

The incidence of drug-induced liver toxicity is not well-known for most antiretroviral medications. Moreover, the contribution of each particular drug in an HAART regimen to the development of hepatotoxicity is diffi cult to determine. One of the liver abnormalities linked to the use of antiretro-virals is the elevation of liver aminotransferases. Liver toxicity is more frequent among subjects with chronic hepatitis C and/or B. Liver disease is now the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14% to 18% of all deaths in this population.25


Continues on page 26


TABLE 1. HAART drug-drug interactions HIV drug category Names of drugs Common drug-drug interactions

Chemokine coreceptor 5 (CCR5) antagonist

Maraviroc (Selzentry)• Data still being collected; multiple drug-drug interactions. See prescription directions.•

Fusion inhibitor (FI) Enfuvirtide (Fuzeon)• Few drug-drug interactions•

Integrase strand transfer inhibitor (INSTI)

Raltegravir (Isentress)• Few drug-drug interactions•

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

Delavirdine (Rescriptor)• Efavirenz (Sustiva)• Eltravirine (Intelence)• Nevirapine (Viramune)• Rilpivirine (Edurant)•

Use caution with statin drugs; may increase statin level in blood. Monitor liver function • and possible myopathy, rhabdomyolysis.Use caution with warfarin; may increase or decrease warfarin effects.• Use caution with clopidogrel (Plavix). may decrease effects of clopidogrel. • Contraindicated. with dabigatran (Pradaxa) and rivaroxaban (Xarelto).

Nucleotide reverse transcriptase inhibitor (NRTI)

Abacavir (Ziagen)• Didanosine (Videx) • Emtricitabine (Emtriva)• Lamivudine (Epivir)• Stavudine (Zerit)• Tenofovir (Viread)• Zalcitabine (Hivid)• Zidovudine (Retrovir)•

Use caution with chlorpropamide (Diabinese), insulin resistance may increase risk of • hyperglycemia.

Protease inhibitor (PI)

Atazanavir (Reyataz)• Darunavir (Prezista)• Fosamprenavir (Lexiva)• Indinavir (Crixivan)• Lopinavir• Nelfi navir (Viracept)• Ritonavir (Norvir)• Saquinavir (Invirase)• Tipranavir (Aptivus)•

Use caution with statin drugs; may increase statin level in blood. Monitor liver function • and possible myopathy, rhabdomyolysis.Use caution with warfarin; may increase or decrease warfarin effects.• Use caution with clopidogrel; may decrease effects of clopidogrel. Contraindicated • with dabigatran and rivaroxaban. Use proton pump inhibitors and histamine• 2-receptor blockers with caution.Use caution with insulin; insulin resistance may increase risk of hyperglycemia.• Use caution with digoxin; can potentiate or antagonize digoxin.• Can increase calcium channel antagonist effect; monitor for hypotension, arrhythmias. • Use caution with beta blockers.• Erectile dysfunction drugs are contraindicated.•

Discerning the number of individual factors that may contribute collectively to liver damage is diffi cult in patients receiving antiretroviral therapy. Several drugs are combined in a given HAART regimen, making the attribution of hepatotoxicity to a particular drug challenging. Moreover, HIV-infected patients also may be receiving concurrent medications with potential for liver toxicity, such as antitu-berculosis (anti-TB) drugs, lipid-lowering agents, antifungals, antibiotics, and anticonvulsants.26 Periodic monitoring of liver enzymes is crucial.

Nephrotoxicity. The antiretroviral agents most strongly associated with direct nephrotoxicity include the NRTI tenofovir and the PI indinavir (Crixivan). Tenofovir and related nucleoside analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir and atazanavir are known to cause neph-rolithiasis, obstructive nephropathy, and interstitial nephritis.

Periodic measurement of serum creatinine is required. Patients with preexisting chronic kidney disease require close monitoring, dose modifi cation, and avoidance or cautious use of potentially nephrotoxic medications. Kidney dam-age related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent.27

Lactic acidosis. A rare side effect, lactic acidosis has been associated with HAART, particularly the NRTIs. The mechanism of NRTI-induced lactic acidosis is thought to be secondary to mitochondrial toxicity. Risk factors associated with increased incidence of lactic acidosis in HIV-infected patients include female sex, high-dose didanosine (Videx) or stavudine (Zerit), impaired renal clearance, low CD4 T-cell count prior to initiation of NRTI therapy, and concomitant hepatitis B or hepatitis C. Patients present with weakness, fever, abdominal pain, nausea, vomiting, and dyspnea.


HAART is effective only when the patient adheres to the recommended daily course of therapy. Failure to do so is a substantial barrier to its success.

Laboratory fi ndings include elevations in liver enzymes, serum lactic acid, amylase, lipase, and creatine kinase. Drug discontinuation will be necessary.28

Possible drug-drug interactions While drug interactions with HAART have been widely investigated for the PIs, information continues to emerge regarding NRTI and NNRTI drug interactions. However, there are fewer clinical data for the FIs, CCR5 antagonists, and the INSTIs (Table 1).

Anti-TB drugs. Tuberculosis is one of the most common opportunistic infections that occur in HIV-positive patients. Therefore, many HIV-positive patients require anti-TB drug treatment. Most interactions between HAART and anti-TB agents as well as other antimycobacterial drugs occur through the stimulation or inhibition of liver enzymes that make up the cytochrome P (CYP) 450 system. Rifampin and rifabutin (Mycobutin), used for the treatment of TB, are strong stimu-lants of the CYP450 enzyme system in the liver. Stimulation of the CYP450 enzymes causes increased breakdown of HAART agents. Concurrent administration of anti-TB drugs with PIs, NNRTIs, INSTIs, or CCR5 antagonists can decrease blood concentrations of the HAART agents. Rifabutin is a less potent inducer of CYP450 than rifampin and may be used as an alternative. There are no major interac-tions between rifampin or rifabutin and the NRTIs abacavir (Ziagen), emtricitabine (Emtriva), didanosine, lamivudine (Epivir), tenofovir, or zidovudine (Retrovir).29

Both HAART and antimycobacterial agents can have toxic side effects. Some of the toxic effects of antiretrovirals and anti-TB drugs are the same, making it diffi cult to determine the causative drug. Patients with chronic liver disease have higher rates of toxicity and need more frequent monitoring of liver function tests.

Antihyperlipidemia (statin) drugs. 3-hydroxymethyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitors, commonly known as statins, are antihyperlipidemia drugs often used in HIV-positive patients. Patients living with HIV are at risk for dyslipidemia as a result of the HIV itself and from treatment with PIs and NNRTIs.30 The statins are extensively metabolized by the liver CYP450 system, as are HAART agents. Drug-drug interactions between the statins and antiretroviral therapy must be considered when treating HIV or dyslipidemia. Liver toxicity is a possible side effect of both HAART and statins.31 High blood concentrations

of statins have also been associated with rhabdomyolysis, the breakdown of muscle tissue. When statins are needed, the lowest effective dosage should be used. Simvastatin (Zocor) and lovastatin (Mevacor), commonly used statin agents, are contraindicated with the use of PIs.32

Antihypertensives. Hypertension is common in patients older than age 50 years. The clinician should be aware of the potential interaction between PIs and beta blockers as well as between PIs and calcium channel blockers.

GI drugs. Concomitant use of acid-reducing drugs and HAART is common.33 A signifi cant drug interaction occurs between PIs and proton pump inhibitors and histamine2-receptor antagonists that are used to treat esophagitis and GERD. Acid-reducing agents decrease plasma PI concentra-tions, which can lead to inadequate viral suppression. The bioavailability of fosamprenavir (Lexiva), indinavir, lopinavir, nelfi navir, and tipranavir (Aptivus) has been reported to be negatively affected to varying degrees by certain acid-reducing agents.34 All proton pump inhibitors (e.g., lanso-prazole) and histamine2-receptor blockers (e.g., cimetidine [Tagamet]) should be used with caution when prescribed for patients taking HAART. Proton pump inhibitors should not be administered with the PIs atazanavir or nelfi navir or with the NNRTI rilpivirine (Edurant). A comprehensive list of drug-drug interactions with HAART is available from the University of Liverpool HIV Pharmacology Group.32

Care of patients on HAARTHAART is a multidrug regimen that is effective only when the patient adheres to the recommended daily course of therapy. Failure to adhere to treatment is a substantial barrier


AT A GLANCE● Older individuals with HIV are dealing with the effects of

age while on HAART and will endure unique side effects because of their age, comorbidities, and other prescribed medications.

● Each category of drugs attempts to interrupt the life cycle of HIV at a different point, and when used together, there is an additive effect.

● The current standard for formulating a HAART regimen recommends the use of either a PI or an NNRTI in combination with two NRTIs.

● Clinicians should also be aware of increased depression, which often develops in HIV-positive patients.

Patients who develop resistance can be changed to another drug in the same class; however, resistance often occurs across drug categories.


HIV-infected population will be experiencing age-related disorders. Adults on HAART are now living into old age with HIV. Older HIV-infected adults face unique health challenges stemming from age-related changes to the body that are accelerated by HIV infection, the side effects of HAART, and treatments for age-associated illnesses.

HAART is composed of a combination of three or four drugs from different categories: RTIs, PIs, INSTIs, CCR5 antagonists, and FIs. The medications of HAART comple-ment each other and are taken together to produce an additive effect. However, drug-drug interactions can occur when HAART is used with other medications. Because many older adults have comorbid conditions, they commonly take four to fi ve prescription drugs plus OTC medications daily. These prescription drugs are essential for such chronic conditions as CVD, diabetes, hypertension, COPD, and/or osteo porosis. With the population of HIV-positive older adults on the rise, clinicians need to be aware of the possible side effects of HAART and how other drugs interact with it. A growing body of research is emerging regarding the adverse effects, contraindications, and drug-drug interactions of the HIV medications. PIs have been well-investigated, but more data are needed regarding the side effects and interactions of drugs from the other medication categories that make up HAART. ■

Dr. Capriotti is a clinical associate professor in the Villanova University College of Nursing, Villanova, Pa., where Ms. Sheerin is a junior honors student.

References1. Centers for Disease Control and Prevention. HIV/AIDS among persons

aged 50 and older. Available at www.cdc.gov/hiv/topics/over50/resources/

factsheets/over50.htm.

2. Centers for Disease Control and Prevention. HIV surveillance report:

Diagnoses of HIV infection and AIDS in the United States and dependent

areas, 2009. Available at www.cdc.gov/hiv/topics/surveillance/basic.htm.

3. Vance DE, McGuinness T, Musgrove K, et al. Successful aging and the

to its success. In addition, maximal effi cacy of HAART requires adequate drug absorption and bioavailability. Lack of compliance in taking medications as prescribed diminishes viral suppression and allows the virus to mutate and develop resistance. Drug resistance is one of the most signifi cant threats to effective therapy. Patients who develop resistance can be changed to another drug in the same class; however, resistance often occurs across drug categories. Laboratory tests are performed when patients are not responding to drug treatment. Genotyping tests detect viral mutation, and phenotyping tests detect a reduction in the sensitivity of the virus to the drugs.35

Clinicians need to provide education and support to patients on HAART. Begin by explaining the importance of adhering to the regimen, and devise a medication schedule that works with the patient’s daily routine. Pillboxes and cell phones or other devices can be used to remind the patient of medica-tion times. Patients on the FI enfuvirtide (Fuzeon) need instruction regarding self-injection and rotation of injection sites. For follow-up of all patients on HAART medications, periodic telephone counseling can be helpful.

In addition to monitoring patients for comorbidities associ-ated with HAART and the drug-drug interactions previously discussed, clinicians should be aware of increased depression, which often develops in HIV-positive patients. The low emo-tional state is associated with nonadherence to the medication regimen. In order to inspire hope, educate patients regarding the ability of HAART to strongly suppress viral replication and increase CD4 T-cell counts. Individuals need to under-stand that HIV is a chronic disorder that is manageable with new treatments. Antidepressants have been shown to increase patient compliance with the HAART regimen. Be sure to inform patients that the OTC supplement St. John’s wort is contraindicated with all PIs, as are all erectile dysfunc-tion drugs. Tricyclic antidepressants and selective serotonin reuptake inhibitorss should be used with caution by patients on HAART. HAART, particularly PIs, can cause elevated blood levels of some antidepressants and lead to toxicity.36

SummaryEstimates indicate that by 2015, nearly half of individuals living with HIV in the United States will be 50 years of age or older. In the past, HIV-infected patients were mainly a young cohort of the population. Because of the increase in life expectancy of patients receiving HAART, however, the

WHAT DO YOU THINK?Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com. You will also see what your colleagues are saying.



20. Aboud M, Elgalib A, Kulasegaram R, Peters B. Insulin resistance and

HIV infection: a review. Int J Clin Pract. 2007;61:463-472.

21. Bonjoch A, Figueras M, Estany C, et al. High prevalence of and progres-

sion to low bone mineral density in HIV-infected patients: a longitudinal

cohort study. AIDS. 2010;24:2827-2833.

22. Mansky KC. Aging, human immunodefi ciency virus, and bone health.

Clin Interv Aging. 2010;5:285-292. Available at www.ncbi.nlm.nih.gov/pmc/

articles/PMC2946855/.

23. Jhaveri MA, Mawad HW, Thornton AC, et al. Tenofovir-associated

severe bone pain: I cannot walk! J Int Assoc Physicians AIDS Care (Chic).

2010;9:328-334.

24. Guaraldi G, Orlando G, Madeddu G, et al. Alendronate reduces

bone resorption in HIV-associated osteopenia/osteoporosis. HIV Clin

Trials. 2004;5:269-277. Available at thomasland.metapress.com/content/

md8v5dlgen3tbrhx/fulltext.pdf.

25. Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin

Gastroenterol Hepatol. 2010;8:1002-1012. Available at www.ncbi.nlm.nih.

gov/pmc/articles/PMC2997131/.

26. Núñez M. Clinical syndromes and consequences of antiretroviral-

related hepatotoxicity. Hepatology. 2010;52:1143-1155.

27. Izzedine H, Harris M, Perazella MA. The nephrotoxic effects of

HAART. Nat Rev Nephrol. 2009;5:563-573.

28. Patel V, Hedayati SS. Lactic acidosis in an HIV-infected patient receiving

highly active antiretroviral therapy. Nat Clin Pract Nephrol. 2006;2:109-114.

Available at www.nature.com/nrneph/journal/v2/n2/full/ncpneph0102.html.

29. Pozniak AL, Collins S, Coyne KM, et al. British HIV Association guidelines

for the treatment of TB/HIV co-infection 2009. Available at www.bhiva.org/

documents/Guidelines/TB/hiv_954_online_fi nal.pdf.

30. Blanco F, San Román J, Vispo E, et al. Management of metabolic complica-

tions and cardiovascular risk in HIV-infected patients. AIDS Rev. 2010;12:231-

241. Available at www.aidsreviews.com/fi les/2010_12_4_231-241.pdf.

31. Ray GM. Antiretroviral and statin drug-drug interactions. Cardiol Rev.

2009;17:44-47.

32. University of Liverpool Pharmacology Group, UK. HIV drug interac-

tions. Available at www.hiv-druginteractions.org.

33. van Lunzen J, Liess H, Arastéh K, et al. Concomitant use of gastric acid-

reducing agents is frequent among HIV-1-infected patients receiving

protease inhibitor-based highly active antiretroviral therapy. HIV Med.

2007;8:220-225.

34. Falcon RW, Kakuda TN. Drug interactions between HIV protease

inhibitors and acid-reducing agents. Clin Pharmacokinet. 2008;47:75-89.

35. Feinberg J. Management of newly diagnosed HIV infection. Ann Intern

Med. 2011;155: ITC41.

36. Watkins CC, Pieper AA, Treisman GJ. Safety considerations in drug

treatment of depression in HIV-positive patients: an updated review.

Drug Saf. 2011;34:623-639.

All electronic documents accessed April 15, 2012.

epidemiology of HIV. Clin Interv Aging. 2011;6:181-192. Available at www

.ncbi.nlm.nih.gov/pmc/articles/PMC3147048/.

4. Vance DE. Aging with HIV: clinical considerations for an emerging popu-

lation. Am J Nurs. 2010;110:42-47.

5. San Francisco AIDS Foundation. HIV/AIDS and aging: emerging issues

in research, care, treatment, and prevention. Available at www.sfaf.org/

hiv-info/hot-topics/hivision/hiv-and-aging-vienna-satellite-2010-07-19-

executive-summary.pdf.

6. Gu Q, Dillon CF, Burt VL. Prescription drug use continues to increase:

U.S. prescription drug data for 2007-2008. Available at www.cdc.gov/nchs/

data/databriefs/db42.pdf.

7. National Institutes of Health. FDA-approved anti-HIV medications.

In: HIV and Its Treatment. Available at aidsinfo.nih.gov/contentfi les/

HIVandItsTreatment_cbrochure_en.pdf.

8. National Institutes of Health. Guidelines regarding treatment of adults

and adolescents with HIV infection/AIDS. Available at aidsinfo.nih.

gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/14/

considerations-for-antiretroviral-use-in-special-patient-populations.

9. New York State Department of Health AIDS Institute and Johns

Hopkins University Division of Infectious Diseases. HIV clinical resource.

Available at www.hivguidelines.org.

10. Leider J, LeLacheur SF, Stewart J. Identifying and co-managing the

HIV-infected adult: a guidebook for the primary care clinician. The Clinical

Advisor. 2011;Suppl S1-S35.

11. Brown TT, Glesby MJ. Management of the metabolic effects of HIV and

HIV drugs. Nat Rev Endocrinol. 2011;8:11-21.

12. Nkuize M, De Wit S, Muls V, et al. Upper gastrointestinal endoscopic fi nd-

ings in the era of highly active antiretroviral therapy. HIV Med. 2010;11:412-417.

13. Mercier S, Gueye NF, Cournil A, et al. Lipodystrophy and metabolic disor-

ders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal:

a case-control study. J Acquir Immune Defi c Syndr. 2009;51;224-230.

14. Freitas P, Carvalho D, Souto S, et al. Impact of lipodystrophy on the

prevalence and components of metabolic syndrome in HIV-infected

patients. BMC Infect Dis. 2011;11: 246. Available at www.biomedcentral.

com/1471-2334/11/246.

15. Chen D, Misra A, Garg A. Clinical review 153: lipodystrophy in human

immunodefi ciency virus-infected patients. J Clin Endocrinol Metab. 2002;87;

4845-4856. Available at jcem.endojournals.org/content/87/11/4845.long.

16. Barbaro G. Visceral fat as target of highly active antiretroviral therapy-

associated metabolic syndrome. Curr Pharm Des. 2007;13;2208-2213.

17. Aberg JA. Cardiovascular complications in HIV management: past,

present, and future. J Acquir Immun Defi c Syndr. 2009;50:54-64. Available at

www.ncbi.nlm.nih.gov/pmc/articles/PMC2746916/.

18. Kotler DP. HIV and antiretroviral therapy: lipid abnormalities and

associated cardiovascular risk in HIV-infected patients. J Acquir Immune Def

Syndr. 2008;49 Suppl 2:S79-S85.

19. Feeney ER, Mallon PW. Insulin resistance in treated HIV infection. Best

Pract Res Clin Endocrinol Metab. 2011;25:443-458.

A boy, age 5 years, presented with a rash around his left armpit, torso, and upper arm that had been present for seven days, according to his mother.

Allergic contact dermatitis• Unilateral laterothoracic exanthem• Chickenpox• Fifth disease •

A girl, age 5 years, presented with a rash on her cheeks that had been present for one day. The girl’s mother thought the rash was likely an allergic reaction to a new product.

Contact dermatitis• Fifth disease• Hand-foot-mouth disease• Sixth disease •

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.

Red plaque with ulceration Asymptomatic eruption on the back

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.

Unilateral pink rash on the left side

Bright pink malar rash

See the full case at ClinicalAdvisor.com/DermDx0512B

WHAT IS YOUR DIAGNOSIS?

WHAT IS YOUR DIAGNOSIS?

See the full case at ClinicalAdvisor.com/DermDx0512A●

●


SPECIAL REPORT: JOE KOPCHA

SALARY SURVEY

With tax season comfortably in the rearview

mirror for most, it’s the perfect time to assess

your current fi nancial situation. Thanks to the

more than 9,000 nurse practitioners and physician

assistants who participated in our second annual

salary survey (nearly twice as many as last year),

you can see how your income compares with

that of your peers. We hope, you will be pleased

with the result. If not, fi nd a male dermatology

PA with 20 or more years of experience working

at an urban hospital in the West—he should be

able to fl oat you a loan.


How are you doing?

Practice areaFamily/adult medicine practitioners represented the most common practice area between both NP (Table 1) and PA (Table 2) respondents. In a departure from last year, geriatric medicine appeared among the top fi ve NP practice areas, replacing obstetrics/gynecology. The PA list remained unchanged.

ExperienceAs we saw last year, experience has little bearing on salary among NPs beyond the fi rst fi ve years of practice (Table 3). More experienced PAs see a slightly larger bump in income as their careers progress (Table 4).

TABLE 1. Average NP salary by practice areaPractice area Response percent Average salary

Family/adult medicine 33.5% $85,974

Pediatrics 6.1% $77,282

Women’s health 5.1% $78,390

Geriatric medicine 4.1% $92,503

Oncology/hematology 3.8% $94,831

TABLE 3. Average NP salary by experience levelYears of experience Response percent Average salary

<5 31.7% $84,944

6-10 20.8% $89,834

11-15 22.7% $91,632

16-20 11.6% $90,693

>20 13.2% $88,528

TABLE 2. Average PA salary by practice areaPractice area Response percent Average salary

Family/adult medicine 24% $89,044

Emergency medicine 9.5% $107,904

Orthopedic medicine 7.1% $100,265

Urgent care 4.6% $98,331

Dermatology 3.7% $110,204

TABLE 4. Average PA salary by experience levelYears of experience Response percent Average salary

<5 39.9% $88,657

6-10 20.7% $98,031

11-15 15.2% $100,186

16-20 7.7% $100,017

>20 16.5% $101,916

SALARY SURVEY 2012


TABLE 5. Average NP salary by practice settingPractice setting Percent response Average salary

Offi ce 24.7% $84,568

Clinic–standalone 16.7% $85,418

Clinic–hospital 15.7% $93,421

Hospital 14.2% $98,288

Walk-in/ambulatory 5.6% $85,585

TABLE 6. Average PA salary by practice settingPractice setting Percent response Average salary

Offi ce 23.6% $101,568

Clinic–standalone 22.7% $91,833

Clinic–hospital 18.8% $93,023

Hospital 16.0% $95,720

Walk-in/ambulatory 3.7% $92,052

SexThe majority of NP and PA respondents were once again women (92.1% and 66.2%, respectively). Men continue to outearn women across the board. The average male NP earned $100,316 last year, compared with $87,393 for a female. This discrepancy was even more pronounced for PAs: Men earned $105,902 on average, whereas women earned $89,728.

Geographic regionUsing the U.S. Census Bureau’s regional designations, the South was heavily represented among survey respondents (Figures 1 and 2). Average salaries had only slight regional variance, particularly among PAs.

Practice settingIn a near duplication of last year’s results, offi ce-based NPs (Table 5) and PAs (Table 6) were best represented in our survey. While hospital-based NPs earned higher salaries than offi ce-based NPs, the opposite was true for PAs.

Practice locationUrban clinicians earned slightly higher salaries than their suburban and rural counterparts. Among NP respondents, 40.8% described their work environment as urban (average salary $91,295), 35.0% as suburban (average salary $87,561), and 24.2% as rural (average salary $85,579). The PA audience broke down as 40.7% urban (average salary $96,087), 40.4% suburban (average salary $94,734), and 18.9% rural (average salary $95,042).

FIGURE 2. Average PA salary by geographic regionFIGURE 1. Average NP salary by geographic region

South39.74% response

$88,766 average salary

South35.15% response

$96,638 average salary

Midwest21.86% response$85,579 average salary

Midwest20.12% response$92,342 average salary

Northeast21.91% response$93,461 average salary

Northeast22.26% response$92,461 average salary

West16.49% response$93,353 average salary

West22.47% response$98,765 average salary

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Job mobilityThe proportion of NPs (Figure 3) and PAs (Figure 4) who move from job to job throughout the week was nearly identical to what was shown in last year’s survey.

History and the futureOverall, clinicians remain optimistic about their fi nancial future. In a slight uptick from last year’s results, just over 46% of NPs (Figure 5) and 50% of PAs (Figure 6) reported an increase in income over last year.

When asked about their predictions for next year, the vast majority of NPs (Figure 7) and PAs (Figure 8) expect their income to rise or remain fl at.

FIGURE 3. Do you work at multiple locations (NPs)?

FIGURE 5. Did you earn more money this year (NPs)?

FIGURE 7. Do you expect to earn more money next year (NPs)?

FIGURE 8. Do you expect to earn more money next year (PAs)?

FIGURE 6. Did you earn more money this year (PAs)?

FIGURE 4. Do you work at multiple locations (PAs)?

36.5%

40.0%

46.2% 40.5%

34.5%

13.7%

4.0% 3.8%

14.8%

38.6%

63.5%

46.3%

49.8% 55.7%

50.7%

61.4%

Yes

No

More

Less

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More

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More

Less

Same

More

Less

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Yes

No

SALARY SURVEY 2012


Weekly outputIn addition to requests for fi nancial information, we included a couple of questions to give us a sense of the average clinician’s workweek. Just like last year, there was little variation in the number of hours our readers put in. On average, approximately 80% of NPs and PAs work between 30 and 50 hours per week.

A more diverse picture emerged with regard to the number of patients seen per week, but the NP (Figure 9) and PA (Figure 10) breakdowns remained similar.

CongratulationsThe winner of the random drawing for a $50 American Express Gift Cheque is Marianne Adolf, a women’s health NP from Hazelwood, Mo. Consider it a head start on next year’s income. Thanks to all who participated in this exercise.

Mr. Kopcha is the editor of The Clinical Advisor.

Finally, prescription-writing behavior stayed consisted across all disciplines. More than two thirds of NPs (Figure 11) and PAs (Figure 12) write fewer 75 prescriptions per week.

FIGURE 9. Number of patients seen per week (NPs) FIGURE 10. Number of patients seen per week (PAs)

FIGURE 12. Number of prescriptions written per week (PAs)

FIGURE 11. Number of prescriptions written per week (NPs)

17.4%

22.7%

16.4%18.0%

26.5%25.5%

36.3% 36.1%

31.6%25.4%

36.1% 31.1%

14.6% 10.9%

6.5% 9.3%

7.6% 9.5%

3.4% 6.2%

3.6% 5.3%

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126-200

76-125

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Blood glucose monitoring is recommended for patients with type 2 diabetes who take insulin.

In the real world, primary-care clinicians have only a few minutes during each appointment to devote to helping patients with diabetes

improve glycemic control. The wise use of today’s technology can help make the most of those minutes. This article reviews some of the diabetes-related technologies available to patients and providers and recommends strategies provid-ers can use to optimize patient care. Blood glucose monitors With more than 60 models of blood glucose monitors on the market, most providers are unable to keep up with the details of all of them. 1 In choosing a blood glucose monitor, consider the patients’ insurance coverage to ensure that he or she will not have to pay out of pocket for test strips, which cost about $1 each. Typically, as long as the patient uses a system that is included in the insurance plan’s formulary, the copay-ment is affordable. A good strategy to follow if you’re not sure what system to prescribe is to write nonbranded prescriptions for a “blood glucose monitoring kit” and “blood glucose test strips.” This gives the patient and the pharmacy some fl exibility in choosing the brand based on features the patient prefers while keeping the copayment affordable.

The amount of digital storage in blood glucose monitors varies. Most providers focus on analyz-ing the most recent records. This is rational, not only because time is limited but also because clinicians need to respond to what is happening now, not what happened a month ago. Digital

Optimizing technology for diabetes care Advancements in diabetes care abound, but busy practice schedules make staying current diffi cult. Follow these strategies to stay ahead.

FEATURE: BETSY B. DOKKEN, NP, PHD

DIABETES TECHNOLOGY


storage of blood glucose results will help improve glycemic control only if those results are analyzed systematically. Some manufacturers provide free data-management software pro-grams to patients, while others require the programs to be purchased separately. These programs allow patients to record such aspects of their diabetes regimen as insulin types and dosages, carbohydrate intake, and physical activity.

E ncourage patients who rely on a monitor’s digital memory (in lieu of a paper log) to download their results on a regular basis to analyze the data for patterns. A list of blood glucose results without corresponding information on medications, meal timing, carbohydrate intake, and unusual physical activity is often more confusing than benefi cial to diabetes manage-ment. The time-and-date stamp on the patient’s monitor must also be set correctly to interpret the electronic records.

In the clinic, using the monitor’s memory to infl uence management decisions can be tricky. Once the intake process is complete, downloading the meter and reviewing the electronic data takes too long to be considered during that appointment. Moreover, scrolling back in the moni-tor’s memory produces a string of meaningless numbers. One practical approach is to include a meter download in the intake process. Typically, sales representatives from the manufacturing companies are eager to train clinic staff in how to download data from patients’ blood glucose moni-tors. The provider can choose the amount of data and the preferred format for the printout, and staff members can present this report with the patient’s intake history. Having this information at the beginning of the visit can mean the difference between a productive visit and a futile one.

Does self-monitoring improve glycemic control? Although blood glucose monitoring is not exactly new technology, confusion still lingers regarding its usefulness. The literature in this area is controversial. 2-7 Blood glucose monitoring is the standard of care in patients with type 1 diabetes and is recommended for patients with type 2 dia-betes who take insulin. 8 Clinicians typically use their own judgment when advising monitoring to patients with type 2 diabetes who are not taking insulin. Consider whether the patient is at risk for hypoglycemia. (If the patient is taking a sulfonylurea, monitoring should be available to identify and/or prevent hypoglycemia.) Another factor infl uenc-ing the decision to monitor is how the results will be used to improve glycemic control. For example, if the patient’s current treatment includes adjustment of basal insulin, the clinician may need only one fasting blood glucose result per day. If the current plan is to tailor carbohydrate amount or

prandial therapy to target postprandial glycemic control, preprandial and postprandial blood glucose testing will be necessary. Because this technology is expensive, blood glu-cose results should be requested only when they will affect clinical decision making or patient self-management.

Patients who are willing and able to adjust their lifestyle choices and diabetes treatment based on glucose results receive vastly more benefi t from monitoring blood glucose than those who are not. Until patients can autonomously make lifestyle and treatment adjustments, diabetes educators can assist primary-care providers in training patients to analyze and interpret blood glucose test results.

Lancets and lancing devices Most patients report that blood glucose monitoring is more diffi cult than taking insulin injections. Finger-sticks are painful, and minimizing this pain may lead to improved patient adherence to the treatment plan. Three factors impact the fi nger-stick procedure: the amount of sample

FIGURE 1. Insulin-connecting peptide, or C-peptide, is the connector between the two chains of the proinsulin molecule.

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DIABETES TECHNOLOGY


improved patient care, point-of-care testing eliminates a trip to the laboratory for the patient and saves the time the offi ce staff might spend tracking down a missing result. Finally, if patients must pay out of pocket for laboratory services, the point-of-care test is more affordable.

Insulin pens Patients who take only one or two daily injections (e.g., basal insulin) may not benefi t greatly from using a pen rather than a syringe and vial. However, patients who take multiple daily insulin injections almost certainly inject while away from home. For these individuals, insulin pens can dramatically improve acceptance of—and adherence to—the treatment regi-men. Although several insulin pens are reusable, with separate insulin cartridges, most are now prefi lled and disposable.

To use a pen, a special needle is screwed onto one end of the reservoir that contains insulin. The dose is dialed, the needle is inserted into the subcutaneous space, and a button is pushed to complete the injection. Some insurance plans charge higher copayments for pens, while others require prior authorization for coverage. Plans that require prior authoriza-tion are typically looking for a medically necessary reason that the patient cannot safely use a syringe to draw insulin out of a vial and inject it. For example, if a patient has a tremor or sensory neuropathy in the fi ngers, using an insulin vial and syringe and injecting the accurate dose is very diffi cult, if not impossible. Poor visual acuity may also qualify a patient for insulin pens through the insurance plan.

Plans that require prior authorization for insulin pens usu-ally will not accept improved patient convenience or adher-ence as a valid reason for the exception. In that situation, a

required by the monitoring system, the lancet device, and the lancet itself.

The size of the blood sample required for monitoring has drastically decreased compared with the amount needed for fi rst-generation monitoring systems. Most current systems require only ≤0.5 µL, approximately the size of the head of a pin. Newer lancet devices minimize motion of the lancet as it penetrates the fi ngertip. Smaller gauge and shorter lancets help minimize the pain associated with the procedure. Most patients just use the brand of lancets and lancing device that come in the kit with the monitor. However, these lancets may not be optimal for that patient. Test strips are expensive, but a new lancet device is a one-time only cost (typically $20-$30), and even the smallest lancet, the Tiniboy (Health Innovation Ideas, Claremont, Calif.), is only $13 for a box of 100, so patients should use the ones that suit them best. Some patients fail to use a new lancet for each fi nger-stick. Aside from the potential for infection, reusing a lancet dulls it and increases pain over time. If your patient reports problems with self-monitoring, troubleshooting each of these factors may be worthwhile, as it will allow you to recommend changes in the patient’s monitoring system.

Point-of-care hemoglobin A 1c testing The American Diabetes Association (ADA) and other expert groups recommend measuring hemoglobin A1c (HbA1c) in every diabetic patient at least twice yearly. Patients whose glycemic control is poor (HbA1c >6.5%-7%) should have an HbA1c determination every three months. 8 Since HbA1c pro-vides a measure of overall glycemic control, a current result can improve clinical decision making. Consider a patient who is in the clinic and reports that while his blood glucose results are usually within his target range, sometimes they are a little high. Would you make a different management decision if you knew the HbA1c was 6.8% that day vs. 7.8%? You probably would. This is the real benefi t of point-of-care HbA1c testing: It helps make every visit more productive. 9,10 Point-of-care HbA1c tests take fi ve to 10 minutes, including the time for the fi nger stick. If diabetic patients are identifi ed ahead of time, staff members can collect the sample during the intake process and the provider can start the visit and have the result in time for management decisions.

Point-of-care HbA1c testing has been granted a waiver under the Clinical Laboratory Improvement Amendment. The HbA1c machine costs about $3,000, and the disposable cartridge for each sample costs approximately $12. The charge code for a point-of-care HbA1c test is 83036, and reimburse-ment for each test ranges from $13 to $20. In addition to

Do you recommend medical apps for smartphones to help your patients manage diabetes?

For more polls, visit www.ClinicalAdvisor/polls

POLL POSITION

Yes

No

Not yet, but I'd like to learn more

13%

26%

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n=38


bolus dose). Specifi c features of insulin pumps vary among manufacturers. A detailed description of each is beyond the scope of this article, but they all share basic functions.

Most insulin pumps are about the size of a pager and house a disposable syringe (insulin reservoir) connected to a length of tubing. The pump is connected to the patient via a can-nula on the end of the tubing, which is inserted into the subcutaneous space, usually in the abdomen. The insertion is similar to that of an IV cannula; the entire unit consists of a sharp needle surrounded by a plastic cannula. The unit is inserted intact, and the needle is removed, leaving the soft cannula in place. The cannula is taped down and remains in place for two to three days, after which it must be changed. The OmniPod (Insulet Corp, Bedford, Mass.) insulin pump is the exception; it requires no tubing.

Because insulin is delivered continuously, there is no need for long-acting insulin. A bolus dose must work quickly, either to cover a meal or to correct hyperglycemia. Only rapid-acting insulin analogs are typically used in pump therapy. Three dif-ferent rapid-acting insulin analogs are currently approved by the FDA for use in pumps: Insulin lispro (Humalog), insulin aspart (NovoLog), and insulin glulisine (Apidra). Although they have slightly different pharmacokinetics, all are effective and appropriate choices for pump therapy.

patient may choose to pay out of pocket for a limited supply of insulin pens to use only when away from home and use a vial and syringe for the remainder of the injections.

Syringes and needles Selection of the appropriate insulin syringe can make a dif-ference in the patient’s acceptance of the treatment regimen. Insulin syringes now come in three sizes that hold 30, 50, or 100 units of insulin, respectively. Needles come in a wide variety of lengths and gauges. Most patients prefer the short (5- to 8-mm) needle and the fi nest gauge available (31-32 G). However, the very fi ne needles bend easily, and this may cause problems for a patient with limited manual dexterity. Syringe size should be determined by the patient’s insulin regimen. For example, patients who take small amounts of a rapid-acting insulin analog several times daily but are given syringes that hold 1 cc (100 units) will have a diffi cult and potentially stressful experience measuring and taking their insulin. Patients taking basal/bolus insulin may need syringes of two different sizes—a larger size for basal doses and a smaller size for bolus doses. Insulin pumps Many clinicians have been waiting decades for the holy grail of diabetes treatment: a closed-loop insulin delivery system, or artifi cial endocrine pancreas, that would sense the blood glucose level and automatically infuse the correct amount of insulin at all times. Unfortunately, a closed-loop system remains on the horizon, but current insulin pumps offer many advantages to some patients. When discussing pump therapy, begin by deter-mining what the patient understands about the benefi ts and limitations of insulin pumps. Patients who are underinformed may assume that currently available pumps are closed-loop systems. When they learn that this is not yet the case, some may no longer be interested.

An insulin pump is a different and sometimes (but not always) better option for insulin delivery. Insulin pumps deliver tiny amounts of insulin continuously, typically a fraction of a unit per hour (the basal rate). Patients are taught to program the pump for larger doses to cover the amount of carbohydrates in meals or to correct hyperglycemia (a

“This article hits on all the technological advances available in the management of diabetes and gives valuable tips on using them effi ciently. I found it to be a wonderful reference from the perspective of both the patient and the provider.”

Eve Roelker, NP, Tucson, Ariz. (via ClinicalAdvisor.com)

PEER PERSPECTIVES

AT A GLANCE● For patients who are having problems with self-monitoring,

troubleshooting each of the factors that impact the fi nger-stick procedure (amount of sample, lancet device, lancet) may allow you to recommend changes.

● Point-of-care hemoglobin A1c testing helps make every visit more productive.

● If cost is an issue, patients may choose to pay out of pocket for a limited supply of insulin pens to use only when away from home.

● Medicare and other third-party payers require proof of insulin defi ciency prior to approving coverage of insulin pump therapy.


DIABETES TECHNOLOGY


allowing the individual to make adjustments to prevent and treat hyperglycemia and hypoglycemia. 17

Most CGM devices can be programmed for a high and a low threshold, outside of which an alarm will sound to alert the patient of the need for treatment or adjustment. These systems are particularly useful for patients with hypoglycemia unawareness—that is, those who lack early warning signs of hypoglycemia and sometimes experience cognitive impair-ment as the fi rst warning of decreased blood glucose. 17-19

CGM devices have also been used successfully in a pediatric population. 20 Overall, however, studies of the ability of CGM devices to improve overall glycemic control have not been consistently positive. 18 Candidates for CGM devices should be chosen carefully. The American Association of Clinical Endocrinologists recommends that candidates for personal CGM include:

Patients with hypoglycemia unawareness or frequent • hypoglycemia Patients with excess glycemic variability• Patients who require HbA• 1c-lowering and would be at extreme risk if they were to become hypoglycemic Women who are planning to become pregnant or who • are already pregnant. 17 The full benefi t of CGM is attainable only when it is used

under the supervision of a provider or a diabetes educator who is knowledgeable, experienced, and willing to take the necessary time to analyze and interpret the copious amounts of data available from these systems.

Diabetes education Diabetes education is critically important in the care of patients with diabetes. Partnering with a diabetes educator or a diabe-tes education program is an excellent strategy for improving patient care. As reviewed here, many technological options

Patients beginning pump therapy are required to complete a rigorous training program that is arranged for and pro-vided by the manufacturer. Training sessions are typically conducted by certifi ed diabetes educators with advanced training in pump therapy.

Although insulin pumps are usually thought of as a treat-ment for type 1 diabetes, many patients with type 2 diabetes may also benefi t. Because type 2 diabetes is a progressive disease, pancreatic beta-cell function wanes over time. Patients who have had type 2 diabetes for a long time may be insulin-defi cient, like their type 1 counterparts. In addi-tion, patients with type 2 diabetes who require multiple daily injections for glycemic control may be insulin-defi cient.

Medicare and other third-party payers require proof of insulin defi ciency prior to approving coverage of insulin-pump therapy. Defi ciency is determined by measuring the concentration of insulin-connecting peptide, or C-peptide, in the blood. Insulin is created from proinsulin by the cleav-age of a 31-amino acid peptide ( Figure 1 ). The peptide gets its name because it once “connected” the two chains of the proinsulin molecule. Insulin and C-peptide are localized within the same secretory vesicle in the beta cell and are secreted together into the circulation. Measurement of the plasma C-peptide concentration is therefore an indirect measure of endogenous insulin production and secretion.

For a detailed explanation of insulin-pump therapy, attend Medtronic MiniMed’s virtual pump school (pumpschool.minimed.com/index.tpl). Registration is required but is free. This is also an excellent tool to recommend to patients, either to help them make a decision regarding pump therapy or to provide a head start on training if they have already decided to start using a pump.

Continuous glucose monitors Continuous glucose monitoring (CGM) can improve glyce-mic control for people with erratic swings in blood glucose levels. 11-16 Two different strategies for CGM are available: professional and personal. Professional CGM equipment is owned by the health-care provider and is typically worn by the patient for three to fi ve days. With this system, the patient is unaware of the CGM results until the data are downloaded and analyzed by the provider. Personal CGM devices are owned by the patient, who has access to continuous results,





MAKING CONTACT

Nearly one-third of patients with diabetes have some type of dermatologic manifestation. To learn more, visit ClinicalAdvisor.com/CutaneousDiabetesSlideshow.

CLINICALSLIDESHOW


are available, and dedicated time and effort on the part of the educator are required to develop expertise in the selection and use of the appropriate tools for each patient. Diabetes educators stay abreast of current trends and can often co-manage patients when given the opportunity. For example, an educator may use a data-management system to help a patient optimize the blood glucose testing schedule and better evaluate a particular treatment regimen. In addition, the educator may recommend a change in treatment regimen that may help improve adher-ence, reduce adverse effects, or improve glycemic control. Some diabetes educators are also advanced-practice clinicians with prescribing privileges, so providers should determine, during the referral process, who will be making treatment changes.

To fi nd a diabetes educator near you, visit the website of the American Association of Diabetes Educators (www.diabe-teseducator.org), and click on “Find a Diabetes Educator.”

To fi nd a diabetes education program that has been certifi ed by the ADA, visit the ADA website (professional.diabetes.org/erp_zip_search.aspx). ■

Dr. Dokken is an assistant professor of medicine in the Section of Endocrinology and a principal investigator in the Diabetes Research Program, University of Arizona, Tucson. References 1. Bunker K, Toves K. Blood glucose meters. Diabetes Forecast. 2011;64:30-42.

2. Waldron-Lynch F, Dinneen S. Self-monitoring of blood glucose did not

improve glycaemic control in patients with type 2 diabetes not treated

with insulin. Evid Based Med. 2008;13:7. Available at ebm ebm.bmj.com/

content/13/1/7.long.

3. Guerci B, Drouin P, Grangé V, et al. Self-monitoring of blood glucose

signifi cantly improves metabolic control in patients with type 2 diabe-

tes mellitus: the Auto-Surveillance Intervention Active (ASIA) study.

Diabetes Metab. 2003;29:587-594. Available at www.em-consulte.com/

article/80262.

4. Harris MI; National Health and Nutrition Examination Survey.

Frequency of blood glucose monitoring in relation to glycemic control in

patients with type 2 diabetes. Diabetes Care. 2001;24:979-982. Available at

care.diabetesjournals.org/content/24/6/979.long.

5. Karter AJ, Ackerson LM, Darbinian JA, et al. Self-monitoring of blood

glucose levels and glycemic control: the Northern California Kaiser

Permanente Diabetes registry. Am J Med. 2001;111:1-9.

6. McAndrew L, Schneider SH, Burns E, Leventhal H. Does patient blood glu-

cose monitoring improve diabetes control? Diabetes Educ. 2007;33:991-1011.

7. Murata GH, Shah JH, Hoffman RM, et al. Intensifi ed blood glucose

monitoring improves glycemic control in stable, insulin-treated veterans

with type 2 diabetes. Diabetes Care. 2003;26:1759-1763. Available at care.

diabetesjournals.org/content/26/6/1759.long.

8. American Diabetes Association. Standards of medical care in diabetes

—2010. Diabetes Care. 2010;33(Suppl 1):S11-S61.

9. Kennedy L, Herman WH, Strange P, et al. Impact of active versus usual

algorithmic titration of basal insulin and point-of-care versus laboratory

measurement of HbA1c on glycemic control in patients with type 2 diabe-

tes: the Glycemic Optimization with Algorithms and Labs at Point of Care

(GOAL A1c) trial. Diabetes Care. 2006;29:1-8. Available at care.diabetes-

journals.org/content/29/1/1.long.

10. Miller CD, Barnes CS, Phillips LS, et al. Rapid A1c availability improves

clinical decision-making in an urban primary care clinic. Diabetes Care. 2003;

26:1158-1163. Available at care.diabetesjournals.org/content/26/4/1158.long.

11. Bailey TS, Zisser HC, Garg SK. Reduction in hemoglobin A1C with real-

time continuous glucose monitoring: results from a 12-week observational

study. Diabetes Technol Ther. 2007;9:203-210.

12. Bode B, Gross K, Rikalo N, et al. Alarms based on real-time sensor

glucose values alert patients to hypo- and hyperglycemia: The Guardian

Continuous Monitoring System. Diabetes Technol Ther. 2004;6:105-113.

13. Bode BW, Gross TM, Thornton KR, Mastrototaro JJ. Continuous glu-

cose monitoring used to adjust diabetes therapy improves glycosylated

hemoglobin: a pilot study. Diabetes Res Clin Pract. 1999;46:183-190.

14. Deiss D, Bolinder J, Riveline JP, et al. Improved glycemic control in

poorly controlled patients with type 1 diabetes using real-time continuous

glucose monitoring. Diabetes Care. 2006;29:2730-2732. Available at care.

diabetesjournals.org/content/29/12/2730.long.

15. Neithercott T. Continuous glucose monitors. Diabetes Forecast.

2011;64:44-46.

16. Reach G. Continuous glucose monitoring and diabetes health out-

comes: a critical appraisal. Diabetes Technol Ther. 2008;10:69-80.

17. Blevins TC, Bode BW, Garg SK, et al. Statement by the American

Association of Clinical Endocrinologists Consensus Panel on continuous

glucose monitoring. Endocr Pract. 2010;16:730-745. Available at aace.meta-

press.com/content/dn0g3p34540303q5/fulltext.pdf.

18. Chico A, Vidal-Ríos P, Subirà M, Novials A. The continuous glucose

monitoring system is useful for detecting unrecognized hypoglycemias in

patients with type 1 and type 2 diabetes but is not better than frequent

capillary glucose measurements for improving metabolic control. Diabetes

Care. 2003;26:1153-1157. Available at care.diabetesjournals.org/con-

tent/26/4/1153.long.

19. Kubiak T, Hermanns N, Schreckling HJ, et al. Assessment of hypo-

glycaemia awareness using continuous glucose monitoring. Diabet Med.

2004;21:487-490.

20. Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the

continuous glucose monitoring system: clinical decisions and glyce-

mic control after its use in pediatric type 1 diabetic subjects. Diabetes

Care. 2001;24:2030-2034.Available at care.diabetesjournals.org/con-

tent/24/12/2030.long.


These are letters from practitioners around the country who want to share their clinical prob-lems and successes, observations, and pearls with their colleagues. Responding consultants are identifi ed below. We invite you to participate.

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 [email protected]. 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.

ConsultationsSecondary malignancy following breast and uterine cancer . . . . . . . . .44

Drug-testing a teenager without permission . . . . . . . . . . . . . . . . . . . .44

Contraception for women older than age 50 years . . . . . . . . . . . . . . .45

Aspirin and clopidogrel after coronary bypass surgery . . . . . . . . . . .45

Clinical PearlsKeeping a bleeding child calm . . . . . .46

Eye-drop application tips . . . . . . . . . . . . 46

Illustrating coronary anatomy . . . . . . .46

Inside the ForumM AY 2 0 1 2


CONSULTATIONS

SECONDARY MALIGNANCY FOLLOWING BREAST AND UTERINE CANCER For the past eight months, a woman aged 78 years has experienced anterior thigh pain that intensifi es when she coughs. She has a history of uterine and breast cancers. X-ray reveals arthritis of the hip and an old bone infarct of the thigh at pain site. Could this be osteosarcoma?—LILLIAN RIDDICK, ANPC, PhD, Bridgeport, Conn.

Breast cancer and uterine cancer do not typically cluster with sarcoma. If the woman received radiation therapy, the risk for such secondary malignancy as sarcoma would be confi ned to the radiation fi eld. If you are concerned about sarcoma, an MRI is the best choice. Re-evaluation with an oncologist will determine if there is any recurrence.—Deborah L. Cross, MPH, CRNP, ANP-BC (163-1)

DRUG-TESTING A TEENAGER WITHOUT PERMISSIONI occasionally get requests from parents to drug-test their teenager at his or her annual physical without the child’s knowledge or consent. The parent usually advises, “Just say you’re doing a cholesterol check.” I tell the parent that this is not possible, and we discuss ways to initiate a conversa-tion regarding drug use. Drug-testing teenagers under false

OUR CONSULTANTS

Maria Kidner, DNP, FNP-C, is a nurse practitioner

with Cheyenne Cardiology Associates in

Cheyenne, Wyo.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program director, Gerontology NP pro-

gram, University of Pennsylvania School of Nursing, Philadelphia.

Eileen Campbell, MSN, CRNP, is associate program director, Family Health NP Program,

University of Pennsylvania School of Nursing, Philadelphia.

Philip R. Cohen, MD, is clinical associate professor of dermatology, University of Texas Medical Center,

Houston.

Rebecca H. Bryan, APRN, CNP, is a lecturer in the Family Health

NP Program, University of Pennsylvania School of Nursing,

Philadelphia.

Advisor Forum


are many low-dose options, including a pill containing only 10 μg of ethinyl estradiol (although there is no contraindication to using a 20 μg pill in this population).

Since OCs can mask menopause, the question is when to stop taking the pill. Some clinicians wait for menopausal symptoms to appear during the hormone-free week, after which the woman can stop OCs and see how her cycle responds. Another option is to periodically check follicle-stimulating hormone (FSH) level. If her FSH is >20 mIU/mL, most clinicians would feel confi dent tak-ing her off OCs, as the risk of pregnancy is virtually nil.—Mary Newberry, CNM, MSN (163-3)

ASPIRIN AND CLOPIDOGREL AFTER CORONARY BYPASS SURGERYWhat are the current evidence-based recommendations for aspirin and clopidogrel (Plavix) use following coronary artery bypass graft (CABG) surgery (both on- and off-pump procedures)? If possible, please include medication dosages and length of treatment.—MERIANNE LORENZEN, PA-C, Bryn Mawr, Pa.

Such studies as the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) (Circulation. 2004;110:1202-1208; available at circ.ahajournals.org/content/110/10/1202.long, accessed April 15, 2012), CASCADE (Clopidogrel After Surgery for Coronary Artery DiseasE) (Curr Control Trials Cardiovasc Med. 2005;6:15; available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1282584/, accessed April 15, 2012), and various meta-analyses of the effi cacy of clopidogrel and aspirin have addressed this topic. Multivariate analysis states that beyond 30 days, there is no signifi cant difference in the end point with the use of aspirin vs. aspirin and clopidogrel. The CURE study subgroup analysis showed no benefi t of clopidogrel following CABG. The

pretenses is unethical and against the policy of my practice setting, but I also believe it is illegal. Am I correct?—BETSY GROTH, APRN, Essex, Ct.

Drug-testing is legal and can be of diagnostic and therapeutic value in the context of treatment in individuals with substance-abuse problems or those in emergency situations. However, involuntary drug-testing is not recommended by the American Academy of Pediatrics (AAP) in a person considered competent, such as an older adolescent (Pediatrics. 2007;119:627-630; available at pediatrics.aappublications.org/content/119/3/627.long, accessed April 15, 2012). Parental permission is not suffi cient for involuntary screening. This is not to say that health-care providers should not screen for drug use and abuse. The AAP recommends the use of a validated screening tool like the CRAFFT, brief offi ce interventions, and appropriate referrals (Pediatrics. 2011;128:e1330-e1340; avail-able at pediatrics.aappublications.org/content/128/5/e1330.long, accessed April 15, 2012).—Julee B. Waldrop, DNP (163-2)

CONTRACEPTION FOR WOMEN OLDER THAN AGE 50 YEARSIs there a preferred contraceptive method for a woman older than age 50 years still having her period?—CONNIE KELLY, FNP, Franklin, N.Y.

The risk of a pregnancy is extremely low in such a woman. Nevertheless, birth control should be continued until menopause is confi rmed (clinically defi ned as one year of no menses in a woman of menopausal age). A 50-year-old woman who is otherwise healthy should be counseled on all birth-control options, but I would guide her away from such invasive and long-term methods as an intrauterine device or Essure, as she is likely on the verge of menopause. If she is interested in oral contraception (OC), there

Debra August King, PHD, PA, is senior physician assistant

of the Department of Cardiothoracic Surgery, Lenox Hill Hospital, New York City.

Sherril Sego, FNP-C, DNP, is a primary-care nurse

practitioner at the Department of Veterans Affairs Medical Center

in Kansas City, Mo.

Claire O’Connell, MPH, PA-C, teaches in the PA Program at the New Jersey Medical

School and Rutgers University, Piscataway, N.J.

Julee B. Waldrop, DNP, teaches at the University of

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

Mary Newberry, CNM, MSN provides well-woman gynecologic

care as a midwife with Prima Medical Group, Greenbrae, Calif.


CASCADE study compared aspirin alone with a combination of aspirin and clopidogrel and showed no signifi cant reduction in the pro-cess of saphenous vein intimal hyperplasia at one year. A retro spective analysis involving more than 15,000 patients concluded that the relative effect of combined treatment did not differ between on- and off-pump ( J Thorac Cardiovasc Surg. 2009;138:1377-1384). Other studies have concluded that there is no signifi cant difference between clopidogrel alone compared to aspirin with clopidogrel in (saphenous) graft patency (Ann Thorac Surg. 2009; 88: 59-62).

It has been recommended to use aspirin indefi nitely and clopi-dogrel for a minimum of one month to one year following CABG. However, each patient should be evaluated independently. The platelet count will dictate the therapy, as will the survival rate, coronary stent placement, risk of GI bleed, and a history of recent myocardial infarction. Aspirin dosage (81 mg vs. 325 mg) has not been clearly established, so assess each patient separately.—Debra King, PhD, PA (163-4)

CLINICAL PEARLS

KEEPING A BLEEDING CHILD CALMKeep dark washcloths in your fi rst-aid kit for treating child-hood cuts and bleeding injuries. The dark color prevents the child (and his or her parents and teammates or classmates)

from being startled by the amount of blood. You will be able to get the injured child to the sidelines, camp infi r-mary, or emergency department before symptoms of shock develop.—E. ROSELLEN DEDLOW, PNP, Gainesville, Fla. (163-5)

EYE-DROP APPLICATION TIPSI instruct patients to warm their eye-drop bottle by hold-ing them for fi ve minutes before use. This reduces thermal shock to the eyes and makes the drops much more easily tolerated. I also tell these patients not to blink for a minute or two after applying the drops and to keep their eyes closed and roll them around under the lids. This helps distribute the medicine and avoids washing it out with tears generated by blinking.—THOMAS URSCHEL, RPAC, Clarendon, N.Y. (163-6)

ILLUSTRATING CORONARY ANATOMYWhen explaining coronary anatomy to a patient, I compare the coronary arteries to the roots that feed a tree. By way of illustration, I wrap the fi ngers of one hand over the fi st of the other.—JOAN M. LACEY, ACNP, ANP, AACC, Greenville, S.C. (163-7) ■

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DVBIC.ORG BRAINLINEMILITARY.ORG [email protected] request copies, email [email protected]

Mild TBI Pocket Guide - Clinical tool for mTBI assessment and treatment

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CASE

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A clinician sues after being fi redDiscriminatory action is raised against an unsuspecting supervisor who was just doing her job.

LEGAL ADVISOR

BY ANN W. LATNER, JDFor more than 10 years, Ms. P, a 40-year-old nurse practitioner, enjoyed a stable and prosperous job in general practice. She had worked her way to a supervisory role at a small practice consisting of one physician, and she was well respected. Two years ago, Ms. P was forced to move on as the physician running the practice retired.

She took a new job at an area nursing home that was associated with a large medical facility. Within a short span of time Ms. P found herself unhappy with the work environment. She was used to being in charge and accustomed to working indepen-dently and was irritated at the level of supervision, amount of paperwork, and general work environ-ment. As a result, there was a good deal of confl ict between Ms. P and her direct supervisor, Ms.S, as well as with other coworkers.

During the course of her employment, Ms. P was reprimanded on several occasions. First, she was pulled aside when she accidently gave a patient medication that had been prescribed to another patient. Ms. P defended herself by saying that the physician orders here were unclear. The second instance occurred when a fellow employee reported

Ms. P for having caused undue trauma to a patient during a catheter removal. Ms. P felt that she was being treated unfairly, and complained to Ms. S, the nursing supervisor, about the nurse who had reported the incident. The supervisor dismissed Ms. P’s complaints.

Ms. P also complained about another coworker who she felt was rude and condescending to her. On several occasions she reported this nurse’s actions or comments, but Ms. S did not follow up nor discipline the other nurse. Ms. P wrote a letter to Ms. S complaining about her failure to respond to the issues with the other employee, but Ms. S still did not act.

The fi nal incident between the two happened after Ms. P wrote in a patient’s fi le that the doctor had ordered that the patient be transferred to the hospital. This was not, in fact, the case. Ms. P had been extremely concerned about the patient, and

Concerned that the physician was not attentive enough, the nurse practitioner ordered the transfer herself.

Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specifi c legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.


felt that the physician wasn’t attentive enough and that the patient needed an immediate transfer to the hospital, so she took it upon herself to write in the chart that the physician had been notifi ed and ordered the hospital transfer.

When it was discovered that the physician had not ordered the hospital transfer, Ms. P was terminated from her employment.

Ms. P became convinced that her fi ring—and her super-visor’s treatment of her—was racially motivated. Ms. P was white, and after ruminating on events she came to the conclusion that Ms. S, who was black, was ignoring her complaints and disciplining her based on her race.

Ms. P fi led a lawsuit against the nursing home, alleging race discrimination in violation of the Civil Rights Act.

The discovery process began and the nursing home pro-duced its records, which included Ms. P’s letter complain-ing that Ms. S was not paying attention to her complaints about her coworker. The disciplinary records regarding the three events for which Ms. P was reprimanded were also brought forward. Depositions began and each side had the opportunity to question potential witnesses.

After the discovery process, but prior to trial, the nurs-ing home attorneys fi led a motion to dismiss the lawsuit, claiming that no discrimination had taken place and that Ms. P had been fi red for cause. The court looked at all three incidents in order to determine whether any racial animus had been shown. In the fi rst incident, the court held that giving a patient the wrong medication was a clear violation of policy and procedure. In the second incident, involving the catheter removal, the court found no evidence of any racial bias regarding this incident. The fi nal issue—writing orders for hospital transfer in a patient’s chart—was also a clear violation of nursing home policy, the court said. The resulting action, the termination of Ms. P, contained no overtones of racial animus, the court found.

Finally, the court examined Ms. P’s claims that her super-visor had ignored her repeated complaints about a black coworker. The court pointed out that Ms. P claimed that had a different nurse (and she named a white one) complained, those complaints would have been heeded. Because of this, said the court, it was clear that Ms. P did not actually believe

that Ms. S’s failure to respond was based on race. The court also pointed out that Ms. S had previously initiated disci-plinary actions against other black employees, indicating that race was not a motivating factor. The court held that Ms. P failed to demonstrate that her termination was based on her race. The case was dismissed.

Legal backgroundTitle VII of the Civil Rights Act of 1964 prohibits employ-ment discrimination based on race, color, religion, sex, or national origin. In the simplest terms, Title VII prohibits employers from making employment-related decisions when the decision is motivated by a person’s protected trait. In order to establish a discrimination claim, the employee must show that there was unfair treatment based on pro-tected traits. In Ms. P’s case, her employer had clear and valid reasons for terminating her employment, which had nothing to do with race.

Protecting yourselfMs. P made several serious errors while working. Giving a patient the wrong medication was certainly grounds for discipline, even if the patient was not injured by the medi-cine. But the most egregious error that Ms. P made was to write physician orders in a patient’s chart when the physician had not ordered the action. By any standards, this clearly crossed the boundary from “mistake” to “intentional action.” Ms. P was terminated from her job because of what she did, not because of her race—and her perception that the supervisor was harder on her because she was black was a mischaracterization of the events and a refl ection of Ms. P’s unwillingness to take responsibility for her own actions. ■

Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

Title VII of the Civil Rights Act of 1964 prohibits employers from making decisions based on “protected” traits.

LEGAL ADVISOR


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“He’s a mental-health critic.”

UV rays have been found to be so destructive that the International Agency for Research on Cancer has labeled them “carcinogenic to humans,” which puts them in the same cat-egory as tobacco, mustard gas, and plutonium (monographs.iarc.fr/ENG/Classifi cation/index.php, accessed April 15, 2012). After recurrent damage, the cells in the body start to mutate, turning into cancer.

The three most common skin cancers are basal cell, squamous cell, and melanoma. Melanoma accounts for only 5% of all skin cancers, but it is the most dangerous.

Be sure your patients understand that cancer that grows on the skin is no less devastating than cancer that grows in the lungs, bones, or brain. One person dies every 62 minutes from mela-noma, which is the second most common cancer in females aged 15 to 29 years (www.skincancer.org/skin-cancer-information/skin-cancer-facts, accessed April 15, 2012). Tanning increases a girl’s risk of melanoma by 75% (www.cdc.gov/cancer/skin/basic_info/indoor_tanning.htm, accessed April 15, 2012).

We tell our kids that smoking is bad, that alcohol is dangerous…but we fail to tell them about the dangers of tanning beds. Health professionals need to help parents help their teenagers understand the long-term risks of tanning beds so these youths can ultimately save their beautiful skin—and their lives. ■


I graduated from college and began working as an inpatient oncology nurse. I will never forget when I saw my fi rst patient die from stage IV melanoma. I vowed on that day that I would never lie down again in a tanning bed.

But even at the age of 22, it was still too late. My boyfriend pointed out a mole on my hip that he noticed was bigger than it used to be, oddly shaped, and changing colors. I called my dermatologist to schedule a biopsy. Two days after Christmas, in 2010, he called me to tell me the results were in: I had melanoma.

My worst fear had come true. The next few months were a whirlwind of surgeries, PET scans, and trips to the oncologist. Fortunately, my melanoma was caught very early, and I am ecstatic to say that I am cancer-free. I am one of the few lucky ones.

Many states now require parental permission for teens to use tanning beds. But do parents really understand what they are consenting to? Girls following in my footsteps will come up with 100 reasons for their parents to grant per-mission, but we as health-care providers need to give parents one really big reason to say no.

Tanning beds emit two different types of ultraviolet (UV) rays: UVA and UVB. The UVB rays are responsible for more superfi cial damage, such as sunburns. UVA rays are what cause deeper damage to the skin. These beds emit 10 to 15 times more UVA than the sun.

At the ageof 22, my

worst fear had come

true. But my melanoma

was caught early, and I am one

of the few lucky ones.

COMMENTARYMandi Bartlett, RN, BSN, is an oncology nurse in Pittsburgh and is graduating this spring as a family nurse practitioner.

Don’t let patients tan their lives awayTo most teenage girls, nothing goes better with summer, sun, and fl ip-fl ops than the perfect tan. Perhaps this is why so many girls visit tanning salons to work on achieving that bronzed skin. My mother was one of those sun-worshippers, and I always envied her deep tans. As I got older,

she would let me come along to the tanning bed with her. At fi rst it was just before special occasions such as a wedding or the prom, and then it became every April or May, “to get ready for summer.” Everyone has heard at one time or another that too much sun exposure can be unhealthy—but no one ever warned my mother or me just how dangerous it could be.

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

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

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 INFORMATIONWARNINGA. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATIONDiscontinuing 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.

*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.

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

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

IMPORTANT SAFETY INFORMATION (cont’d)

WARNING (cont’d)B. SPINAL/EPIDURAL HEMATOMAEpidural 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.

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.

Learn more at www.XARELTOhcp.com

§ Event 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.

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 HEMATOMAA. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL

FIBRILLATIONDiscontinuing 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 anti coagulation 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 HEMATOMAEpidural 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 USAGEReduction 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 well-controlled [see Clinical Studies (14.1) in full Prescribing Information].CONTRAINDICATIONSXARELTO is contraindicated in patients with:• activepathologicalbleeding[see Warnings and Precautions]• severehypersensitivityreactiontoXARELTO[see Warnings and Precautions]WARNINGS AND PRECAUTIONSIncreased 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, hypo tension, or fetal distress).

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 REACTIONSClinical 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 XARELTON = 7111

n (%)

Event Rate (per 100 Pt-yrs)

WarfarinN = 7125

n (%)

Event Rate (per 100 Pt-yrs)

Major bleeding† 395 (5.6) 3.6 386 (5.4) 3.5Bleeding into a critical organ‡

91 (1.3) 0.8 133 (1.9) 1.2

Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5Bleeding resulting in transfusion of ≥ 2 units of whole blood or packed red blood cells

183 (2.6) 1.7 149 (2.1) 1.3

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: agranulocytosisGastrointestinal disorders: retroperitoneal hemorrhageHepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitisImmune system disorders: hypersensitivity, anaphylactic reaction, anaphy lactic shockNervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesisSkin and subcutaneous tissue disorders: Stevens-Johnson syndromeDRUG INTERACTIONSRivaroxaban 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 pharmaco-dynamic 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.

XARELTO® (rivaroxaban) tablets

Janssen Pharmaceuticals, Inc.

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

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.

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 warfarin-treated 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.

Learn more at www.XARELTOhcp.com

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 pharmaco dynamic 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 concom itantly with XARELTO. In a single-dose 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 POPULATIONSPregnancy: 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

Parameter

Renal Impairment Class[CrCl (mL/min)]

Mild[50 to 79]

N=8

Moderate[30 to 49]

N=8

Severe[15 to 29]

N=8Exposure AUC 44 52 64

(% increase relative to normal) Cmax 28 12 26FXa Inhibition AUC 50 86 100

(% increase relative to normal) Emax 9 10 12PT Prolongation AUC 33 116 144

(% increase relative to normal) Emax 4 17 20PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearancePatients 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 pharmaco-dynamic 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

Parameter

Hepatic Impairment Class(Child-Pugh Class)

Mild(Child-Pugh A)

N=8

Moderate(Child-Pugh B)

N=8Exposure AUC 15 127

(% increase relative to normal) Cmax 0 27FXa Inhibition AUC 8 159

(% increase relative to normal) Emax 0 24PT Prolongation AUC 6 114

(% increase relative to normal) Emax 2 41PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effectAvoid 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 [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].

OVERDOSAGEOverdose 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 for: Licensed from: Manufactured by: Janssen Pharmaceuticals, Inc. Bayer HealthCare AGJanssen Ortho, LLC Titusville, NJ 08560 51368 Leverkusen, GermanyGurabo, PR 00778

© Janssen Pharmaceuticals, Inc. 2011 1018520102X11309BBA

XARELTO® (rivaroxaban) tablets XARELTO® (rivaroxaban) tablets

Dermatology Clinic■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review

up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 70 ■ ADDITIONAL CME/CE: Pages 23, 65


KERRI ROBBINS, MDAn otherwise healthy Hispanic woman, age 43 years, presented to the dermatology clinic for evaluation of a rash. The rash had begun approximately 18 months earlier and started as dark spots on her abdomen that had since spread to involve her proximal extremities. No pruritus or pain was reported, and no new medications were used prior to the onset of the rash. No treatment had been attempted. On clinical examination, numerous ash-gray to blue macules coalescing into patches were seen in a symmetric distribution on the trunk and proximal extremities.

What is your diagnosis? Turn to page 60

Macules spread from abdomen to extremities

ESTHER STERN, NP-CA 78-year-old woman with Alzheimer disease was brought in for evaluation of a scalp lesion fi rst noticed by her granddaughter one month earlier. Because of her dementia, the patient was unable to provide a reliable history. Her granddaughter reported no patient or family history of previous skin cancer or other malignancy. Physical examination revealed a 10-mm × 5-mm pink, somewhat pearly, and fi rm nodule on the vertex of the scalp. Examination of the head and neck was otherwise unremarkable, and no appreciable adenopathy was detected.

What is your diagnosis? Turn to page 61

Pink nodule on the crown of the head

CASE #1

CASE #2

CMECE


Erythema dyschromicum perstans (EDP) is a disorder that most commonly affects Latin Americans and Asians. However, there have been cases reported in Caucasians as well, particularly individu-als with skin types III and IV.1 Although some researchers claim that EDP affects women

more than men, there are no key fi ndings to support this. The age of onset has a wide range, most commonly affect-ing those between the fi rst and third decade of life. There have been cases reported in those who were as young as age 1 year and as old as age 80 years.

EDP has no known pathogenesis. It has been suggested that the condition is a cell-mediated immune reaction against an ingestant, which leads to pigmentary incontinence. In 1973, Pinkus claimed EDP was caused by the effects of environ-mental pollution in genetically susceptible individuals.1,2 The retrospective examination of various patients has led to the development of a variety of possible predisposing factors, none of which is consistent, however. These factors include orally administered radiographic media (barium sulfate), ammonium nitrates, fertilizer, pesticides, fungicides, and such drugs as penicillin and benzodiazepines.2,3 Other possible etiologies include whipworm infections (intestinal parasitosis caused by nematodes) and HIV. Even chlorothalonil from bananas has been raised as a possible cause of EDP.

Genetic research has shown an HLA-DR4 allele asso-ciation with EDP in some Hispanic patients.4 The major histocompatibility complex region is believed to house the genes responsible for the disease. Examination of immu-nologic chemistry demonstrates expression of cell adhesion molecules as well as lymphocyte activation molecules. No specifi c or consistent microbe, drug, or agent has been identifi ed as the cause, and more research is needed in this area. Numerous laboratory experiments in persons with EDP have shown negative results for bacterial, viral, and mycologic studies. Evaluations of such tests as a complete blood count, comprehensive metabolic panel, and urinalysis have not shown any abnormalities in patients with EDP.

EDP is a slow, progressive, acquired, and chronic hyper-pigmentation. The ash-gray to blue macules start small but think big; they progress slowly and eventually grow to cover large areas of the body. The macules and patches may

be oval, with their long axes following skin cleavage lines (circular or irregularly shaped). Macules/patches range in diameter from 0.5 cm to 2.5 cm.1 They are uncommonly surrounded by an erythematous peripheral margin that can measure 1 mm to 2 mm in diameter.1 The macules can cover a wide area of the body and tend to occur in a symmetrical pattern on the trunk, face, neck, and proximal upper extremities. The lesions do not affect mucous mem-branes and rarely progress to the palms, soles, or scalp. EDP is generally asymptomatic, but some patients have reported pruritus. For the most part, the disease does not regress in

adults; however, there have been a few cases in children in which spontaneous regression has occurred.5,6

Histologic fi ndings will vary depending on the age of the lesion. In the early stage, the erythematous border (active region) will show vacuolar alteration of the basal layer. Necrotic keratinocytes or colloid bodies may be occasionally seen.7 Melanophages will be mingled with a perivascular and/or lichenoid infi ltrate of lymphocytes and histiocytes within the dermis.8 Later in the development of EDP, the ash-gray lesions (inactive region) may have a considerable amount of epidermal change; these include atrophy and effacement of the normal pattern of rete ridges.8 There is also a considerable amount of pigment incontinence.

Since its discovery, some researchers and authors have regarded EDP as a variant of lichen planus due to the simi-larity of their clinical and histologic features. Direct immu-nofl uorescence studies of the active border of EDP have shown immunoglobulin (Ig)M, IgG, and fi brinogen, just as is seen with lichen planus. However, EDP will often only demonstrate fi brinogen at the dermal-epidermal junction.1 Additionally, immunofl uorescence studies have shown the dermal infi ltrate to be composed of CD4+ and CD8+ T cells, also commonly seen in lichen planus. Making the clini-cal distinction between the two conditions may be diffi cult. Lichen planus is usually distinguished clinically by fl at-topped papules and plaques, which are features not seen in EDP. Fixed-drug eruptions (FDEs) must also be in the differential diagnosis. The infi ltrate and pigmentary incontinence seen in FDEs may appear very similar to EDP. However, the lesions

CASE #1Erythema dyschromicum perstans

The ash-gray to blue macules start small and progress slowly and eventually grow to cover large areas of the body.

Dermatology ClinicCMECE


seen in FDEs are often more circular and brown in color. Pityriasis rosea, small plaque parapsoriasis, post-infl ammatory hyperpigmentation, melasma, erythema multiforme, and other drug reactions must also be considered.

EDP is chronic, and there are no effective treatments for the disease. Topical corticosteroids, hydroquinone, and sun protection have been ineffective in treating EDP. Retinoids, vitamin C, vitamin A, chemical peels, UV light therapy, antimarials, and antibiotics have all failed to produce any signifi cant results.1 In a small series, treatment with dapsone and clofazimine (Lamprene) was reported as effective.1

EDP is benign and will not cause death. Lesions have been known to spontaneously resolve in prepubertal children but often chronically persist in adults.5,6 Most patients will be concerned about cosmetic issues related to the disease and may suffer from anxiety and depression. The unpleasant sight of the blue-grayish lesions can cause signifi cant damage to the patient’s self-esteem. As always, it is important for clinicians to pay close attention to the patient’s emotions and psychological distress.

The patient in this case was counseled on the chronic nature of the disease and the poor treatment regimens available. She was given reassurance and strongly advised to use sun protection. ■

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

References1. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.:

Elsevier Mosby; 2008:178-179, 940-942.

2. Pinkus H. Lichenoid tissue reactions. A speculative review of the clinical

spectrum of epidermal basal cell damage with special reference to ery-

thema dyschromicum perstans. Arch Dermatol. 1973;107:840-846.

3. Schwartz RA. Erythema dyschromicum perstans: the continuing enigma

of Cinderella or ashy dermatosis. Int J Dermatol. 2004;43:230-232.

4. Correa MC, Memije EV, Vargas-Alarcón G, et al. HLA-DR association

with the genetic susceptibility to develop ashy dermatosis in Mexican

Mestizo patients. J Am Acad Dermatol. 2007;56:617-620.

5. Lee SJ, Chung KY. Erythema dyschromicum perstans in early childhood.

J Dermatol. 1999; 26:119-121.

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

Philadelphia, Pa.: Elsevier Saunders; 2006:293-294.

7. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby;

2005:70.

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

the Skin. 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins;

2009:172-173.



Histopathology fi ndings were consistent with a diagnosis of cutaneous angiosarcoma (AS). ASs are a group of rare malig-nant sarcomas originating from neoplastic transformation of the vascular endothelial cells. Most ASs are known to be very aggressive, with a high rate of metastases and mortality. Both

the intrinsic biologic properties of the tumor and the high rate of misdiagnosis contribute to the poor prognosis.

Although AS may arise in almost any organ, the skin and soft tissue are most commonly found to be the primary tumor site. Cutaneous AS, which originates in the skin, accounts for approximately 60% off all ASs.1

The fi ve-year survival rate for cutaneous AS is dismal and estimated to be approximately 30%.2 Prognosis is poorer in those individuals with tumor external diameter greater than 5 cm, depth of invasion greater than 3 mm, positive surgical margins, metastases, and tumor recurrence.3

Risk factors for AS include a history of radiation therapy; lymphedema; exposure to such toxins as arsenic, Thorotrast (a radioactive contrast dye used in radiology from about 1930 to the mid-1950s), and polyvinyl chloride (used in plastics); and presence of such foreign bodies as bone wax, dialysis shunts made of Dacron, metal bodies, surgical sponges, and plastic graft material. In addition, AS occurs more frequently in individuals with AIDS.

Cutaneous AS is divided into four variants: (1) AS of the head and neck; (2) Stewart-Treves variant, occurring in the context of lymphedema; (3) radiation-induced AS; and (4) epithelioid AS.

AS of the head and neck, also known as Wilson-Jones AS, is the most common form and occurs almost exclusively in the elderly. The male-to-female ratio is approximately 2:1. The tumor initially appears as an ill-defi ned bluish macule that is frequently mistaken for a bruise or cellulitis. With time, the tumor grows and evolves into an indurated bluish nodule or plaque that is usually asymmetric, nodular, or ulcerated. Spontaneous localized bleeding, satellite nodules, intratumoral hemorrhage, and a peripheral erythematous ring are other distinguishing features of AS of the head and neck. Systemic bleeding or altered coagulation are ominous signs and usually indicative of metastases.

CASE #2 Cutaneous angiosarcoma


The Stewart-Treves variant, or lymphedema-associated AS, develops in an area of the skin affected with chronic lymphedema. This variant is most frequently seen in the upper arm of a post-mastectomy patient, with an estimated 0.07% to 0.45% prevalence rate post-mastectomy.1 Stewart-Treves is seen less commonly in patients with a history of lymph node dissection or chronic idiopathic lymphedema. Although there is no known cause for the correlation between AS and lymphedema, several theories exist. Some believe that the decreased clearance of the local lymph node causes the sur-rounding tissue to be chronically exposed to carcinogens. Others propose that the lymph node removal triggers angio-genesis, subsequently allowing for the growth of malignant cells. Lymphedema-associated AS occurs an average of 10 to 12 years postsurgery. This subtype usually appears as a violaceous ulcerating plaque or nodule superimposed on a background of brawny, nonpitting edema.

The third subtype, radiation-induced AS, occurs anywhere from four to 40 years postradiation exposure. Quicker disease onset is seen in those patients who were treated with radiation for a malignant condition rather than for a benign condition. These tumors present initially with ecchymosis or thickening of the skin within a previously radiated area.

The fi nal subtype includes a rare and more recently dis-covered aggressive variant called epithelioid AS. Because epithelioid AS often mimics common vascular and non-vascular neoplasms histologically, both a high clinical index of suspicion and an expert thorough histopathologic examination is needed.4

Biopsy of the tumor allows for diagnosis. Care should be taken to provide proper hemostasis after the biopsy to avoid blood extravasation, which would allow for dissemination of the tumor cells. Diagnosis is based on the microscopic features of the biopsy specimen and ultrastructural and histochemical markers. On microscopy, AS will present with irregularly shaped vascular spaces lined with atypical endothelial tumor cells. Unlike benign hemangiomas, AS vascular channels disrupt normal tissue planes and form a network of sinusoids.

Tumors are often characterized as well-differentiated (low-grade), moderately differentiated, or poorly dif-ferentiated (high-grade). Well-differentiated tumors are more easily diagnosed, while the latter may require special staining techniques to aid in identifi cation.

MRI and/or CT imaging studies should be performed as part of the initial workup, as up to 50% of patients will have evidence of metastasis at the time of diagnosis.

Individuals diagnosed with AS should be referred to a multidisciplinary cancer center. For limited disease, com-plete surgical excision of the macroscopic tumor followed by moderate-dose and wide-fi eld radiation offers the best opportunity for cure.5 Surgical treatment is contraindicated in patients with tumors that extend into vital organs or those that are of very large size. Systemic therapies are limited, but chemotherapy with doxorubicin (Adriamycin, Rubex) followed by radiotherapy is a reasonable approach.6 Newer

therapeutic options may include antiangiogenic, immu-notherapy, and multimodality treatments. Unfortunately, treatment for extensive disease is mostly palliative.

All patients with angiosarcoma should be closely moni-tored for life. Recurrences may occur years later or as early as two years post-cure.

The patient in this case was referred to a hematologist/oncologist for treatment. Presurgical workup revealed no sign of metastases, and primary surgical removal was planned. Unfortunately, the patient was lost to follow-up. ■

Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J.

References1. Liddy Shriver Sarcoma Initiative. Angiosarcoma. Available at sarcomahelp

.org/learning_center/angiosarcoma.html.

2. Fury MG, Antonescu CR, Van Zee KJ, et al. A 14-year retrospective review

of angiosarcoma: clinical characteristics, prognostic factors, and treatment

outcomes with surgery and chemotherapy. Cancer J. 2005;11:241-247.

3. Morgan MB, Swann M, Somach S, et al. Cutaneous angiosarcoma: a case

series with prognostic correlation. J Am Acad Dermatol. 2004;50:867-874.

4. Mobini N. Cutaneous epithelioid angiosarcoma: a neoplasm with poten-

tial pitfalls in diagnosis. J Cutan Pathol. 2009;36:362-369.

5. Morrison WH, Byers RM, Garden AS, et al. Cutaneous angiosarcoma of

the head and neck. A therapeutic dilemma. Cancer. 1995;76:319-327.

6. Wollina U, Füller J, Graefe T, et al. Angiosarcoma of the scalp: treat-

ment with liposomal doxorubicin and radiotherapy. J Cancer Res Clin Oncol.

2001;127:396-369.


On microscopy, angiosarcoma will present with irregularly shaped vascular spaces lined with atypical endothelial tumor cells.



and showed lower levels of such infl ammatory markers as C-reactive protein (CRP) and interleukin-6 than did the placebo group.3

Tart cherry juice was also tested in connection with its ability to relieve oxidative stress and muscle damage in the elderly. One study examined 12 healthy volunteers aged 61-75 years.4,5 Each group was given one cup (240 ml) of either cherry juice or fl avored water twice daily for two weeks.4,5 Subsequent measurements of oxidized amino acids in urinary output were less in the active treatment group when compared to the placebo, indicating lower levels of cellular damage.4,5

In a small trial, 10 obese volunteers (BMI 27.0-36.0) were studied for potential cardiovascular benefi ts connected to tart cherry ingestion. Respective cohorts received eight ounces of tart cherry juice or fl avored water daily for four weeks.6 At the end of the trial, glucose, high-sensitivity CRP (hs-CRP), total cholesterol, triglycerides, LDL, VLDL, and HDL cholesterol were measured and compared to baseline. Of the measurements, triglycerides and VLDL were signifi cantly


Background

Tart cherries contain several potent antioxidants—among them anthocyanins—which give the cherries their rich, distinctive color.2 In addition, tart cherries have been found to contain a unique set of antioxidative compounds, called superoxide dis-umutase, that are even more potent than the anthocyanins.2

Science

Multiple studies have explored using tart cherry juice to offset infl ammation. One study examined the effect of cherry juice consumption on rapid-onset oxidative stress. Researchers enrolled 20 recreational marathon runners into a placebo-controlled trial and gave the active treatment group cherry juice prior to and just after the race.3 Isometric strength, muscle enzymes, and infl ammatory markers were measured in each participant after the marathon. Data showed that the cherry-juice cohort recovered isometric strength faster

Tart cherryTart cherries are a source of antioxidants that are fast emerging as a superfruit. A growing body of evidence has linked the tart cherry to substantial anti-infl ammatory benefi ts, including reduced arthritic and gout pain, and several cardiac benefi ts. Prunus cerasus—the sour cherry—is the smallest of the stone fruits.1 It’s sweeter cousins—the Bing, Rainier, and Lambert cherries—are usually eaten raw and are slightly larger than sour cherries. Tart cherries are typically reserved for making pies and preserves. So, the next time you feel like indulg-ing in a piece of cherry pie, remember that you can—sort of—justify the indulgence.

ALTERNATIVE MEDS UPDATE 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.

What you should know about the herbs and supplements patients use

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powder-fi lled capsules. The dose considered in most studies is the equivalent of 8 oz of pure cherry juice each day. Many of the extracts and powders on the market are concentrated, reducing the fl uid volume to as little as 1 oz. Cost varies with the type of product, ranging from $15 to $50 for a one-month supply.

Summary

Tart cherries are a safe product for individuals seeking a healthy, broad-spectrum antioxidant to add to their daily arsenal. ■

References1. Alternative medicine supplements page. About.

com website. Available at altmedicine.about.com/od/

completeazindex/a/tart_cherry.htm.

2. USDA nutrient data laboratory page. United States

Department of Agriculture website. Available at

www.ars.usda.gov/nutrientdata.

3. Howatson G, McHugh MP, Hill JA, et al. Infl uence of tart

cherry juice on indices of recovery following marathon

running. Scan J Med Sci Sports. 2010;20:843-852.

4. Connolly DA, McHugh MP, Padilla-Zakour OI, et al.

Effi cacy of a tart cherry juice blend in preventing the symp-

toms of muscle damage. Br J Sports Med. 2006;40:679-683.

5. Traustadottir T, Davies SS, Stock AA, et al. Tart cherry

juice decreases oxidative stress in healthy older men

and women. J Nutr. 2009;139:1896-1900. Available at

jn.nutrition.org/content/139/10/1896.long.

6. Martin K, Bopp J, Neupane S, Vega-Lopez S. Tart cherry

juice reduces plasma triglycerides and CVD risk in overweight

and obese subjects. J Am Soc Exp Biol. 2010;37:722-740.

7. Schumacher R. Double blind cross-over study of the

effi cacy of a tart cherry juice blend in treatment of osteo-

arthritis (OA) of the knee. Poster abstract: 2011 American

College of Rheumatology Scientifi c Meeting, Chicago.

8. Howatson G, Bell, PG, Tallent J, et al. Effect of tart cherry

juice (Prunus cerasus) on melatonin levels and enhanced

sleep quality. Eur J Nutr. 2011;13:579-83.

9. Pigeon WR, Carr M, Gorman C, Perlis ML. Effects of

a tart cherry juice beverage on the sleep of older adults

with insomnia: A pilot study. J Med Food. 2010;13:579-

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

PMC3133468/.

All electronic documents accessed on April 15, 2012

reduced in the cherry-juice group, suggesting a reduction in cardio vascular risk.6

Tart cherry juice has also been studied in connection with its effect on arthritic and rheu-matologic conditions. In a recently published study, 59 arthritis patients were given 240 ml of cherry juice twice daily for six weeks, and placebo patients were given fl avored water.7 At the end of the study, the juice drinkers had signifi cantly decreased hs-CRP levels and pain scores on the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and some subjects noted unsolicited subjective pain relief.7 Study participants were administered the standardized WOMAC questionnaire to accurately determine symptom scores.7

An added benefi t of tart cherry juice is that it contains melatonin. Known as the hormone infl uencing human sleep cycles, melatonin is a potential antioxidant.8 Given this source of exogenous melatonin, studies show improve-ments in sleep latency, sleep time, and overall sleep effi cacy.8

Two randomized, placebo-controlled trials studied 35 healthy adults with complaints of sleep-cycle disturbances.8,9 Active-treatment group participants were given daily supplementation of two 8-oz servings of tart cherry juice formulation per day.8,9 Both trials verifi ed improved scores on all study variables, including total sleep time, sleep-cycle effi cacy, and sleep latency, as wll as urinary excretion of melatonin.8,9

Safety, interactions

Tart cherries contain signifi cant amounts of sorbitol, a sugar alcohol that has been known to trigger symptoms in people with irritable bowel syndrome. Caution should also be used when administering tart-cherry therapy in patients who are taking warfarin, since the high-level of antioxidants may activate warfarin’s anti-thrombotic action.

Dosage and cost

Tart cherries are available in almost any form—as fresh fruit, dried fruit, juice extracts, and ©

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ALTERNATIVE MEDS UPDATE

A growing body of evidence has linked the tart cherry to several anti-infl ammatory benefi ts.

In clinical trials, tart cherry juice was found to aid sleep effi ciency.


Bimalar facial rashesJOE R. MONROE, MPAS, PA

A nurse, age 54 years, arrived for evaluation of what she and her fellow hospital workers presumed to be lupus. The rash had been present for approximately one month. Such systemic symptoms as joint pain, fever, and malaise were not reported. The rash burned and itched and had persisted despite the application of a number of OTC creams and ointments. An antinuclear antibody (ANA) test ordered by the patient’s primary-care provider was nonreactive. A complete blood count and comprehensive metabolic profi le showed no abnormal results.

CASE #1

A 26-year-old woman fi rst noticed a facial rash early in the summer but had to wait several weeks before she could be seen in the dermatology clinic. Feeling the need to try something in the meantime, she used OTC moisturizers and 1% hydrocortisone cream to obtain relief from mild itching and burning. Neither of the OTC treatments was helpful, and the rash grew more erythematous. The woman’s symptoms were particu-larly exacerbated after a day spent in the sun working as a landscaper.

CASE #2

Dermatologic Look-Alikes■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions

with similar presentations.

■ COMPLETE THE POSTTEST: Page 70 ■ ADDITIONAL CME/CE: Pages 23, 59


CMECE


Every medical student hears about the butterf ly rash of lupus. However, the clas-sic bimalar rash of lupus is not at al l common, even in conf irmed lupus cases. Additionally, as with virtually all medical diagnoses, there is a differential for fl orid facial rashes that includes a number

of far more common conditions, including contact vs. irri-tant dermatitis, psoriasis, and seborrheic dermatitis.1

This patient’s rash was reddish-orange and fl orid, affecting sharply demarcated convex areas of the cheeks, chin, and forehead, where the lesions took on more of an annular morphology. The nasal bridge was spared. Little if any edema was appreciated, and there was no increase in surface warmth in the areas. A KOH examination of scrapings from the surfaces of the lesions showed no fungal elements or signs of Demodex, a mite that is part of normal fl ora inhabiting follicles and sebaceous glands, especially in periocular areas, and occasionally implicated in rosacealike facial eruptions.2

Approximately 95% of systemic lupus cases are ANA-positive. The negative ANA in this case served only to rule out systemic lupus erythematosus, since seronegative cutaneous lupus can still present in a wide variety of ways, including facial involvement. A 3-mm biopsy was performed and showed none of the features consistent with lupus (i.e., vacuolar interface dermatitis, a universal fi nding in active lupus lesions). Such other fi ndings consistent with lupus as parakeratosis and mild hyperkeratosis were also missing in this case.1

Instead, spongiotic dermatitis with mild follicular accen-tuation was seen in this patient. While not diagnostic, these changes made lupus less likely, as did the lack of such other fi ndings as atrophy, dilated follicles, or alopecia.2

Clinicians were also able to rule out sarcoidosis, poly-morphous light eruption, lichen planus, tertiary syphilis,

and lymphocytic infi ltration of Jessner, all of which would have shown fi ndings suggestive—if not diagnostic—of those entities.

Unfortunately, a diagnosis of spongiotic dermatitis, however useful, only gains the clinician admission to a rather large ballpark and not to a specifi c seat. Commonly seen in irritant and contact dermatoses, spongiosis simply implies intercellular edema of the epidermis triggered by infl ammation.3

“Clinical correlation” comes into play at this point, which involves a more in-depth discussion with the patient to determine exactly when and how this condition started and whether there is any history of skin problems or other signifi cant medical problems or family history of such skin diseases as psoriasis. It is also helpful to ask which products had been used to treat the rash.

The woman described in this case was desperate to obtain relief and had used a number of products on her face over

the fi rst few weeks of her rash. She was advised to stop all topical products except those prescribed by a clinician. It is extremely common for a patient’s self-prescribed “treat-ment” to cause far more problems than the original condi-tion he or she set out to remedy. Neither stopping OTC treatment nor ceasing b.i.d. application of topical desonide (DesOwen, Tridesilon) lotion was successful in controlling the woman’s rash.

There was no family history of skin disease, but the patient did recall having a milder version of her current outbreak on a number of occasions over the years. In the past, these eruptions had always involved the same areas of her face as well as the scalp and bilateral postauricular skin. These episodes always were preceded by periods of exceptional emotional stress. The patient did confi rm that similar conditions had preceded this most recent eruption, and examination confi rmed the involvement of the skin behind and in both ears with a shiny and scaly rash similar to the one on her face.

A diagnosis of seborrheic dermatitis—possibly worsened by irritation brought on by use of OTC products—was eventually made. Seborrheic dermatitis is an extremely

CASE #1 Seborrheic dermatitis

It is very common for self-prescribed “treatment” to cause far more problems than the original condition.

Dermatologic Look-AlikesCMECE


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.

Facial rashes, an extremely common complaint, are typi-cally diagnosed and treated with relative ease. But there is a bewildering and exten-sive range of possible expla-nations for facial complaints that falls outside the usual and customary. For obvious rea-sons, patients are often very

concerned about their appearance, especially early on when a clear diagnosis and effective treatment are elusive.

By the time this patient was examined by dermatology, both sides of her face were quite red. Discrete and confl uent blanchable papules, nodules, and plaques (many of which were polycyclic) with clearing and slightly atrophic cen-ters were noted. Little if any scale was seen, although the

common papulosquamous condition that affects up to 20% of the population. Its most common form is that of dandruff, but seborrheic dermatitis also manifests as a minimally scaly and pinkish-red rash on nasolabial folds, beard area, glabella, eyebrows, and in and behind the ears. Thought to represent an abnormal response to the commensal yeast Malassezia furfur, seborrheic dermatitis can affect a wide array of other anatomic areas as well, including the trunk, chest, axillae, and genitals.4

The patient was successfully treated with b.i.d. application of difl orasone (Apexicon, Maxifl or, Psorcon) ointment, a relatively powerful (Class 2) topical steroid that is seldom used on the face. The difl orasone was tapered down over a period of two weeks and was gradually replaced by tac-rolimus (Hecoria, Protopic) ointment, a topical macrolide immunosuppressant.5 She was also advised to wash her face twice daily with OTC ketoconazole (Nizoral) shampoo to reduce the numbers of M. furfur yeast. Within three weeks, the patient was able to stop all medications.

Since a permanent cure is not available, treatment of seborrheic dermatitis usually focuses on control with a combination of topical steroids and such antifungal mea-sures as imidazole creams or shampoos used as face wash. Seborrheic dermatitis is usually obvious clinically, but as this case illustrates, it can be complicated by patient and provider misdiagnosis.

patient reported scrubbing fi ne scale away each morning and night. Her lesions were confi ned to sun-exposed skin and stopped abruptly at her neckline.

The patient reported no fever, joint pain, or malaise and denied any personal or family history of similar problems. Strongly suspecting lupus, the provider obtained a 3 mm punch biopsy specimen from the peripheral face and sub-mitted it to pathology with a working differential of lupus vs. polymorphous light eruption. At the same time, an additional specimen was obtained for separate processing

and sent to pathology in Michel’s transport medium for direct immunofl uorescence studies.

A dermatopathologist was able to verify the diagnosis of probable subacute cutaneous lupus erythematosus (SCLE), a clinically distinct form of lupus fi rst described in 1979.6,7

Pathology showed vacuolar interface dermatitis but no follicular plugging, basement membrane thickening, or heavy lymphoid aggregates, which might have suggested discoid lupus (DLE).

Differential item functioning studies were positive for a dustlike particulate deposition of immunoglobulin G in epidermal nuclei, also consistent with what is seen in approximately one third of individuals with SCLE.8

SCLE is mostly found in white women aged 15 to 40 years. Lesions can be scaly and evolve as polycyclic annular lesions with clearing centers.6

Unlike DLE, SCLE lesions seldom involve the follicle, do not scar, and tend to be transitory. However, patients with SCLE can have concomitant DLE in other locations. As seen in this case, photosensitivity is a prominent feature in the majority of individuals with SCLE.

Bloodwork from this patient demonstrated a positive ANA, as is the case approximately 80% of the time with SCLE.9 The rest of this patient’s lupus profi le is pending, but a positive Ro/SSA antigen is expected.

Clinically, most cases of SCLE run a mild course and respond to sun protection and the use of antimalarials. Topical steroids are usually not necessary but can be useful for local control.10

CASE #2 Chronic cutaneous lupus



Lesions of subacute cutaneous lupus erythematosus seldom involve the follicle, do not scar, and tend to be transitory.


Drugs that can trigger an eruption similar to that of SCLE include hydrochlorothiazide, ACE inhibitors, and calcium channel blockers, among others.

Besides the differential mentioned above, other items to be considered include erythema multiforme, psoriasis, tertiary syphilis, and dermatomyositis.

The woman in this case will be managed by dermatol-ogy and rheumatology, given her potential for systemic involvement, which can include such overlap syndromes as Sjögren’s. It is possible that she will have to be treated with multiple systemic medications in the event of nonre-sponse to conservative treatment. Because of the role sun exposure played in the genesis of the patient’s disease, she was advised to consider changing careers. ■

Mr. Monroe is a physician assistant specializing in dermatology at Dawkins Dermatology in Oklahoma City.

References1. Medscape Reference. Seborrheic dermatitis. Available at emedicine

.medscape.com/article/1108312-overview.

2. James WD, Berger TG, Elston DM. Seborrheic dermatitis. In: Andrews’

Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.:

Saunders-Elsevier; 2006:191-193

3. Belew PW, Rosenberg EW, Jennings BR. Activation of the alterna-

tive pathway of complement by Malassezia ovalis (Pityrosporum ovale).

Mycopathologia. 1980;70:187-191.

4. Green CA, Farr PM, Shuster S. Treatment of seborrhoeic dermatitis

with ketoconazole: II. Response of seborrhoeic dermatitis of the face, scalp

and trunk to topical ketoconazole. Br J Dermatol. 1987;116:217-221.

5. Meshkinpour A, Sun J, Weinstein G. An open pilot study using tac-

rolimus ointment in the treatment of seborrheic dermatitis. J Am Acad

Dermatol. 2003;49:145-147.

6. James WD, Berger TG, Elston DM. Connective tissue diseases. In:

Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia,

Pa.: Saunders-Elsevier; 2006:157-166.

7. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year

evolution of a prototypic subset (subphenotype) of lupus erythematosus

defi ned by characteristic cutaneous, pathological, immunological, and

genetic fi ndings. Autoimmun Rev. 2005;4:253-263.

8. Medscape Reference. Subacute cutaneous lupus erythematosus (SCLE).

Available at emedicine.medscape.com/article/1065657-overview.

9. Fabbri P, Cardinali C, Giomi B, Caproni M. Cutaneous lupus erythema-

tosus: diagnosis and management. Am J Clin Dermatol. 2003;4:449-465.

10. Wozniacka A, McCauliffe DP. Optimal use of antimalarials in treating

cutaneous lupus erythematosus. Am J Clin Dermatol. 2005;6:1-11.




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“It’s a magic potion that makes everything you say interesting.”

“Sorry, Bad Cop’s already been here, and he took your donut.”

“So near and yet so far!”

99 Hudson Street, 12th Floor

New York, NY 100132815

Tel: 18002214904

Email: [email protected]

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Because Your Own Malpractice Policy Is Your Best Protection.

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CE POSTTESTExpiration date: May 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.

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureMay2012

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermMay2012

CREDITS: 0.5

Featurepage 23

HAART meds: Implications for the older adult patient

1. The activity of some protease inhibi-tors (PIs) is boosted by the addition of which medication to the regimen?

Raltegravir (ISENTRESS)a. Abacavir (Ziagen)b. Ritonavir (Norvir)c. Enfuvirtide (Fuzeon)d.

2. What is the most common adverse effect associated with highly active antiretroviral therapy (HAART)?

Immune suppressiona. Metabolic abnormalitiesb. Nephrotoxicityc. Esophagitisd.

3. Some of the strongest data regarding the association of HAART with bone mineral density reductions have been observed with which medication?

Abacavira. Zidovudine (Retrovir)b. Tenofovir (Viread)c. Lopinavir (Kaletra)d.

4. Which medication is contraindicated in a patient taking PIs?

Proton pump inhibitora. Digoxinb. Beta blockerc. Erectile dysfunction drug d.

CREDITS: 0.5

Dermatology Clinicpage 59

Erythema dyschromicum perstans

1. How is lichen planus usually distinguished clinically?

Waxy dome-shaped, umbilicated a. papulesFlat-topped papules and plaquesb. Caulifl ower-shaped lesions with c. petechiaeSolid, fi rm, thick plaques with d. scaling

2. What is the treatment for erythema dyschromicum perstans?

UV light therapya. Chemical peelsb. Cryosurgeryc. There is no effective therapyd.

Cutaneous angiosarcoma

3. What is a risk factor for angiosarcoma (AS)?

Fair skina. History of radiation therapyb. Older agec. Previous severe skin injuryd.

4. Which sign is usually indicative of metastases of AS?

Lymph node enlargementa. Systemic bleedingb. Increasing tumor depthc. Satellite lesionsd.

Dermatologic Look-Alikespage 65

Seborrheic dermatitis

1. What is a universal fi nding in active systemic lupus erythematosus lesions?

Vacuolar interface dermatitisa. Well-demarcated areas of erythemab. Plaques and scaling with lichenifi cationc. Scattered macules with greasy d. appearance

2. What OTC medication is used to reduce the numbers of Malassezia furfur yeast?

Nystatin creama. Clotrimazole topical solutionb. Ketoconazole (Nizoral) shampooc. Topical corticosteroidd.

Chronic cutaneous lupus

3. Which feature is suggestive of discoid lupus erythematosus?

Follicular plugginga. Basement membrane thickeningb. Heavy lymphoid aggregatesc. All of the aboved.

4. Which drug class can trigger an eruption similar to that of subacute cutaneous lupus erythematosus?

Calcium channel blockersa. Tricyclic antidepressantsb. Proton pump inhibitorsc. Statinsd.

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 May 2012. Participants may submit the self-assessment at any time during that period.

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

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


Expiration date: May 2013



CREDITS: 0.5

Featurepage 23

HAART meds: Implications for the older adult patient

1. The activity of some protease inhibi-tors (PIs) is boosted by the addition of which medication to the regimen?

Raltegravir (ISENTRESS)a. Abacavir (Ziagen)b. Ritonavir (Norvir)c. Enfuvirtide (Fuzeon)d.

2. What is the most common adverse effect associated with highly active antiretroviral therapy (HAART)?

Immune suppressiona. Metabolic abnormalitiesb. Nephrotoxicityc. Esophagitisd.

3. Some of the strongest data regarding the association of HAART with bone mineral density reductions have been observed with which medication?

Abacavira. Zidovudine (Retrovir)b. Tenofovir (Viread)c. Lopinavir (Kaletra)d.

4. Which medication is contraindicated in a patient taking PIs?

Proton pump inhibitora. Digoxinb. Beta blockerc. Erectile dysfunction drugd.

CREDITS: 0.5

Dermatology Clinicpage 59

Erythema dyschromicum perstans

1. How is lichen planus usually distinguished clinically?

Waxy dome-shaped, umbilicated a. papulesFlat-topped papules and plaquesb. Caulifl ower-shaped lesions with c. petechiaeSolid, fi rm, thick plaques with d. scaling

2. What is the treatment for erythema dyschromicum perstans?

UV light therapya. Chemical peelsb. Cryosurgeryc. There is no effective therapyd.

Cutaneous angiosarcoma

3. What is a risk factor for angiosarcoma (AS)?

Fair skina. History of radiation therapyb. Older agec. Previous severe skin injuryd.

4. Which sign is usually indicative of metastases of AS?

Lymph node enlargementa. Systemic bleedingb. Increasing tumor depthc. Satellite lesionsd.

Dermatologic Look-Alikespage 65

Seborrheic dermatitis

1. What is a universal fi nding in active systemic lupus erythematosus lesions?

Vacuolar interface dermatitisa. Well-demarcated areas of erythemab. Plaques and scaling with lichenifi cationc. Scattered macules with greasy d. appearance

2. What OTC medication is used to reduce the numbers of Malassezia furfur yeast?

Nystatin creama. Clotrimazole topical solutionb. Ketoconazole (Nizoral) shampooc. Topical corticosteroidd.

Chronic cutaneous lupus

3. Which feature is suggestive of discoid lupus erythematosus?

Follicular plugginga. Basement membrane thickeningb. Heavy lymphoid aggregatesc. All of the aboved.

4. Which drug class can trigger an eruption similar to that of subacute cutaneous lupus erythematosus?

Calcium channel blockersa. Tricyclic antidepressantsb. Proton pump inhibitorsc. Statinsd.

CME POSTTEST

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“The knuckle sandwich looks good.”

“Regime change is never easy, dear.”

“Make it look like natural selection.”

NEW for 2011-2012To listen on the go, download audio fi les to your MP3 player

or burn them to a CD

PANCE/PANRE

ONLINE REVIEW COURSE

DELIVERED VIA 5 MODULES FOR EASY REVIEW—EACH MODULE IS INDIVIDUALLY ACCREDITED—ACCESS AT MYCME.COM/UMDNJ

Module 1 Cardiology/EKG Review

Module 2 Pulmonology, Pediatrics, Ophthalmology, Otorhinolaryn gology

Module 3 Orthopedics, Neurology, Psychiatry

Module 4 Infectious Disease, Gastroenterology, Dermatology

Module 5Reproductive System, Endocrinology, Genitourinary System, Hematology

DELIVERED VIA 5 MODULES FOR EASY REVIEW—EACH MODULE IS INDIVIDUALLY ACCREDITED—ACCESS AT MYCME.COM/UMDNJ

Module 1 Cardiology/EKG Review

Module 2 Pulmonology, Pediatrics, Ophthalmology, Otorhinolaryn gology

Module 3 Orthopedics, Neurology, Psychiatry

Module 4 Infectious Disease, Gastroenterology, Dermatology

Module 5Reproductive System, Endocrinology,Genitourinary System, Hematology

ACCREDITATION INFORMATION

This program has been reviewed and is approved for a maxi mum of 27.25 hours of AAPA Category 1 CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of October 17, 2011. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with the AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. This program has been planned without commercial support.

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Convenient: Study where and when you want. Practice examination questions at the end of each module. Download all slides and handouts to print or review.

Comprehensive: All topics on the NCCPA examination blueprint are covered in more than 27 hours of instruction. Self-reported 98.6% pass rate.

Cost-effective: Only $349 for all 5 modules or $99 for an individual module.


PA WANTED MEDICAL EDUCATION

PA WANTEDPA WANTED

CLASSIFIEDSFor advertising information, contact: Russell Johns Associates, LLC

1001 S Myrtle Ave, #7, Clearwater, FL 33756Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: [email protected]

Champlain Valley Heart Center, located in Plattsburgh, NY, is seeking a Staff PA for our Cardiothoracic Surgical program.

The heart surgical program at CVPH was begun in 2005 and continuesto grow, surrounded by the very best in advanced technology. We per-formed 739 PCI’s and 130 Open Hearts in 2011; an additional 100+ general thoracic procedures are performed annually, with anticipated growth. Our cardiology and cardiac surgical services have received numerous national and state awards and recognitions for both clinical excellence and outcomes.

Join the CVPH cardiothoracic surgical team at CVPH! Interested Staff PA candidates must have at least two to three years of cardiac surgical experience with the desire to become profi cient with Endoscopic Vein Harvesting (EVH), surgical fi rst-assisting, and to work collaboratively as part of the Cardiac Surgery team to provide excellent patient care. With a generous annual compensation and benefi ts package, we’re verycompetitive with other cardiac surgical programs.

The benefi t package includes relocation up to $10K. In addition, CVPH will offer either a sign-on bonus or up to $20,000 in loan forgiveness for a 2-year employment commitment.

Plattsburgh is a picturesque community of 38,000 located on Lake Champlain and at the foothills of the Adirondack Mountains.

We live where others vacation!

Contact: Becky Larkin, CVPH Medical Center75 Beekman Street • Plattsburgh, NY 12901

Phone: 518-314-3025 • Email: [email protected]: www.cvph.org, select “Careers” in upper left column.

Veterans Affairs Ann Arbor Healthcare SystemPhysician’s Assistant (Gastroenterology)

The VA Ann Arbor Healthcare System is looking for a Physician’s Assistant (PA) within Medicine Service’s Gastroenterology department.

The role of Physician Assistant is to include, but not limited to, functioning as an expert consultant, maintaining current knowledge of practice standards and guidelines related to Gastroenterology and specifi c to their Gastroenterology subspecialties; including general gastroenterology, general hepatology, evaluation and treatment of patients with chronic

hepatitis B and/or C, pre-operative assessment for endoscopic procedures, and infl ammatory bowel disease care. Full-time/perm.

Performs new patient Gastroenterology Consultation and follow-up Gastroenterology visits in both Gastroenterology and Liver clinics, as well as telephone/video conferencing

follow-up visits and collaborates as identifi ed with Gastroenterology Staff.

Performs oversight of Gastroenterology studies, appropriate scheduling of staff and patients, patient fl ow, safety, quality management. Participates in Peer Review.

All interested applicants please go to http://www.usajobs.gov/GetJob/ViewDetails/313157700 to apply for this position.

Questions about this job:Rhi Seelbinder

Phone: (734) 845-3464Ann Arbor, MI 48105



NP WANTED PA/NP WANTED

PA WANTED

MEDICAL EDUCATION

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VACATION CME

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1-800-940-5860

Family Nurse Practitioner Positions available in the following areas:

Family Practice/Pediatrics, Women’s Health, Prenatal, Adult Care and Homeless Population.The Children’s Clinic, Serving Children and TheirFamilies is a non-profi t community clinic serving low-income patients at eight sites in Long Beach and Bell-fl ower. We have a strong emphasis on compassion-ate patient centered care and are seeking a Nurse Practitioner who is mission driven and committed to serving this population. We are focused on disease management and participate in the BPHC Health Disparities Collaborative for Diabetes. Epic EMR im-plemented successfully. We are a National Health Service Corps (NHSC) loan repayment site.

Principal ResponsibilitiesUnder the supervision of a physician, Nurse Prac-titioner assesses patients’ medical/surgical con-ditions; administers treatments; facilitates commu-nication; assists as directed within parameters as outlined and utilizes the protocols for all independent and interdependent nursing practice. Services may include but are not limited to initial health screening to determine client’s status, acute care needs, and diagnostic impression, linkage to appropriate levels of mental health and physical health care, provides support and follow up care as needed.

Minimum RequirementsGraduation from an accredited nurse practitionerprogram with an MSN or MN and current licensure as an RN Nurse Practitioner in California. Spanish Preferred.

Application ProcessInterested candidates are invited to apply bysending CV/resume with salary requirements to:[email protected] or Fax: (562) 933-0538. EOE M/F/D/V. For more information, please visit web site: www.thechildrensclinic.org

Deadline: Applications will be accepteduntil position is fi lled.

*Please feel free to post or forward thisinformation to interested person*

CLASSIFIEDSFor advertising information, contact: Russell Johns Associates, LLC1001 S Myrtle Ave, #7, Clearwater, FL 33756Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: [email protected]

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Walk-in clinic located near Jupiter Island offering competi-tive compensation and benefi ts. Supported by well trained licensed professional staff. Our practice model is walk-in

urgent care and family medicine appointments. Applicants should have a minimum of 2 years experience in an urgent care setting and be comfortable with minor surgical proce-dures as well as reading x-rays. The clinic is spacious and

well-equipped. Please submit your resume via email or fax.

You may visit our website at www.helixcares.com

Skills: Current Florida License • Minimum 2 years experi-ence in urgent care • Suturing • Minor surgical procedures • Work comp and occmed experience • Familiar with wet reads

Additional Information: Masters or Graduate Degree

BJ Stone, GM750 S Federal Hwy, Deerfi eld Beach, FL 33441954-421-8181, ex. 226 • Fax: 954-426-2967

[email protected]

PA/ARNP

Phoenix Joint Replacement Orthopaedic needs PA-C.

20 yr+ Solo MD needs PA to assist in Surgeryand Offi ce while maintaining the high level of excellence that our doctor has established.

Competitive salary, pension plan and benefi ts.Contact:

[email protected]

Classifi ed Advertising(877) 394-1388

Fax: (727) 445-9380Email: [email protected]

may 2012 clinical advisor

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