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Home , Continuous fever, Intermittent fever, Nicardipine, Phenytoin, Remittent fever

Volume 25, Number 6 June 2011 Drugs & Therapy B N U N L N L N E N T N I N N

ADVERSE DRUG REACTIONS FORMULARY UPDATE The Pharmacy and Therapeutics The truth about drug Committee met May 17, 2011. 4 products were added in the Formu- t is estimated that about 3–7% of antimicrobials (median 6 days). Cardiac lary; 2 were deleted and designated I febrile episodes are attributed to drug and central nervous system medica- nonformulary and not available. 1 reactions; however, the true incidence is tions can induce fever at a much slower interchange was approved, while 3 unknown due to underreporting and fre- interval, median of 10 and 16 days after criteria for uses were changed. quent misdiagnosis.1 In the hospitalized initiation, respectively. patient, the most common presentation Fever patterns may present as a for drug fever is a patient with a resolv- (temperature does not ing , on antimicrobial therapy, vary), (where tempera- ◆ ADDED and after initial defervescence. Fever in tures vary, but are consistently elevat- Acetaminophen IV this patient can result in the over-utili- ed), (with normal (Ofirmev® by Cadence zation of antimicrobials and the addition temperatures in between), or the most Pharmaceuticals)* of agents to treat an infection that is not common: hectic fever (combination of 4 *Restricted present. This could potentially cause remittent and intermittent). Degree more adverse effects and further contrib- of pyrexia tends to range from 38.8°C Carglumic Acid ute to antimicrobial resistance. (102°F) to 40°C (104°F) but has been ® (Carbaglu by Orphan Europe) One study evaluating 51 episodes reported as high as 42.8°C (109°F). Mannitol Bronchial Challenge of drug fever in 2 Dallas hospitals from Clinically, patients with drug fever Test Kit (Aridol® by Pharmaxis) 1959 to 1986 found that episodes of drug look “inappropriately well” and are fever resulted in a mean prolongation of frequently unaware they are febrile. One Tobramycin- hospital stay of 8.7 days, an average in- of the most important clues to detection Ophthalmic Suspension crease of 5 blood cultures, 2.85 more ra- of drug fever is a relative bradycardia (Tobradex® by Alcon) diologic studies, and 0.53 more courses where the heart rate does not increase of .2 While no study evaluating to the extent that would be expected ◆ DELETED another large group of patients has been given the temperature elevation. In gen- Dextran 70 (Generic)† performed since, procedures for ruling eral, a temperature greater than 39°C out infectious and other causes of should elicit a heart rate greater than Polysaccharide Iron Complex have not changed significantly and likely 110 beats per minute (assuming the pa- Liquid (Generic)† still reflect these findings. tient is not on a beta-blocker and has no †Nonformulary and not available Drug fever is difficult to diagnose conduction abnormalities).4 Findings of because it is a diagnosis of exclusion.1,3 leukocytosis, with or without a left shift, ◆ INTERCHANGES The febrile response should coincide peripheral , and erythrocyte Digibind® for Digifab®‡ temporally with the administration of a sedimentation rate of greater than 100 new drug and occur in the absence of mm/hour complicate the diagnosis of ® ‡Once Digibind supplies are underlying conditions that could con- drug fever and warrant further investi- exhausted, it will be interchanged 3 to Digifab® tribute to the cause. Practitioners should gation of infection. always have drug fever on their differen- In 18-29% of patients with drug fever, ◆ CRITERIA-FOR-USE CHANGES tial, especially if the patient is receiving cutaneous manifestations of hypersensi- an agent that is frequently implicated tivity are also present and allow for eas- Epoprostenol with fever. These agents include anti- ier identification of a as the ® ® (Flolan and Veletri )* biotics (especially beta-lactams and source of fever.3 Fever is most commonly *Restricted: Must use EPIC order set sulfonamides), antineoplastics, anti- caused by hypersensitivity to a drug and convulsants (especially and may precede more overt clinical mani- IV (Cardene® IV)* ), antiarrhythmics (mainly festations of a drug reaction. Drug fever *Restricted use expanded to select and ), and other due to hypersensitivity may develop adult uses cardiac (methyldopa).1 over several days to weeks;however, Treprostinil IV (Remodulin®)* Drug fever can occur at any point dur- if the drug is discontinued and rein- *Restricted: Must use EPIC order set ing a course of therapy with significant troduced days, months, or years later, variation among patients.3,4 The median fever will likely develop within hours of time to presentation of fever is 7 to 10 re-administration. days, with a faster onset with antineo- (continued on page 4) (continued on next page) plastic agents (median 0.5 days) and

◆ CRITERIA-FOR-USE CHANGES (cont.) Formulary update, from page 1 or enteral dosage form when other medi- consensus is that the mannitol test is Intravenous (IV) acetaminophen is cations are being given orally or enterally. a more specific but less sensitive test an antipyretic and analgesic with FDA- Rectal acetaminophen is an alternative to than the methacholine challenge test. labeled indications for use in adults and IV acetaminophen that should always be Many trials have examined the children (greater than 2 years old) for considered. diagnostic properties of both the management of pain and fever. Formu- Since, IV acetaminophen should be mannitol and methacholine challenge lation issues previously limited acet- used only when patients cannot take tests. One of the main limitations seen aminophen’s IV stability and its use as other oral medications, using more than 4 across all studies is the fact there is no an injectable agent. IV acetaminophen grams per day of acetaminophen should “gold-standard” definition for asthma has fewer local adverse events and not be a concern with IV acetaminophen. diagnosis to compare the challenge test similar efficacy to propacetamol, the Overdose remains a concern with oral results. Consequently, the definition intravenous prodrug of acetaminophen acetaminophen and acetaminophen for asthma diagnosis is highly variable that has been used in Europe. combinations like Percocet®, and pre- across studies. This affects overall gen- IV acetaminophen works centrally to scribers should monitor the total dose eralizability of study results since it is inhibit cyclooxygenase (COX) enzymes of acetaminophen (eg, do not exceed 4 possible that diagnoses of asthma will to disrupt prostaglandin synthesis. grams per day in adults). vary from physician to physician. Other The for analgesia and Carglumic acid is a carbamoyl phos- limitations of these trials include pos- antipyretic effects is expected to occur phatase synthetase 1 (CPS1) activator sible sampling bias and the utilization within 15 and 30 minutes, respectively, with labeled indications for the treatment of younger population samples. of the start of the infusion. Prescrib- of acute hyperammonemia due to the Although most studies indicated ers should remember, however, that it deficiency of the hepatic enzyme N-acetyl- that mannitol is a more specific test is just an intravenous dosage form of glutamate synthase (NAGS) and for main- than methacholine, 1 study found that acetaminophen and works just like oral tenance therapy of chronic hyperammo- the sensitivity and specificity for both and rectal acetaminophen. nemia due the deficiency of NAGS. NAGS mannitol and methacholine to identify IV acetaminophen is supplied as a deficiency is a rare disorder, and, there- exercise-induced bronchospasm and 100-mL, single-use vial of 10 mg/mL fore, its safety and efficacy was evaluated a clinician diagnosis of asthma were and is administered as a 15-minute in only 23 patients before it was approved equivalent. Unlike populations in other infusion. The labeled dose for adults by the FDA. Few cases of NAGS deficiency studies, the population evaluated in this and adolescents greater than 50 kg is have been reported and the overall inci- study consisted of subjects with normal 1000 mg every 6 hours or 650 mg every dence is unknown. NAGS deficiency is one FEV1, mild symptoms, and mild airway 4 hours. Children 2 to 12 years of age of several urea cycle disorders. hyperresponsiveness. Essentially, and adolescents less than 50 kg should In February, the P&T Committee these subjects did not have a confirmed receive 12.5 mg/kg every 4 hours or designated carglumic acid a high-priority diagnosis of asthma; they only had 15 mg/kg every 6 hours. There is no nonformulary drug with instructions in symptoms suggestive of asthma. This advantage for the 4-hour dosage inter- our computer systems on how to obtain population is, therefore, more analogous val, which is more expensive because it. Carglumic acid is available from Ac- to populations in which these challenge it uses more product and increases credo, and we have already purchased it tests would actually be utilized. waste. twice when a patient was admitted and The mannitol challenge test was In studies evaluating IV acetamino- could not provide their own supply. added in the Formulary as an alterna- phen’s use in adults, it was effective The original assumption for designat- tive to the methacholine challenge test. when compared to placebo for post- ing this product a high-priority nonfor- It should be used as part of a clinician’s operative analgesia. Studies show a mulary drug was that it would rarely be overall evaluation of asthma and should decrease in use in the first 24 used. It is very expensive and has a short not serve as the sole criterion for diag- hours when IV acetaminophen is used. shelf life. A 5-tablet bottle costs $685 nosis or as a screening test for asthma. There are no published studies ($137 per tablet), while a 60-tablet bottle Patients must not have a past medical comparing oral or rectal acetaminophen costs $8220. Bottles must be discarded 1 history significant for aortic or cerebral to the IV route, and the suggestion that month after opening. The 60-tablet bottle aneurysm, uncontrolled , IV acetaminophen is less hepatotoxic will not be purchased for inpatient use. recent myocardial infarction, or cere- or more effective is not supported by The courier service that delivers this bral vascular accident. Patients must evidence. product charges over $500 for delivery. have an FEV1 greater than 70% of the The cost of a vial of IV acetamino- This high cost of delivery, the fact we an- predicted value in order to qualify for phen is more than 170 times more ticipate using this product, and its unique administration of the mannitol broncho- expensive than oral acetaminophen therapeutic niche made addition in the provocation tests. The challenge test and more than 40 times more expen- Formulary the preferred option. must be stopped if after administration sive than acetaminophen suppositories. Inhaled mannitol powder is an alterna- of the 0-mg dose (control), the patient’s Small IV doses used in children waste tive to methacholine for the assessment of FEV1 drops 10% or more from the pre- most of a vial because it is a single- bronchial hyperresponsiveness in patients challenge value. dose vial (ie, once a vial is opened, 6 years of age or older who do not have Tobradex® is an ophthalmic mixture it cannot be stored and used later). clinically apparent asthma. It is in a ready- of the aminoglycoside tobra- Therefore, this agent could have a to-use form and eliminates the need to mycin and the corticosteroid dexameth- significant impact on pharmaceutical make dilutions of methacholine in the IV asone. Both individual ingredients are expenditures, which will be closely Center. listed in the Formulary. The addition of monitored. Bronchoprovocation tests are used to this dosage form in the Formulary was IV acetaminophen was restricted assess, quantify, and establish airway based on the volume of nonformulary to post-operative use up to 24 hours hyperresponsiveness associated with requests. and as a single dose in the ED. Further asthma. Bronchoprovocation tests serve Dextran 70 is a colloid volume ex- restrictions include no PRN orders, no as an objective tool for establishing a pander. It was an alternative to albumin inclusion in EPIC order sets (except in diagnosis of asthma. The 2 classes of or crystalloids like saline. All dextran 70 the PACU), and only dosage regimens bronchoprovocation tests used are direct products are now off the market; there- for every-6-hour intervals in adults and (methacholine and histamine) and indi- fore, it was deleted from the Formulary children (ie, no every-4-hour regimens). rect challenges (mannitol). The available and designated nonformulary and not Also, it was added in the IV-to-PO data are conflicting in terms of which is available. policy permitting conversion to an oral the better diagnostic tool, but the general (continued on next page) 2 Formulary update, from page 2 ner equivalent to Digibind®. Both Digifab® Studies have shown the safety and ef- Polysaccharide-iron complex is and Digibind® effectively lowered the ficacy of nicardipine in acute stroke pa- intended to provide an oral iron supple- levels of free to below detectable tients when compared to sodium nitro- ment with less gastrointestinal adverse in all subjects studied. prusside and to IV labetalol with fewer effects. These products were added in Therefore, the therapeutic interchange adverse events seen with nicardipine. the Formulary in 1992 without evidence of Digifab® and Digibind® was approved Guidelines recommend the use of to support superiority over ferrous by the P&T Committee. Epoprostenol and nicardipine for blood pressure manage- sulfate. treprostinil are prostaglandins used intra- ment in stroke patients and that sodium Since the liquid version of this venously for the treatment of pulmonary nitroprusside should be avoided due to product is no longer on the market, arterial hypertension. These agents are its ability to increase ICP. Additionally, it was deleted from the Formulary difficult to use correctly and there can be nicardipine has been proven safe and and designated nonformulary and not confusion between different brands of the effective for the management of hyper- available. Ferrous sulfate drops are the same product (eg, Flolan® and Veletri®), tensive emergency and perioperative liquid alternative to polysaccharide-iron which may be dosed and administered hypertension and is recommended in complex liquid listed in the Formulary. differently. guidelines for these indications. Polysaccharide iron-complex capsules Restricting these agents to EPIC order The criteria for IV nicardipine were remain in the Formulary. sets was intended to encourage the safe extended to include adult patients who Digibind® and Digifab® are both use of these products. The order set require continuous infusion agents for digoxin immune fab products. There guides prescribers, particularly prescrib- blood pressure management. However, are no clinically relevant differences ers who do not specialize in the use of it should be used only when blood pres- reported in administration, storage, these agents, by using standardized con- sure is either poorly controlled with the dosing, efficacy, and safety of Digibind® centrations, dosages, monitoring, and ad- formulary alternatives or when patients and Digifab®. ministration. In addition, they recommend have experienced an adverse reaction Digibind® is being discontinued from additional drugs to support the use of or have a contraindication to formulary the market. Once supplies of Digibind® these agents. This should improve safety alternatives. The following will be used are exhausted, Digibind® will be deleted for these high-risk, rarely used drugs. to determine whether a patient meets from the Formulary and designated non- Nicardipine IV has been listed in the these criteria: formulary and not available. Digifab® Formulary but restricted to PICU for use n Continuous infusion medication will then be stocked. Because the use of in patients with renal failure who have required for blood pressure control these products is not predictable, it is failed initial hypertension management and 1 of the following: not clear when this will occur; however, with a labetalol infusion. It was reviewed • Failure of combination sodium the Digibind® in stock will expire in because of concerns about toxicity and nitroprusside and labetalol defined 2013. adverse events that have occurred with as less than a 15% decrease in Digoxin immune fab is a protein that formulary alternatives for IV nicardipine blood pressure after 1 hour OR not consists of antibody fragments that are in adults. These adverse events include reaching blood pressure goal after used as an antidote for toxicity. cyanide toxicity (associated with the use 2 hours on sodium nitroprusside Digibind® is produced by immunizing a of sodium nitroprusside) and difficult- 3 mcg/kg/min and labetalol sheep with digoxin coupled to human to-reverse upon anesthesia 120 mg/hr. albumin, then isolating immunoglobu- induction (which has been associated • Failure of sodium nitroprusside lins from the sheep serum and then with labetalol use in patients undergoing in patients with contraindication/ obtaining specific antibody fragments neurosurgery). ADR to labetalol. Failure defined from the immunoglobulins. Digifab® is Nicardipine is a dihydropyridine as less than a 15% decrease in produced in a similar manner except blocker approved for blood pressure after 1 hour OR not that digoxindicarboxymethlyamine (a management of hypertension when oral reaching blood pressure goal after digoxin derivative) is used instead of therapy is not feasible or desirable. It has 2 hours on sodium nitroprusside digoxin coupled to human albumin. also been shown to be safe and effective 3 mcg/kg/min. Digibind® and Digifab® come as for blood pressure control in the setting • Contraindications/ADRs to labetalol sterile lyophilized powders that are of neurological injury and perioperative defined as one of the following: reconstituted with 4 mL of sterile water. hypertension in both cardiac and non-car- – Heart rate less than 60 beats Each vial of Digibind® contains 38 mg diac surgeries. It is as effective as sodium per minute of digoxin immune fab, while each vial nitroprusside in the reduction of blood – 2-3 degree heart block of Digifab® contains 40 mg of digoxin pressure. Nicardipine's advantages include – Cardiogenic shock immune fab. Each vial of Digibind® or a relatively fast onset and offset, a lack of – Acute decompensated heart Digifab® binds approximately 0.5 mg of association with the accumulation of toxic failure digoxin. Digibind® and Digifab® must metabolites like sodium nitroprusside, – Sick sinus syndrome be stored in the refrigerator and, once and a lack of association with an increase • Failure of labetalol in patients with reconstituted, must be used within 4 in intracranial pressure (ICP). Nicardipine contraindication/ADR to sodium hours. Both Digibind® and Digifab® can has a faster onset of action than sodium nitroprusside. Failure defined be diluted with sterile isotonic saline to nitroprusside, is associated with fewer as less than a 15% decrease in a convenient concentration. Both should adverse events than sodium nitroprusside, blood pressure after 1 hour OR not be administered by intravenous infusion requires fewer dosage adjustments than reaching blood pressure goal after for at least 30 minutes, but they can be sodium nitroprusside or labetalol, and may 2 hours on labetalol 120 mg/hr. given as a bolus in case of imminent confer in-hospital mortality benefit com- Contraindications/ADRs to sodium cardiac arrest. All calculations and for- pared to sodium nitroprusside in patients nitroprusside defined as any one of mulas used in the treatment of digoxin with intracerebral hemorrhage (ICH). the following: toxicity with Digibind® also apply to Nicardipine can be administered in large – Renal Failure defined as one of Digifab®, so no adjustments in dosing peripheral veins; however, the peripheral the following: requiring hemo- will be necessary due to the transition infusion site must be changed every 12 dialysis, anuric for 12 hours, from Digibind® to Digifab®. hours to avoid adverse administration tripling of serum creatinine (SCr) A study done in healthy patients to reactions. Disadvantages to nicardipine from baseline, SCr greater than compare the of Digi- include cost, contraindication in aortic 4, urine output less than 0.3 mL/ fab® and Digibind® shows that Digifab® stenosis, and the potential for interaction kg/hr for 24 hours binds and neutralizes digoxin in a man- with anesthetics. (continued on next page) 3 Drugs & Therapy SHANDS NON-PROFIT ORG. B N U N L N L N E N T N I N N Shands at the University of Florida U.S. POSTAGE DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 25, No. 6 June 2011 PO Box 100316 PERMIT NO. 94 Gainesville, FL 32610-0316 This publication is produced by the Drug Information and Pharmacy Re- source Center under the direction of the Department of Pharmacy Services and the Pharmacy and Therapeutics Committee. EDITOR, DRUGS & THERAPY BULLETIN Randy C. Hatton, PharmD DIRECTOR, PHARMACY SERVICES Alan Knudsen, MS, RPh CHAIRMAN, PHARMACY & THERAPEUTICS COMMITTEE I. David Weiner, MD Professor of Medicine and Physiology and Functional Genomics University of Florida, College of Medicine EDITING, DESIGN, & PRODUCTION Shands HealthCare’s Publication Svcs. © Copyright 2011. All rights reserved. No portion of the Drugs & Therapy Bulletin may be reproduced without the written consent of its editor. 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Adverse drug reactions, from page 1 , aztreonam, tetracy- tests and exposure to antibiotics until A review of drug fever during antibi- clines, macrolides, , fluoroqui- infection is ruled out. Drug fever does otic administration was performed in a nolones, and aminoglycosides.4 not present in a classic manner and is a University hospital in Japan during the After discontinuing the offending challenging diagnosis. It is appropriate late 1980s.5 In their study, they found agent, rapid defervescence should oc- to keep medications near the bottom of that 13% of patients (51 of 390) being cur within 72 hours. Rechallenging the the differential for fever until more seri- treated with antibiotics for respira- patient with the suspected drug is very ous causes have been ruled out. tory for more than 7 days controversial and should only be per- By Danielle Lazear, PharmD developed a fever of 37.5°C (99.5°F). It formed if the benefit of confirming the REFERENCES was found that 49 of the 56 episodes of diagnosis of drug fever outweighs the 1. Dimopoulos G, Falagas ME. Approach to the Febrile Patient risk of hypersensitivity.4 Additionally, in the ICU. Infect Dis Clin N Am. 2009;23:471–484. fever were greater than or equal to 38°C 2. Mackowiak PA, LeMaistre CF. Drug Fever: A Critical Appraisal (100.4°F) and they were all unrelated to testing for antidrug antibodies or his- of Conventional Concepts. Ann Intern Med. 1987;106:728- a true infectious process. Beta-lactams tone antibodies does not confirm or rule 733. 3. Patel RA, Gallagher JC. Drug Fever. Pharmacotherapy. were the agents primarily used in this out drug-induced fever and is, therefore, 2010;30(1):57-69. study. The onset of drug fever ranged not recommended for evaluation of drug 4. Johnson DH, Cunha BA. Drug Fever. Infect Dis Clin N Am. 1996;10:85-91. from 7 to 35 days and varied based on hypersensitivity as a cause of fever. 5. Oizumi K, Onuma K, Watanabe A, Motomiya M. Clinical previous exposure to a beta-lactam. A patient with drug fever is likely Study of Drug Fever Induced by Parenteral Administration of Fever patterns were most commonly de- to undergo a number of unnecessary Antibiotics. Tohoku J Exp Med. 1989;159:45-56. scribed as low-grade at onset, followed by high and remittent fever. Eosinophilia was found in 25% of patients. Formulary update, from page 3 Additionally, nicardipine IV was In the febrile patient completing – Lactate greater than 4 or 20% approved for the limited population of antimicrobial therapy for a resolving increase from baseline patients with an acute intracranial pro- infection, it is recommended to discon- – Methemoglobinemia cess in whom operative intervention is tinue therapy if the infection is resolved – Elevated ICP planned within 24 hours for use through the peri-operative period, followed by and further infections have been ruled • First line in patients with contra- transition to a more cost-effective con- out.3 If the patient is stable but the indication/ADR to labetalol AND tinuous infusion antihypertensive agent. infection is unresolved, the most likely sodium nitroprusside as described IV nicardipine can be used in adults in offending agents should be removed above. the Emergency Department, Operating and a modification should be made to n Neurosurgery/Neurology patients in the perioperative period (48 hours Room, Post Anesthesia Care Unit, and the antimicrobial regimen so that further before and 24 hours after neuro- Intensive Care Units. A 6-month medica- drug sensitization is avoided. Antibiotics surgical procedure) tion use evalution is planned to assess with a lower association of fever include compliance with these criteria. , vancomycin (new formu- 4 lations are not associated with fever),