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 fever 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- continuous fever (temperature does not ing infection, on antimicrobial therapy, vary), remittent fever (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), intermittent fever (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-Dexamethasone 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 antibiotics.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 fevers 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 eosinophilia, 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 medication 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 phenytoin and may precede more overt clinical mani- Nicardipine IV (Cardene® IV)* carbamazepine), antiarrhythmics (mainly festations of a drug reaction. Drug fever *Restricted use expanded to select quinidine and procainamide), and other due to hypersensitivity may develop adult uses cardiac medications (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 onset of action 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 opioid 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.