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Volume 27, Number 11 December 2013

MEDICATION SAFETY FORMULARY UPDATE The Pharmacy and Therapeutics Re-dosing of reversal agents in Committee met November 19, 2013. 3 drugs were added in the Formulary, the inpatient setting 1 product was deleted, 5 drugs were designated non-formulary and not ntidotes and reversal agents play a minutes to work when administered via available, 1 product was designated Acritical role in both intentional and these alternative routes. The initial dose high-priority non-formulary, and 1 unintentional medication overdose. The of for adults is 0.04-0.4 mg. If therapeutic interchange was approved. ideal or reversal agent would there is no response, the dose should completely counteract the uninten- then be repeated every two to three tional consequences of medication minutes. Doses should be initiated low ◆ ADDED overdose. In a perfect world, this would with increases until an adequate level Diphtheria, Tetanus Toxoid, and be achieved via a single dosage of the of alertness is achieved. If no response Acellular Pertussis, Hepatitis B, antidote. However; this is often not is observed after 10 mg, the respiratory depression is likely not due to opioid in- and Inactivated Poliovirus the case. A number of agents require intense monitoring post-administration toxication.[3] After naloxone administra- (Pediarix®) (vital signs, laboratory values, etc.) with tion, monitor for a reduction in opioid ef- Hydroxyethyl Starch 6% Solution potential re-administration necessary fects in regards to blood pressure, heart (Voluven®)* to treat continued adverse effects. This rate, and respiratory rate. Naloxone may *Restricted to submucosal injections article serves to summarize common also precipitate signs and symptoms of during endoscopic resection. antidote and reversal agents utilized at opioid withdrawal such as: abdominal UF Health Shands Hospital. cramps, shaking, chills, nausea, vomit- Poractant alfa (Curosurf®) Opioid analgesia is considered a rela- ing, and diarrhea.[3] ◆ DELETED tively safe treatment option for patients, Benzodiazepines (BZDs) are widely although sometimes associated with ad- prescribed for anxiety in the outpatient Calfactant (Infasurf®) verse events, the most serious of which setting, but are also used for other indi- is respiratory arrest. The risk of adverse ◆ NON-FORMULARY AND cations while patients are in the hospi- consequences of therapy increases tal. is a competitive inhibitor NOT AVAILABLE with higher opioid doses, the morbidly of the gamma aminobutyric acid (GABA) Bupivacaine Liposomal (Exparel®) obese, pediatric and geriatric popula- receptor (BZD binding site) and is used tions, critically ill patients, and also to reverse benzodiazepine-related seda- ® Calfactant (Infasurf ) those who receive concurrent central tion. The classic presentation of BZD Etidronate (generic) nervous and respiratory depressants overdose manifests as CNS depression (such as anxiolytics and sedatives).[1] At with slurred speech, ataxia, and altered Lispro (Humapen® the bedside, the most easily recogniz- mental status with more severe toxici- LuxuraTM) able sign of is a decline ties resulting in lethargy or coma.[5] The in respiratory rate. A rate of 12 breaths recommended dose for sedation reversal Vortioxetine (Brintellix®) per minute or less strongly suggests is 0.2 mg given IV over 30 seconds. ◆ HIGH-PRIORITY an opioid intoxication, predominantly Repeated doses of 0.2 mg up to a maxi- NON-FORMULARY when the patient is lethargic as well. mum single dose of 1 mg administered [2] Naloxone, an antidote for opioid over 30 seconds may be given at one ® Insulin Glulisine (Apidra )* intoxication, is a competitive mu opioid- minute intervals until the desired effect *Restricted to use in insulin pump only. receptor antagonist which causes a is achieved, with no more than 3 mg of ◆ THERAPEUTIC INTERCHANGES reversal of all signs and symptoms of flumazenil given within one hour.[6] The opioid intoxication. The onset of action reversal of BZD toxicity occurs rapidly, Vitamin B Complex Tablet§ of IV naloxone is less than two min- approximately 6-10 minutes after IV ad- §Interchanged to individual ingredients: 50 mg, niacin 50 mg, cyano utes and has a duration of action of 20 ministration. As with naloxone, the du- cobalamin 50 mcg, and pyridoxine to 90 minutes (a much shorter period ration of the flumazenil is much shorter 50 mg of action than that of many opioids). than many of the agents it is reversing. Common opioid elimination half-lives Many benzodiazepine elimination half- are listed in Table 1. Doses may also be lives are listed in Table 1. In the event administered intramuscularly, subcuta- of re-sedation, repeated doses may be (continued on next page) neously, or orally, but may take up to 15 (continued on page 5) Formulary update, from page 1 animal studies and 1 small human study Initial concerns with a switch to showing extended duration of “lift” when poractant included the need to Diphtheria, Tetanus Toxoid, and HES is used in comparison to normal maintain calfactant in the Formulary Acellular Pertussis, Hepatitis B, and saline. The data concluded that HES was for treatment of meconium aspiration Inactivated Poliovirus (Pediarix®) superior to NS in the provision of an in full term infants (no surfactant combination vaccine is indicated for elevated time of mucosal cushion after product currently carries FDA approv- patients at least 6 weeks of age to 6 injection in patients with lesions > 3 cm. al for this indication). However, a years of age born to HBsAg negative The use of this agent was not study published in China indicated the mothers. The CDC currently recom- requested as a wholesale conversion, safety and efficacy of poractant use in mends vaccination for Hepatitis B, but rather for use in patients with full term babies for this indication. The DTaP, Hib, PPSV 23 and IPV at 2, 4, lesions greater than 2 cm, with early neonatal physician group has indi- and 6 months of age. cancer or high-grade dysplasia (approxi- cated approval to use poractant in the In infants who are born premature- mately 5 patients per month with full term babies which would elimi- ly, it is possible that they would expected growth as program expands). nate the need to maintain two receive their 2, 4 and 6 month At the current rate, this switch will be products in the Formulary. vaccinations while in the hospital. effectively cost-neutral. The P&T The Committee recommended that This would require 3 needle sticks approved addition of this product in the poractant be added in the Formulary secondary to lack of a combination and calfactant be removed and be vaccine available in the Formulary. Formulary with a restriction to submu- designated non-formulary and not Historically, UF Health has carried cosal injection. Intravenous administra- available. In addition, the Committee only single entity vaccines due to the tion of this agent will not be allowed. ® recommended that calfactant be wide availability of vaccinations in Poractant alfa (Curosurf ) was FDA retrospectively reviewed for incidence the outpatient setting. approved in November of 1999 for the of ET tube occlusion and/or airway Evaluation of current practices treatment (rescue) of respiratory occlusion. Poractant would be indicated a potential for decreased distress syndrome (RDS) in premature evaluated for these same adverse needle sticks in infants who remain infants. It is an extract of natural outcomes at a 6 month time period. hospitalized for prolonged periods of porcine lung surfactant which consists

time. A cost evaluation was per- of 99% polar lipids and 1% hydrophobic Bupivacaine Liposomal Injection ® formed which yielded annual low molecular weight proteins (surfac- (Exparel ) was approved by the FDA cost-avoidance with conversion to the tant associated proteins SP-B and SP-C). in October 2011 for single-dose combination vaccination secondary to This agent was requested for addition infiltration into the surgical site prior potential elimination of poliovirus in the Formulary secondary to the to bunionectomy or hemorrhoidectomy vaccine waste. The Committee voted supposition that this agent results in a to produce post-surgical anesthesia. In to add Pediarix® in the Formulary lower incidence of endotracheal tube January 2012, the P&T Committee while retaining the single-component (ET tube) reflux than our current designated bupivacaine liposomal vaccines for use in patients not surfactant product, calfactant. injection non-formulary and not requiring the combination series. Administration of any surfactant available. The Committee stipulated Hydroxyethyl Starch 6% (Voluven®) carries a risk of ET tube occlusion and that this product could be re-evaluated was designated non-formulary and reflux as well as complete airway if published literature provided not available in August 2013. The obstruction. Product labeling for sufficient evidence that it would be Pharmacy and Therapeutics Commit- calfactant indicates it has a 23% cost-effective in the inpatient setting. tee removed all hydroxyethyl starch incidence of ET tube occlusion/reflux In August 2013, liposomal bupivacaine (HES) products at that time second- versus no listed incidence with porac- was evaluated at the request ary to a June 2013, FDA-issued tant alfa. An open label comparison of of The Department of Surgery for MedWatch. This MedWatch noted poractant to calfactant boasts a statisti- use in hemorrhoidectomy and that intravenous HES should not be cally significant difference in ET tube rectal surgeries. used in critically ill adults secondary occlusion rates (3.5% vs. 13.2% respec- Bupivacaine liposomal injectable to increased risk of morbidity, tively, p< 0.001). It has been proposed suspension is an extended-release including bleeding and renal injury, that administration of calfactant as a formulation of bupivacaine. It works as well as mortality. Since that time continuous infusion via syringe pump as a local anesthetic whereby upon period, the use of 6% HES for may lessen the incidence of reflux into injection, bupivacaine is released from submucosal injection during endo- the ET tube. multivesicular liposomes over time scopic mucosal resection (EMR) was A cost analysis was performed and with resultant analgesia up to 72 requested by the Department of showed that when using equivalent hours. Bupivacaine exerts its anes- Gastroenterology. EMR is used to dosing (i.e. same number of doses) thetic effect by blocking the genera- treat precancerous gastrointestinal annual expenditures would be expected tion and conduction of nerve impulses. lesions as well as early malignancies, to increase approximately $84,000. This is accomplished through revers- including laterally spreading tumors However, there is limited data that ible binding to voltage-gated sodium in the colonic wall. Historically, 0.9% shows that when poractant is utilized, channels which inhibits sodium influx. normal saline in combination with repeat dosing is often unnecessary. An open-label colectomy trial epinephrine has been utilized as Conservative estimates indicate that we compared multimodal analgesia submucosal injection to provide a could reduce the incidence of re-dosing (bupivacaine liposomal, NSAID and “fluid cushion” for a safe and by about 25% in our NICU population. acetaminophen) to an opioid-based effective resection. This would decrease the annual expendi- analgesia regimen. This was a Recently, data supporting the use of ture increase to less than $60,000. Of non-randomized, prospective sequen- HES for this purpose has emerged with note, this is only an estimate. (continued on next page) 2 Formulary update, from page 2 comprising of members of pharmacy, recommended dose varies depending tial cohort study which had 39 anesthesia, nursing, risk management, on the indication with dosing for the patients. A reduction of approximate- and OR services met to develop a prevention and/or treatment of HO in ly 50% in morphine equivalents proposal for safe medication administra- burn patients not well-defined. (p=0.025), a 26% decrease in hospital tion of liposomal bupivacaine in the OR. A retrospective cohort study cost (p=0.027) and a 59% reduction in The main safety concerns centered examining all adult patients with 25% median length of stay post-surgery around the appearance of the medica- or greater total body surface area (p=0.004) was noted in the multimod- tion and its potential for mix up with (TBSA) thermal burns admitted to the al treatment arm. The authors propofol as well as an inability to easily Arizona Burn Center over a three-year concluded that these results were identify patients who received the long period evaluated the incidence of HO both clinically and statistically acting product and ensure they did in burn patients treated prophylacti- significant. The clinical significance is not receive additional bupivacaine cally with etridronate. This was debatable as the primary endpoint post-operatively. compared to patients who did not examined opioid use in two distinctly Limitations in the proposal and receive any prophylactic therapy. The different treatment arms. Confound- potential points of error were discussed two groups were well matched for ers, including the use of NSAIDs and and again centered around administra- age and sex but the etidronate group acetaminophen in the multimodal arm tion of the drug intravenously in error. had significantly greater mean compared to liposomal bupivacaine Upon presentation of the suggestions as %TBSA involvement (p = 0.03), a alone, may have altered the well as limitations, the Medication characteristic associated with an reported results. Safety and Pharmacy and Therapeutics increased risk of HO development. Another study evaluated hemor- Committee agreed that there were still The results of the study showed that rhoidectomy procedures in a random- significant points in the process where 46.4% of those treated with etidronate ized, double-blind, parallel phase II human error would potentially occur. developed HO while only 13.8% of the active control study. It included 100 The P&T Committees noted that efficacy untreated group did (p = 0.01), with patients and compared 75 mg data did not outweigh the significant all ossification occurring in the elbow. bupivacaine plus epinephrine safety concerns associated with use of Patient assignment to groups was not 1:200,000 to three doses (66 mg, 199 this medication and therefore desig- randomized – the decision to treat mg and 266 mg) of bupivacaine nated the product non-formulary and with etidronate was left up to the liposome injection. Statistically not available. surgeon. Thus, patients with larger significant reductions in mean area Etidronate is a first generation burns and therefore a higher likeli- under the curve cumulative pain bisphosphonate which was reviewed for hood to develop HO may have been scores from 0-72 hours were noted for the treatment and prevention of preferentially treated with etidronate the bupivacaine liposome injection heterotopic ossification (HO) in burn (selection bias). However, when 199 mg and 266 mg groups. The rehabilitation patients. Like other %TBSA alone and %TBSA, age, and authors concluded that these results bisphosphonates, etidronate binds sex were controlled for via logistic were both statistically and clinically hydroxyapatite crystals in bone regression, the greater incidence of significant. The sample size of this preventing enzymatic degradation by HO in the treatment group persisted study, in conjunction with the osteoclasts. Unlike other bisphospho- and remained statistically significant relatively healthy population makes nates, however, etidronate also binds to (p = 0.004 & 0.03, respectively). the generalizability of this precursors and prevents the aggrega- The most commonly observed study difficult. tion and formation of hydroxyapatite, adverse effects of etidronate in Bupivacaine liposome injection is a thereby reducing mineralization of new clinical trials were generally mild and milky-white substance which creates bone. This characteristic is believed to involved the gastrointestinal tract. a risk of medication error in the OR be the mechanism by which etidronate This medication has been associated environment due to the potential for prevents the formation of heterotopic with fractures when used for extend- confusion between propofol and bone, or bone that forms inappropriately ed periods, due to its unique mecha- liposomal bupivacaine. Intravenous within soft tissue. Central nervous nism of action which results in the injection of the bupivacaine in error system injury, total hip arthroplasty, and inhibition of mineralization of severe burn injury are events that can would result in a catastrophic event. developing bone. Post marketing data precipitate the formation of bone in soft The Committee felt a formal investi- involving bisphosphonates has gation into the safety of providing tissue areas surrounding major joints. revealed serious adverse effects this medication to patients in the Etidronate has an FDA approved associated with these medications, outpatient OR setting both at UF indication for the treatment of HO including esophageal erosion and Health Shands Hospital and Florida following spinal cord injury and total perforation, which most commonly Surgical Center was necessary. It was hip arthroplasty. occur in concert with incorrect recommended to table the vote for Etidronate is available generically as medication administration. formulary inclusion, and have the 200 mg & 400 mg tablets. Bioavailability Based on the lack of conclusive Medication Safety Committee perform is inherently low (~3% of an oral dose) clinical evidence, serious adverse a Failure Mode and Effects Analysis and can be further reduced to negligible effects related to incorrect administra- (FMEA) to outline a procedure for the levels when the drug is administered tion, and an elevated cost compared safe administration of the product if with food. Specific administration to alternatives, the Committee added in the Formulary. recommendations must be strictly designated etidronate non-formulary The FMEA was conducted and followed to ensure adequate absorption and not available. presented to the Committee in and to reduce the risk of severe side November 2013. An adhoc group effects such as esophageal erosion. The (continued on next page) 3 3 Formulary update, from page 3 equivalent at our institution (with the combination product is designated Insulin Lispro (HumaPen® Luxura™) availability of 0.5 unit titration with the non-formulary and not available. A ® is a rapid-acting insulin analog NovoPen Junior device), the increased therapeutic interchange was proposed commonly used in combination with potential for medication errors associ- to allow the conversion to four basal insulin for glucose control in ated with addition of insulin lispro, and separate tablets including: thiamine 50 patients with diabetes. From 2000 to the alternative methods available for mg, niacin 50 mg, cyanocobalamin 50 2002, insulin lispro was in the training patients before discharge, the mcg, and pyridoxine 50 mg. This interchange will direct prescribers to Formulary at UF Health Shands Committee designated insulin lispro as the appropriate products and allow for Hospital, but it was replaced by the non-formulary and not available. It was automatic conversion in order to satisfy rapid-acting analog in proposed that UF Health pursue acquisi- ® the medication order. This interchange 2002 primarily due to cost consider- tion of HumaPen Luxura™ training was approved by the Committee. ations. Insulin lispro was reviewed for devices such as “dummy pens” if it is desired that patients are trained on that addition in the Formulary as the specific device prior to discharge. HumaPen® LuxuraTM device, which Vortioxetine (Brintellix®) inhibits the allows for dosing in 0.5 unit incre- reuptake of serotonin while antagoniz- ments, an important consideration in ing 5-HT3, 5-HT1D, and 5-HT7 receptors some pediatric patients. Addition of and agonizing 5-HT1A and partially ago- this insulin/device would allow nizing 5-HT1B receptors. It is approved patients who would utilize this device for once daily administration for the as an outpatient to be trained on its treatment of major depressive disorders. use prior to discharge. The dose of vortioxetine is 5-20 mg/day The efficacy of insulin lispro is well without regard to meals. Data indicates established in adults, adolescents, and vortioxetine may be abruptly discontin- children at least 3 years of age. ued, however, it is proposed that doses Extensive clinical trial evidence exists of 15-20 mg/day be reduced to 10 mg/ showing insulin lispro to be at least as day for a week (when possible) prior to effective as insulin regular in the full discontinuation. control of blood glucose in type 1 and Vortioxetine is contraindicated with type 2 diabetics. Clinical trials in some MAO-I agents and should not be used Drug patient populations have found insulin within 14 days of starting or stopping an lispro to be more effective than regular MAO-I. It should also not be initiated in a information insulin in blunting postprandial spikes patient receiving linezolid or methylene in blood glucose. The overall side blue. A medication guide is suggested questions? effect profile of insulin lispro is similar upon initial fill and refill (although not to that of insulin regular, but some required as part of official REMS). studies have associated insulin lispro Vortioxetine was designated non-formu- Contact the with a reduced incidence of hypogly- lary and not available with patients able cemic events. to take their own medication. Drug Information Service With the advent of subsequent Insulin glulisine (Apidra®) is a rapid-acting analogs, therapeutic rapid-acting insulin product which had equivalence testing was necessary. As previously been unavailable for use at Call 265-0408 a result, head-to-head trials involving UF Health. Periodically, patients are insulin lispro, insulin aspart, and admitted with an insulin infusing pump insulin glulisine have been conducted containing this rapid-acting insulin. The and demonstrate similar pharmacoki- Pharmacy and Therapeutics Committee Or submit your netic/pharmacodynamic properties, recommended allowing patients to question online at effect on glucose management, and utilize their own insulin glulisine when http://professionals.uf- side effect profiles among the agents. housed within an insulin pump on health.org/resources/drug- Insulin lispro is available in multiple admission. Patients would not be able information-and-pharmacy- dosage forms, all with a concentration to utilize their own glulisine pens or resource-center/ of 100 units/mL. Dosage forms include vials while admitted. TM 3 mL prefilled KwikPens , 10 mL vials It was recommended that insulin n This service is for referring containing solution for injection, and 3 glulisine be designated non-formulary, physicians and other healthcare mL cartridges for use in the HumaPen® high priority with use restricted to professionals taking care of UF LuxuraTM administration device. All refilling medication in an existing insulin Health Shands Hospital patients insulin lispro products are marginally pump. Patients should utilize their supply more expensive than insulin aspart (already existing in pump upon admis- n Phones are staffed from 9 am to products (roughly $5 more for lispro as sion); however, when and if the pump 4:30 pm, Monday – Friday opposed to aspart). One concern with runs dry, the pharmacy would obtain having an additional insulin product in insulin glulisine on a high-priority, n All answers are thoroughly non-formulary basis to refill the pump. the Formulary is a heightened risk of researched and referenced confusion potentially leading to Vitamin B Complex orders are often received as admission orders for medication errors. For emergent questions that do not patients receiving this therapy in the Based on the immediate availability need thorough research, go to the outpatient setting. Currently, this of insulin aspart as a therapeutic pharmacy servicing your area. 4 4 Reversal agents, from page 1 minutes.[8] is cleared from UF Health Shands Hospital. This article administered at 20 minute intervals as circulation quickly, with a half-life of highlights these agents that potentially [9] needed with no more than 1 mg given about 7 minutes. The half-life of IV require a second administration and the at once, and a max of 3 mg in one hour. is 60-90 minutes when given methods used to re-dose these medica- [7] After administration of flumazenil, as an infusion, and the amount of tions in order to return the patient to monitor for a return of alertness, reduc- heparin received in the previous 2-3 their previous state. tion in sedation, and the ability to obey hours is used to calculate the dose of commands. The potential for re-seda- protamine administered. The aPTT –Stephanie Worrall, Pharm.D. tion is high when used following the should be measured in 5-15 minutes REFERENCES 1. Paice JA, Gordon DB, Contreras J, et al. Safe administration of long-acting benzo- after protamine is given, then again in use of opioids in hospitals. Sentinel Event Alert diazepines. Flumazenil administration 2-8 hours to determine the effective- 2012;48:1-5. 2. Boyer EW. Management of Opioid Analgesic Over- carries a risk for cardiac arrhythmias ness and need for re-dosing. dose. N Engl. J Med 2012;367:146-55. and signs/symptoms of benzodiazepine If a low molecular weight heparin 3. International Medication Systems, Limited. Nalox- one hydrochloride injection package labeling. So. El withdrawal (including seizures, hot (LMWH) has been given within the Monte, Ca 91733. Revised Apr 2012. flashes, tremors, and agitation.)[6] previous 8 hours, protamine should be 4. Barr J, Fraser GL, Puntillo K, et al. Clinical Practice Guidelines for the Management of Pain, Agitation, Therapeutic anticoagulation reduces given at a dose of 1 mg per 100 anti-Xa and Delirium in Adult Patients in the Intensive Care the risk of thromboembolism, but may units (1 mg enoxaparin equals approxi- Unit. Crit Care Med 2013;41(1):263-306. [8] 5. Weinbroum AA, Flashon R, Sorkine P, et al. A risk- place the patient at a higher risk of mately 100 anti-Xa units). A second benefit assessment of flumazenil in the management bleeding. The treatment of clinically dose of 0.5 mg protamine per 100 of benzodiazepine overdose. Drug Saf 1997;17:181. 6. Akorn-Strides, LLC. Flumazenil package insert. significant severe bleeding due to hep- anti-Xa units should be administered http://dailymed.nlm.n ih.gov/dailymed/lookup. arin therapy is achieved with neutral- if bleeding continues. Unlike unfrac- cfm?setid= 11882e93-aa624d24-895c-6f01d97fc730. Accessed on November 19, 2013. ization by protamine sulfate. Protamine tionated heparin, reversal of LMWH is 7. Marraffa JM, Cohen V, Howland MA. for binds to heparin, forming an inactive incomplete and difficult to measure. toxicological emergencies: A practical review. Am J Health Syst Pharm 2012;69(3):199-212. complex that is rapidly cleared, normal- To reverse the anticoagulation effect 8. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral izing clotting times. Side effects of of warfarin in patients with clinically Antithrombotic Therapy and Prevention of Throm- bosis, 9th ed: American College of Chest Physicians protamine can include or significant bleeding, administer vitamin Evidence-Based Clinical Practice Guidelines. Chest bradycardia, which can be minimized K (phytonadione). The full reversal ef- 2012;141(2 Suppl):e24S-e43S. 9. Ainle FN, Preston RJ, Jenkins, PV, et al. Protamine by administering protamine slowly. fect of the INR has been shown to take sulfate down-regulates generation by inhib- Those who have previously received up to 24 hours, therefore for immediate iting factor V activation. 10. Ageno W, Gallus A, Wittowsky A, et al. Oral protamine sulfate-containing insulin reversal during serious or life-threat- Therapy: Antithrombotic Therapy and (NPH) or those sensitive to fish, are at ening bleeds, it must be used together Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical an increased risk to have previously with faster-acting agents such as fresh Practice Guidelines. Chest 2012;141(2 Suppl): formed antibodies and experience aller- frozen plasma (FFP) or prothrombin e44S-e88S. [10-11] 11. Bauer KA. Reversal of antithrombotic agents. Am gic reactions, including .[8] complex concentrate (PCC). The J Hematol 2012;87:S119-S126. A dose of 1 mg IV protamine will management of supratherapeutic INRs 12. Guyatt GH, Aki EA, Crowther M, et al. Antithrom- botic Therapy and Prevention of Thrombosis, 9th ed: reverse approximately 100 units of is detailed in Table 2. American College of Chest Physicians Evidence- heparin remaining in the patient, with Many of the medications discussed in Based Clinical Practice Guidelines. Chest 2012 a maximum of 50 mg given over 10 the article are used daily in practice at Table 1. The reversal agents and their durations

1 1 Medication Class (t /2) Reversal Agent (t /2) Monitor Opioids4 Naloxone3 • Reduction in opioid drug effects: including respiratory • Fentanyl (2-4 hours) (30-80 minutes) depression, blood pressure, heart rate, and respiratory rate • Hydromorphone (2-3 hours) • Signs and symptoms of opioid withdrawal: abdominal cramps, rhinorrhea, sialorrhea, anxiety, diaphoresis, • Morphine (3-4 hours) shaking chills, gooseflesh of the skin, nausea, , • Methadone (15-60 hours) and diarrhea) Benzodiazepines4 Flumazenil6 • Return of alertness, reduction in sedation, the ability to • Midazolam (3-11 hours) (54 minutes) comprehend and obey commands, and improvements in time/space orientation • Lorazepam (8-15 hours) • Re-sedation and respiratory depression, hyptonia, • (20-120 hours) somnolence, areflexia, dizziness, and ataxia • Cardiac arrhythmias (bradycardia or tachycardia) and hypertension may develop • Signs and symptoms of withdrawal: seizures, hot flashes, tremors, and agitation Heparin8 Protamine8 • studies, such as heparin titration test with (1-1.5 hours) (7 minutes) protamine or plasma thrombin time, that may reveal a need for additional doses • Blood pressure and heart rate Warfarin10 Vitamin K10 • Reduction in bleeding (60-72 hours) (1.5-3 hours) • Prothrombin time/INR for both therapeutic effect and for excess hypoprothrombinemia

(continued on page 6) 5 UF Health Shands Hospital NON-PROFIT ORG. University of Florida U.S. POSTAGE DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 27, No. 11 December 2013 PO Box 100316 PERMIT NO. 94 This publication is produced by the Gainesville, FL 32610-0316 Drug Information and Pharmacy Resource Center under the direction of the Department of Pharmacy Services and the Pharmacy and Therapeutics Committee. EDITOR, DRUGS & THERAPY BULLETIN Carrie A. Lagasse, PharmD DIRECTOR, PHARMACY SERVICES Thomas E. Johns, PharmD 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 UF Health Shands Publication Services © Copyright 2013. All rights reserved. No portion of the Drugs & Therapy Bulletin may be reproduced without the written consent of its editor. FOR MORE INFORMATION, VISIT US ONLINE http://professionals.ufhealth.org/ resources/drug-information-and- pharmacy-resource-center/bulletins/

Reversal agents, from page 5 Table 2. ACCP recommendations for managing elevated INRs or bleeding in warfarin patients12

INR Management

INR above therapeutic • Lower dose or omit dose, monitor more frequently, and resume at lower dose when INR range but < 5; no is therapeutic significant bleeding • If only minimally above therapeutic range, no dose reduction may be required INR ≥ 5 but < 9; no • Omit next one or two doses, monitor more frequently and resume at lower dose when INR is in significant bleeding therapeutic range • Alternatively, omit dose and give (≤ 5 mg orally), particularly if at increased risk of bleeding • If more rapid reversal is required because the patient requires urgent surgery, vitamin K (2-4 mg orally) can be given with the exception that a reduction of the INR will occur in 24 hours • If the INR is still high, administer an additional 1-2 mg oral vitamin K INR ≥ 9; no significant • Hold warfarin therapy and give higher dose of vitamin K (2.5-5 mg orally) with the expectation bleeding that the INR will be reduced substantially in 24-48 hours • Monitor more frequently and use additional vitamin K if necessary • Resume therapy at lower dose when INR is therapeutic Serious bleeding at • Hold warfarin therapy and vitamin K (10 mg by slow IV infusion), supplemented with fresh any elevation of INR frozen plasma (FFP) • Vitamin K can be repeated every 12 hours, if necessary Life-threatening • Hold warfarin therapy and give fresh frozen plasma (FFP), supplemented with vitamin K (10 mg bleeding by slow IV infusion) • Repeat if necessary, depending on INR • Consider Prothrombin Complex Concentrates

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