Drug Shortage Alert 11/15/2012

Transcription

1 Drug Shortage Alert 11/15/2012 Recommendations and information provided in Drug Shortage Alerts are compiled by experts in the field. Practitioners always are advised to consult with staff to ensure response to any drug shortage is in line with internal policies and procedures. Drug Shortages Alert Loop Diuretics (furosemide, bumetanide, torsemide) Introduction The Society of Critical Care Medicine s Drug Shortages Task Force has identified a shortage leading to variable availability of intravenous loop diuretics, including bumetanide, furosemide, and torsemide. Furosemide Injection o The primary factors contributing to the shortage of this agent include manufacturing delays and an inability to meet market demand. Furthermore, one manufacturer has discontinued production. Torsemide Injection o Two manufacturers have approval for production of torsemide injection, but manufacturing delays have resulted in limited availability. An additional manufacturer has discontinued the product. Bumetanide Injection o Reliable availability of this agent is limited by suspension of production and/or distribution among only four manufacturers. No superiority in dose response exists among the intravenous loop diuretics when used at equipotent doses. However, safety must be considered when switching between drugs with different potencies. In addition, issues with practitioner familiarity need to be considered. This alert provides information on conversion/equivalency between loop diuretics, alternative dosing strategies, and a step-wise approach to diuretic therapy. Additional information and shortage updates can be accessed at

2 Management Strategies Step-wise approach to diuretic therapy: 1. Attempt oral loop therapy if appropriate and augment dose/frequency as indicated based on clinical response (refer to Table 1). a. Intravenous (IV) diuretics should be given for acute pulmonary congestion. b. Torsemide or bumetanide have good bioavailability and may be preferred as oral agents. 2. If the patient is not responding adequately to escalated oral therapy or if oral therapy is inappropriate, switch to IV. 3. Escalate IV dose/frequency. 4. If inadequate response at escalated dose/frequency, consider one of the following: a. Add a thiazide/thiazide-like diuretic to intermittent IV loop diuretic (refer to Table 3).* b. Change to continuous infusion loop diuretic based on availability (refer to Table 2).* *Choosing between these two approaches depends on the clinical condition being treated and evidence of loop diuretic resistance (lack of response to intravenous furosemide doses of 160 mg or equivalent). 5. If patient remains volume overloaded with inadequate response to escalated therapy, initiate continuous infusion loop diuretic and consider addition of a thiazide/thiazide-like diuretic (refer to Table 3). Table 1. Loop Diuretic Comparison to Furosemide Loop Diuretic Bioavailability* Equivalent Dosing Dosing* Frequency Bumetanide (Bumex ) IV 100% 1 mg Daily to Q12H Bumetanide (Bumex ) 80%-90% 1 mg Daily to Q12H Torsemide (Demadex ) IV Not Available Torsemide (Demadex ) 80%-100% 20 mg Daily to Q12H Furosemide (Lasix ) IV 100% 20 mg Daily to Q8H Furosemide (Lasix ) ~50% (varies) 40 mg Daily to Q8H Ethacrynic Acid (Edecrin ) IV 100% 50 mg Daily to Q8H Ethacrynate Sodium (Edecrin ) 100% 50 mg Daily to Q8H *Bioavailability and dose response depends on disease state and prior exposure to diuretics.

3 Table 2. Equipotent Dosing of Continuous Loop Diuretic Infusions Furosemide (Lasix ) Bumetanide (Bumex ) 2.5 mg/hr mg/hr 5 mg/hr 0.25 mg/hr 7.5 mg/hr mg /hr 10 mg/hr 0.5 mg /hr 20 mg/hr 1 mg/hr 40 mg/hr 2 mg /hr Table 3. Thiazide and Thiazide-like Diuretics Thiazide-like Diuretic Bioavailability* Equivalent Recommended Dosing* Dosing Intervals Chlorothiazide (Diuril ) IV 100% 250 mg Daily to Q12H Hydrochlorothiazide 65%-75% 25 mg Daily to Q12H Metolazone (Zaroxolyn ) ** 40%-65% 2.5 mg Daily * Bioavailability and dose response depends on disease state and prior exposure to diuretics ** Long half-life and greater risk of electrolyte abnormalities Pharmacotherapeutic Considerations All drugs within the loop diuretic class have a similar time to onset, peak effect and duration of action. However, differences exist in metabolism, bioavailability, halflife, and effect of food on absorption (refer to Table 4). Bumetanide, ethacrynic acid, and torsemide have more predictable bioavailability compared to furosemide. Route of Administration o administration is altered in the presence of gastrointestinal edema, gastroparesis and delayed gastric emptying. o Administration by the IV route may result in improved efficacy, except in the case of ethacrynic acid. If continuous infusion is used, a loading dose of a loop diuretic should be administered before initiating the continuous infusion or when the rate is increased to decrease the time for the drug s onset of action. o The loading dose and initial infusion rate are usually determined by the patient s renal function and previous dose response. In diuretic-naïve patients, the recommended initial loading dose for IV furosemide is 40 mg (maximum 200 mg) and bumetanide is 1 mg (maximum 5 mg). Combination therapy with thiazide diuretic o No thiazide diuretic has proven superiority for concomitant use with loop diuretics. o Thiazides have a longer half-life than loop diuretics, resulting in prolonged diuresis.

4 Table 4. Pharmacokinetics of Loop Diuretics Property Bumetanide (Bumex ) Ethacrynic acid (Edecrin ) Furosemide (Lasix ) Torsemide (Demadex ) Onset of action (min) IV Unavailable IV Time to peak effect (min) Half-life (hours) Renal dysfunction Hepatic dysfunction Heart failure Metabolism 50% hepatic hepatic Effect of food on absorption % renal conjugation % hepatic Decreased None Decreased None Safety Implications Pertinent adverse effects include hypovolemia, hypotension, decreased serum electrolytes (i.e., sodium, potassium, magnesium, chloride, and calcium), and metabolic alkalosis. Individualized dosing and close monitoring is therefore recommended. Loop diuretics can cause ototoxicity as a result of high peak concentrations. To minimize this adverse effect: o Consider administration via continuous infusion as opposed to high bolus doses. o Avoid ethacrynic acid, which has the greatest risk of ototoxicity. A sulfonamide allergy without a previous diuretic reaction should not prohibit administration of a loop diuretic containing a sulfa moiety (furosemide, bumetanide, torsemide). In rare instances of a reaction, ethacrynic acid could be used as an alternative. Impact on ICU Care Intravenous furosemide is commonly used in the ICU. However, there is not enough evidence to support the use of one loop diuretic over another. Healthcare providers (i.e., physicians, affiliate providers, pharmacists, and nurses) should be familiar with differences in dosing between loop diuretics in order to prevent potential dosing errors. Most loop diuretics are available in a generic formulation, but there are differences in cost (refer to Table 5).

5 Table 5. Acquisition Costs for Diuretics Drug Strength Average Wholesale Price ($) Bumetanide (Bumex ) IV Furosemide (Lasix ) IV (10 mg/ml) 1 mg 1 mg/4 ml 40 mg 40 mg/4 ml Torsemide (Demadex ) 10 mg 0.70 Ethacrynic Acid (Edecrin )* IV 25 mg 50 mg Chlorothiazide (Diuril ) IV 500 mg Hydrochlorothiazide PO 25 mg 0.15 Metolazone (Zaroxolyn ) PO 5 mg 1.69 *No generic available References 1. Asare K. Management of loop diuretic resistance in the intensive care unit. Am J Health-Syst Pharm. 2009;66(18): Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6): Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9): Wargo KA, Banta WM. A comprehensive review of the loop diuretics: should furosemide be first line? Ann Pharmacother. 2009;43(11): Feldman DS, Elton TS, Pickworth K. Chapter 23: Diuretics: utility and limitations. In: Kirklin JK, Banner N, Jessup M, eds. ISHLT Monograph Series Volume 3: Advanced Heart Failure, Part 1. New York, NY: Elsevier; 2009.

6 Contributed By Erik E. Abel, PharmD, BCPS Cardiology/Cardiothoracic Surgery Specialty Pharmacist Clinical Assistant Professor Department of Pharmacy The Ohio State University Wexner Medical Center Columbus, Ohio, USA Stacey L. Folse, PharmD, MPH, BCPS Clinical Pharmacy Specialist, Medical ICU PGY 2 Residency Director, Critical Care Emory University Hospital Adjunct Clinical Assistant Professor Mercer University School of Pharmacy and Health Sciences Atlanta, Georgia, USA Pamela K. Burcham, PharmD, BCPS Cardiology/Cardiothoracic Surgery Specialty Pharmacist Department of Pharmacy The Ohio State University Wexner Medical Center Columbus, Ohio, USA Antoinette Spevetz, MD, FACP, FCCM Associate Professor of Medicine Designated Institution Official, Graduate Medical Education Associate Director, MSICU for Operations Director, Intermediate Care Unit Associate Director, Internal Medicine Residency Program Section of Critical Care Medicine Cooper University Hospital Camden, New Jersey, USA Kerry Pickworth, PharmD Cardiology Specialty Pharmacist Associate Professor Department of Pharmacy The Ohio State University Wexner Medical Center Columbus, Ohio, USA Reviewers: Scott Bolesta, PharmD, BCPS Gail Gesin, PharmD

7 John Lewin, PharmD, MBA