Rational Management of Hospitalized Patients with Hyponatremia: Application to Patient Cases

APRIL 2014 | ASHP ADVANTAGE E-NEWSLETTER

FREQUENTLY ASKED QUESTIONS Other learning opportunities in the series include ABOUT MANAGING HYPONATREMIA the following: The management of hyponatremia in hospitalized • On-demand web-based activity based on the patients is the focus of a series of learning opportunities January 29 webinar, which provides 1 hour of planned by ASHP Advantage. The learning opportunities continuing pharmacy education. are designed to build on each other to provide practical strategies for managing the electrolyte disorder safely • A faculty roundtable discussion exploring important and effectively in various types of hospitalized patients. issues related to the management of hyponatremia in hospitalized patients and led by Professor Joseph Dasta. A live symposium with case scenarios on the optimal management of hospitalized patients with hyponatremia For more information and to access these was conducted on December 9, 2013, during the 48th learning opportunities, go to the web portal at ASHP Midyear Clinical Meeting and Exhibition in Orlando, www.ashpadvantage.com/hyponatremiacases. Florida. In addition, a live webinar with a similar format The activities are supported by an educational grant was conducted on January 29, 2014. Frequently asked from Otsuka America Pharmaceutical, Inc. questions (FAQs) submitted during these live activities were later addressed by Initiative Chair Joseph F. Dasta,

M.S., FCCM, FCCP, and faculty member, Jodie L. Pepin, FACULTY Pharm.D., in another live webinar on March 4. Those FAQs Joseph F. Dasta, M.S., FCCM, FCCP, Activity Chair also serve as the basis for two e-newsletters that are Professor Emeritus part of the educational initiative. The March 2014 issue The Ohio State University College of Pharmacy focused on the impact of fluctuations in serum sodium Adjunct Professor The University of Texas College of Pharmacy concentration on patient outcomes and barriers to and Austin, Texas strategies for improving the management of hyponatremia in hospitalized patients. This issue focuses on the use Amy L. Dzierba, Pharm.D., BCPS, FCCM Clinical Pharmacist, Adult Critical Care of arginine vasopressin (AVP) receptor antagonists New York-Presbyterian Hospital (also known as vaptans) to manage hyponatremia Lecturer in hospitalized patients with heart failure, a patient Columbia University School of Nursing population that can be especially challenging. The role New York, New York of protocols, algorithms, and standardized order sets in Jodie L. Pepin, Pharm.D. managing this electrolyte disorder in hospitalized patients Director of Pharmacy also is discussed. Seton Medical Center Williamson Seton Healthcare Family Clinical Assistant Professor of Health Outcomes and Pharmacy Practice The University of Texas College of Pharmacy Austin, Texas

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APRIL 2014 | ASHP ADVANTAGE E-NEWSLETTER

FREQUENTLY ASKED QUESTIONS

Question: Patients with heart failure often present Vaptans are an attractive therapeutic option in patients with with chronic hyponatremia. What are some key points to heart failure and hypervolemic hyponatremia, although keep in mind in identifying the best treatment option for studies demonstrating improved outcomes and guidelines these patients? for use of the drugs in these patients are not available. Hyponatremia (usually defined as a serum sodium Therapy must be initiated in a hospital setting where the concentration less than 135 mEq/L) is the most common serum sodium concentration can be monitored closely. electrolyte abnormality in hospitalized patients.1-3 The The decision to use vaptans in this patient population hyponatremia associated with heart failure usually is is based on clinical judgment, taking into consideration hypervolemic, with increased total body water and the need for an alternative to conventional therapy, total body sodium, and characterized by edema.4 The safety factors, and availability of resources for outpatient hyponatremia in these patients typically is chronic and continuation of therapy initiated in a hospital setting. must be corrected slowly to avoid osmotic demyelination syndrome, a brain demyelinating disease that results in Question: What differences between conivaptan significant morbidity and mortality.2,5 The volume status and tolvaptan might influence product selection for of the patient should be considered, and treatments that hospitalized patients with hyponatremia? exacerbate hypervolemia should be avoided. Conivaptan antagonizes the vasopressin V1a and V2 Patients with heart failure and hypervolemic hyponatremia receptors. Tolvaptan is a selective antagonist of vasopressin V receptors. The predominant pharmacodynamic effects of often are difficult to treat because they are volume 2 overloaded despite the use of diuretic therapy. Initial both drugs in patients with hyponatremia are mediated by V receptor antagonism in the renal collecting ducts, which efforts should include fluid restriction and optimization of 2 8 diuretic therapy, which may provide modest improvement increases urine volume and decreases urine osmolality. The clinical significance of vasopressin V receptor in hyponatremia. Improved outcomes have been reported 1a 9 by using hypertonic saline infusions in combination with antagonism by conivaptan is unclear. large doses of loop diuretics instead of diuretics alone.6 Conivaptan was approved by the Food and Drug Serum sodium should be monitored frequently if this Administration (FDA) in 2004 to raise serum sodium approach is used. concentration in hospitalized patients with euvolemic and

10 The introduction of AVP receptor antagonists expanded hypervolemic hyponatremia. Euvolemic hyponatremia the therapeutic options for managing hyponatremia. is characterized by an increase in total body water with no change in total body sodium.4 Tolvaptan was approved These agents antagonize the vasopressin V2 receptors in the renal collecting ducts, which promotes aquaresis (i.e., by FDA in 2009 for the treatment of clinically significant increased free water excretion without a substantial effect hypervolemic and euvolemic hyponatremia (serum on electrolyte excretion), the formation of a highly hypotonic sodium <125 mEq/L or less marked hyponatremia that urine, and increases in serum sodium concentration. Fluid is symptomatic and has resisted correction with fluid restriction should be avoided during vaptan therapy.7 restriction), including patients with heart failure and

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7 syndrome of inappropriate antidiuretic hormone (SIADH). 2-4 days. If the serum sodium concentration does not In patients with SIADH, plasma AVP concentrations are rise at the desired rate, the dosage may be increased to inappropriately elevated, resulting in impaired renal water 40 mg/day. The duration of conivaptan infusion should be excretion, increased total body water, limited to 4 days. and hyponatremia.11,12 Limited data are available on the compatibility of The vaptans differ in several ways that may affect product conivaptan with other i.v. drugs. The use of conivaptan is selection for hospitalized patients with hyponatremia contraindicated in patients receiving potent cytochrome (Table 1). Conivaptan is administered intravenously (i.v.) into P450 (CYP) 3A enzyme inhibitors (e.g., ketoconazole, a large vein. Infusion-site reactions are the most common itraconazole, indinavir) because conivaptan is metabolized adverse effects from the drug, affecting 63% to 73% of by these enzymes and concomitant use of these drugs 10 patients. The infusion site should be changed every can increase exposure to conivaptan.10 The use of 24 hours to minimize the risk for these reactions. A loading conivaptan with CYP 3A substrates (e.g., midazolam, dose of 20 mg should be infused over 30 minutes followed simvastatin, amlodipine) should be avoided. by a continuous infusion of 20 mg over 24 hours for

TABLE 1. Characteristics of Vaptans7-10

CHARACTERISTIC CONIVAPTAN TOLVAPTAN

Receptors antagonized V1a, V2 V2 Half-life (hr) 5 12

Year approved by FDA 2004 2009

FDA-approved To raise serum sodium in hospitalized patients with Treatment of clinically significant hypervolemic and indication euvolemic and hypervolemic hyponatremia euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and SIADH

Dosage form and route 20 mg/100 mL solution in 5% dextrose for 15-mg and 30-mg tablets for oral administration of administration i.v. administration

Dosing 20 mg loading dose over 30 min, then 20 mg by 15 mg once daily; may increase at intervals of at least 24 hr continuous infusion over 24 hr for 2-4 days; after day 1, to 30 mg once daily or a maximum of 60 mg once daily as may increase to 40 mg/day by continuous infusion as needed to raise serum sodium needed to raise serum sodium

Maximum duration of 4 30 therapy (days)

Drug interactions Contraindicated with potent CYP 3A inhibitors Contraindicated with potent CYP 3A inhibitors Avoid with CYP 3A substrates Avoid with CYP 3A inducers and moderate CYP 3A inhibitors Dosage reduction may be needed if used with P-gp inhibitors

Cautions Change infusion site every 24 hr Avoid use in patients with underlying liver disease Reduce dosage by 50% in moderate hepatic impairment Discontinue if liver injury suspected

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Tolvaptan is administered orally.7 Health care providers polycystic kidney disease.13,14 Doses as high as 120 mg/day, should review with the patient the FDA-approved which exceeds the maximum recommended daily dosage Medication Guide for tolvaptan, which contains (60 mg), were used. The effects on liver enzymes, which had information about the proper use of the drug to minimize not been seen in clinical trials before tolvaptan marketing safety risks. Tolvaptan therapy should be initiated using approval, were reversible after discontinuation of the drug. 15 mg once daily. The dosage may be increased at Because patients taking tolvaptan to treat hyponatremia intervals of no less than 24 hours to 30 mg once daily or may be at risk for irreversible and fatal liver injury leading to a maximum of 60 mg once daily as needed to raise the liver transplantation or death, the prescribing information serum sodium concentration. Tolvaptan 15-60 mg/day was modified. Tolvaptan should not be used in patients with produces aquaresis within 2-4 hours, with peak effects underlying liver disease, including cirrhosis, and use of the on serum sodium concentration and urine output noted drug should be limited to 30 days.7,13 Tolvaptan should be within 4-8 hours.7 Dosages exceeding 60 mg/day have discontinued if symptoms of liver injury (e.g., fatigue, fever, not been shown to be more effective for increasing itching, anorexia, right upper abdominal discomfort, dark serum sodium concentrations than smaller dosages.7 The urine, jaundice) occur. use of tolvaptan is contraindicated in patients receiving potent CYP 3A enzyme inhibitors because tolvaptan is Question: Can tolvaptan be crushed and given by metabolized by these enzymes and concomitant use nasogastric (NG) tube in patients unable to swallow tablets? of these drugs can increase exposure to tolvaptan. The The results of a randomized crossover study comparing use of tolvaptan with CYP 3A inducers (e.g., rifampin) the bioavailability of tolvaptan when the tablets are and moderate CYP 3A inhibitors (e.g., erythromycin, crushed, suspended in water, and administered by NG fluconazole, aprepitant, diltiazem, verapamil) should be tube instead of swallowed intact recently were reported.15 avoided. Dosage reduction may be needed if tolvaptan The study was conducted in 28 healthy adults who is used in patients receiving P-glycoprotein inhibitors received two 15-mg doses (one as an intact tablet and (e.g., cyclosporine). Thirst and dry mouth were the most the other by NG tube, not necessarily in that order) common adverse effects from tolvaptan in clinical trials. with a washout period of at least 7 days between doses. The area under the plasma concentration-time curve (i.e., Question: What recent news about vaptans that might bioavailability) for tolvaptan was approximately 25% lower affect their use for the treatment of hyponatremia after NG administration than after taking the intact tablets. should I be aware of? The investigators concluded that the NG route of In 2013, FDA issued a safety warning about the risk for administration can be used for administration of serious and potentially fatal liver injury from tolvaptan based tolvaptan, although the effects on the pharmacodynamics on liver enzyme elevations observed in a randomized, of the drug remain to be evaluated in patients with double-blind, placebo-controlled study of the drug in hyponatremia receiving multiple doses. approximately 1400 patients with autosomal dominant

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Question: What other considerations enter into Dr. Pepin described the protocol and standardized order set decisions to use tolvaptan in patients with heart failure? that have been developed for the use of hypertonic saline The etiology of hyponatremia in patients with heart failure at her health system. These materials provide prompts for should be considered. The electrolyte disorder may documenting the indications for use of hypertonic saline based on laboratory test results, symptoms, and clinical resolve if underlying conditions are corrected. status. Calculations of the sodium deficit (i.e., requirement) Cost is a consideration because patients with heart failure and initial infusion rate are facilitated. have a high rate of readmission, and reimbursement Expert panel recommendations for the diagnosis, from the Centers for Medicare and Medicaid Services is evaluation, and treatment of hyponatremia based on reduced for readmissions within 30 days after hospital the underlying etiology, serum sodium concentration, discharge. Although tolvaptan is an oral therapy, it must and severity of symptoms were published in late 2013.3 be initiated or reinitiated in a hospital setting where Most of these recommendations are not supported by the serum sodium concentration can be monitored data from randomized, double-blind, placebo-controlled closely.7 The need for hospitalization to initiate or trials, but the recommendations represent the consensus reinitiate tolvaptan therapy and the potential economic opinion of experts on the current best practices based on implications of hospital readmission within 30 days after extensive clinical and research experience.3 An evidence- discharge are disadvantages of the long term use of the based clinical practice guideline on the diagnosis and drug to treat hyponatremia in patients with heart failure. treatment of hyponatremia recently was released by The European Society of Intensive Care Medicine, European Society of Endocrinology, and European Question: The treatment of hyponatremia in hospitalized Renal Association–European Dialysis and Transplant patients is extremely complex. Unfortunately, therapy Association,17 but the guideline needs to be adapted to often is based on clinical judgment, and it can be the local culture of practice since practices are different inconsistent within and among hospitals because of in Europe than in the U.S. Despite their limitations, in the the lack of U.S. guidelines for treatment of the disorder. absence of an evidence-based clinical practice guideline What can pharmacists do to address this problem? in the U.S., these two new resources provide valuable guidance for pharmacists interested in evaluating and The use of hospital protocols, algorithms, and improving the management of hyponatremia. standardized order sets for the safe and effective treatment of hyponatremia can help ensure that the Pharmacists should work with an interdisciplinary disorder is properly and consistently managed and team in developing hyponatremia treatment protocols, patient outcomes are optimized. Protocols may be algorithms, and order sets. A physician champion disease-based (i.e., facilitating therapeutic decision should be identified to facilitate development and implementation of the materials. Other team members making for patients with a diagnosis of hyponatremia) or might include hospitalists, nephrologists, critical care treatment-based, outlining the proper use of a particular specialists, cardiologists, neurologists, emergency intervention, such as fluid restriction, hypertonic saline, department physicians, pharmacists, and nurses. or vaptans. Algorithms can be used to stratify patients with hyponatremia based on symptoms, laboratory test The hospital staff should receive education about new results, or etiology to determine the most appropriate disease-based or therapy-based protocols to promote treatment. An example of such an algorithm used at the adherence. Protocols should be revised periodically Cleveland Clinic is available online.16 to reflect new clinical evidence and experience in the treatment of hyponatremia.

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REFERENCES 15. McNeely EB, Talameh JA, Adams KF Jr et al. Relative bioavailability of tolvaptan administered via nasogastric tube 1. Bagshaw SM, Townsend DR, McDermid RC. Disorders of and tolvaptan tablets swallowed intact. Am J Health-Syst Pharm. sodium and water balance in hospitalized patients. 2013; 70:1230-7. Can J Anaesth. 2009; 56:151-67. 16. Cleveland Clinic Center for Continuing Education. 2. Ghali JK. Mechanisms, risks, and new treatment options for Algorithms for the medical intensive care unit: hyponatremia hyponatremia. Cardiology. 2008; 111:147-57. (Na < 135 mEq/L). http://www.clevelandclinicmeded.com/ 3. Verbalis JG, Goldsmith SR, Greenberg A et al. Diagnosis, medicalpubs/micu/hyponatremia.htm (accessed 2014 Feb 25). evaluation, and treatment of hyponatremia: expert panel 17. Spasovski G, Vanholder R, Allolio B et al. Clinical practice recommendations. Am J Med. 2013; 126:S1-S42. guideline on diagnosis and treatment of hyponatraemia. 4. Cawley MJ. Hyponatremia: current treatment strategies and the role Intensive Care Med. 2014; 30:320-31 of vasopressin antagonists. Ann Pharmacother. 2007; 41:840-50. 5. Verbalis JG, Goldsmith SR, Greenberg A et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007; 120(suppl 1):S1-S21. ADDITIONAL ASHP ADVANTAGE 6. Licata G, Di Pasquale P, Parrinello G et al. Effects of high-dose EDUCATIONAL ACTIVITIES furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in Visit the ASHP Advantage website to browse listings refractory congestive heart failure: long-term effects. of convenient on-demand continuing education (CE) Am Heart J. 2003; 145:459-66. activities, as well as publications, podcasts, and live webinars. More than 40 hours of free on-demand CE 7. Samsca (tolvaptan) prescribing information. Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2013 Apr. programming are available. Learn more and find a www.samsca.com/pdf/prescribing-information-samsca.pdf full listing of topics and activities at (accessed 2014 Feb 11). www.ashpadvantage.com 8. Decaux G, Soupart A, Vassart G. Non-peptide arginine- vasopressin antagonists: the vaptans. Lancet. 2008; 371:1624-32. 9. Lee CR, Watkins ML, Patterson JH et al. Vasopressin: a new target for the treatment of heart failure. For complete information about this educational initiative, visit Am Heart J. 2003; 146:9-18. www.ashpadvantage.com/hyponatremiacases. There is no charge for the activities, and ASHP membership is not required. 10. Vaprisol (conivaptan hydrochloride) injection prescribing information. Deerfield, IL: Astellas Pharma US, Inc; 2012 Oct. Planned and coordinated by ASHP Advantage. This activity http://www.astellas.us/docs/vaprisol.pdf (accessed 2014 Feb 11). is supported by an educational grant from Otsuka America Pharmaceutical, Inc. 11. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980; 31:315-27. 12. Munger MA. New agents for managing hyponatremia in hospitalized patients. Am J Health-Syst Pharm. 2007; 64:253-65. 13. U.S. Food and Drug Administration. FDA drug safety communication: FDA limits duration and usage of Samsca Contact ASHP Advantage for assistance or questions. (tolvaptan) due to possible liver injury leading to organ Copyright 2014 | Trademark ASHP | Privacy Policy transplant or death. April 30, 2013. http://www.fda.gov/Drugs/ DrugSafety/ucm350062.htm (accessed 2014 Feb 14). 14. Torres VE, Chapman AB, Devuyst O et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012; 367:2407-18.

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