May 2014 FAQs
May 2014 FAQs
What is the effective dose and duration of oral ribavirin for immunocompromised adult patients with RSV infection?
What is the effective dose and duration of oral ribavirin for immunocompromised adult patients with RSV infection?
Respiratory syncytial virus (RSV) is an RNA virus in the Paramyxoviridae family.1 It is transmitted in the secretions of infected individuals and survives various surfaces from 3 to 30 hours. The virus is responsible for the hospitalization of more than 120,000 children annually, especially in the first year of life. Although RSV is typically considered an infectious disease of early childhood, the frequency of infections is increasing in the adult population as well, especially among those who are immunocompromised.2 In adults over 65 years, RSV infections are responsible for 177,000 hospitalizations and 14,000 deaths annually in the United States.3
Infection from RSV occurs in 2% to 17% of hematopoietic stem cell transplant (HSCT) recipients.4 Risk factors for RSV-related complications in patients after HSCT include older age, severe immunodeficiency, neutropenia and lymphopenia, unmatched donor, and HSCT less than 1 month prior. 2 Progression of upper respiratory tract infections (URTI) to lower respiratory tract infections (LRTI) and pneumonia is a strong predictor of mortality, with an estimated range of 7% to 84%.4 In fact, this progression is associated with high mortality despite the use of antiviral therapy with ribavirin or palivizumab.5 In lung transplant recipients, long-term graft and patient survivals are limited by development of bronchiolitis obliterans syndrome (BOS), a process by which fibrosis leads to the obliteration of the airways.6,7 Infection with RSV is associated with the development of BOS, and RSV occurs in up to 21% of adult lung transplant recipients with a resulting mortality of 10% to 20%.7
Guidelines for management of RSV in hospitalized adults status post HSCT, developed by an international group of experts, list several treatment option such as aerosolized ribavirin, RSV antibodies (eg, intravenous immune globulin [IVIG]), and RSV monoclonal antibodies (eg, palivizumab), though they do not recommend any one agent over another.8 Another guideline from a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) also lacks a strong recommendation, but mentions the use of ribavirin and IVIG as having the most evidence available at publication. 2
Ribavirin is a synthetic nucleoside antiviral medication.9 The mechanism of action against RSV is unknown, but the inhibitory activity of ribavirin is selective to the virus. Systemic absorption of the aerosolized formulation does occur, and ribavirin accumulates in the red blood cells of humans.
Oral ribavirin has a Food and Drug Administration approval for chronic hepatitis C virus (HCV) combined with interferon in children and adults. 10 Oral ribavirin is available as a 200, 400, and 600 mg capsule and dosing for HCV ranges from 800 mg to 1400 mg daily.10 The inhaled dosage formulation (Virazole) is only approved for RSV infection in infants and children.9,10 Recommended dosing is a 20-mg/mL solution continuously aerosolized over 12 to 18 hours once a day for 3 to 7 days. An injectable formulation for intravenous administration exists in some countries and has been studied in adult populations, but is not currently available in the United States.10,11
Inhaled ribavirin contains a boxed warning for potential sudden deterioration of respiratory function when initiating the aerosolization in infants. 9 Furthermore, administering the drug as an aerosol in patients on mechanical ventilation can lead to ventilator dysfunction as a result of particle accumulation. Ribavirin is a known teratogen, and healthcare workers administering the medication or providing care during drug administration are at a risk of harmful exposure. Aerosolized ribavirin requires at least 6 air changes per hour for 18 hours every day in a well-ventilated room.11 For these reasons, there has been an increased interest in the use of oral ribavirin for treatment of RSV infection in immunocompromised adult patients.
Although the off-label use of aerosolized ribavirin in adults has been extensively reported, data for oral use is limited.4 Several studies of oral ribavirin included a mixture of administration routes, including oral, aerosolized, and intravenous.5,7,12-15 Some studies evaluated the use of oral ribavirin for RSV as well as for other Paramyxoviruses such as parainfluenza virus and human metapneumovirus.13,16-18 All studies reported if the patient presented with an URTI, LRTI, or experienced progression to LRTI or BOS as a way to determine efficacy of the regimen. 5,7,11-20 A brief summary of the trials is presented below with additional information in the Table.
Bone marrow transplant
The most widely studied patient population receiving oral ribavirin for RSV infection is post bone marrow transplant.5,12-14,17,19 The 6 published studies used a variety of oral dosing strategies, including dose escalation, nonweight-based dosing, and a weight-based regimen of 15 to 20 mg/kg/d, divided in 3 doses.
Lung, heart-lung transplant
In 2 published studies, the dosing was weight-based: 15 to 20 mg/kg/d divided in 2 to 3 doses for 5 to14 days, depending on the study.11,18 This dosing is higher than that used in the studies involving moderately to severely immunocompromised adults. The third study in this patient population used a nonweight-based dosing regimen for 5 to 10 days.7 The regimens with 3 doses per day for 5 to 10 days had no progression to BOS, whereas the twice daily dosing for a median of 14 days had more cases of progression.7,11,18
Two studies used similar definitions for moderate and severe immunosuppression, involving solid organ transplant and HSCT within certain time periods, with specific laboratory requirements or reasons for augmented immunosuppression.15,20 The more recent article from 2013 used a weight-based ribavirin dosing for 5 to 10 days.20 The second used a regimen consisting of a loading dose followed by a set, nonweight-based escalating dose for the next 2 days.15 The dose on day 3 was continued for a median of 14 to 16 days. Both studies included IVIG as cotherapy, and the study by Khanna15 added palivizumab for severely immunocompromised patients.15,20 In the Khanna15 study, there were 6 deaths attributed to RSV, and 20% of patients experienced severe adverse drug reactions compared to 0 deaths and 6% of patients with adverse drug reactions in the study by Marcelin.20 However, both were retrospective chart reviews with different methodologies, so deaths cannot be linked to the dosing regimen used. A third study did not define levels of immunosuppression but included inpatients with hematological diseases, half of which had an HSCT.16 A weight-based regimen was used for a median duration of 12 days, and 5 deaths occurred in those receiving ribavirin treatment.
Based on the available literature, several dosing strategies may be trialed for immunocompromised adult patients with RSV infection. 5,7,11-20 For patients who underwent HSCT, it seems that a higher dosing range is most effective, at 15 to 20 mg/kg/d divided in 3 doses. Alternatively, a lower initial dose of 10 or 15 mg/kg has been used, with subsequent dose-doubling required to achieve viral clearance. No studies have evaluated a dosing higher than 60 mg/kg/d. The planned or median duration of these dosing strategies varied widely and likely should be continued until the patient is asymptomatic or displays viral clearance. For the adult lung or heart-lung transplant recipient, there are less data to recommend a particular dosing strategy. In general, a loading dose has not been evaluated, and a dose of 15 to 20 mg/kg/d for 5 to 14 days has shown positive results.
The implications for ease of administration, healthcare worker safety, and cost savings have led to the use of oral ribavirin in place of aerosolized ribavirin in immunocompromised adults with RSV infection. Although there are published data supporting the use of oral ribavirin for immunocompromised adults with RSV infection, there are several limitations that may restrict the applicability of the results. In many of these studies, the effect of concomitant steroids, IVIG, or palivizumab cannot be determined as these were often given at the clinician’s discretion or for other underlying conditions. Additionally, some of these studies allowed for administration of intravenous and/or aerosolized formulations of ribavirin, making it difficult to determine the effectiveness of the oral route of administration. The low-quality evidence from retrospective or prospective observational studies and a case report makes it difficult to attribute efficacy solely to ribavirin. Because the prevalence of disease is so low and a placebo arm would be considered unethical, conducting a randomized controlled trial would be challenging. Therefore, decisions for dosing of oral ribavirin should be made on a case-by-case basis, applying the available literature presented in this review.
1. Hall CB. Respiratory syncytial virus. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Vol 2. 7th ed. Philadelphia, PA: Churchill Livingstone; 2010:2207-2221.
2. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis. 2013;56(2):258-266.
3. Respiratory syncytial virus infection (RSV): trends and surveillance. Centers for Disease Control and Prevention Website. http://www.cdc.gov/rsv/research/us-surveillance.html. Updated December 2, 2013. Accessed April 28, 2014.
4. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117(10):2755-2763.
5. Avetisyan G, Mattsson J, Sparrelid E, Ljungman P. Respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: a retrospective study of the incidence, clinical features, and outcome. Transplantation. 2009;88(10):1222-1226.
6. Kotloff RM. Lung transplantation. In: Mason RJ, Broaddus VC, Martin TR, et al, eds. Murray and Nadel’s Textbook of Respiratory Medicine. 5th ed. Philadelphia, PA: Saunders Elsevier; 2010. http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4160-4710-0..00095-X–s0095&isbn=978-1-4160-4710-0&sid=1520289135&uniqId=444687865-8. Accessed April 28, 2014.
7. Li L, Avery R, Budev M, Mossad S, Danziger-Isakov L. Oral versus inhaled ribavirin therapy for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant. 2012;31(8):839-844.
8. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238.
9. Virazole [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals; 2013.
10. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2013. http://www.micromedexsolutions.com/. Accessed April 28, 2014.
11. Pelaez A, Lyon GM, Force SD, et al. Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant. 2009;28(1):67-71.
12. Gueller S, Duenzinger U, Wolf T, et al. Successful systemic high-dose ribavirin treatment of respiratory syncytial virus-induced infections occurring pre-engraftment in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2013;15(4):435-440.
13. Chakrabarti S, Collingham KE, Holder K, Fegan CD, Osman H, Milligan DW. Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant. 2001;28(8):759-763.
14. Sparrelid E, Ljungman P, Ekelöf-Andström E, et al. Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections. Bone Marrow Transplant. 1997;19(9):905-908.
15. Khanna N, Widmer AF, Decker M, et al. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clin Infect Dis. 2008;46(3):402-412.
16. Park SY, Baek S, Lee SO, et al. Efficacy of oral ribavirin in hematologic disease patients with paramyxovirus infection: analytic strategy using propensity scores. Antimicrob Agents Chemother. 2013;57(2):983-989.
17. Casey J, Morris K, Narayana M, Nakagaki M, Kennedy GA. Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2013;48(12):1558-1561.
18. Fuehner T, Dierich M, Duesberg C, et al. Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections. Antivir Ther. 2011;16(5):733-740.
19. Mori T, Nakamura Y, Kato J, et al. Oral ribavirin therapy for lower respiratory tract infection of respiratory syncytial virus complicating bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2011;93(1):132-134.
20. Marcelin JR, Wilson JW, Razonable RR; Mayo Clinic Hematology/Oncology and Transplant Infectious Diseases Services. Oral ribavirin therapy for respiratory syncytial virus infections in moderately to severely immunocompromised patients. Transpl Infect Dis. 2014;16(2):242-250.
Table. Studies reporting use of oral ribavirin for RSV infection. 5,7,11-20
Author, year, location Study design Population (n) RBV regimen Duration No. presented with URTI No. presented with LRTI Death or progression Comments Bone Marrow Transplant Gueller 201312 Germany Retrospective analysis Hospitalized HSCT (n=10) LRTI (n=5): IV RBV x 10 d followed by Oral RBV 1800 mg/d (22.5 mg/kg/d assuming 80 kg patient) URTI (n=5): PO RBV 1800 mg/d until symptoms resolved URTI: Median 16 days 5 5 No deaths No progression to pneumonia, no RSV-related deaths Casey 201317 Australia Retrospective review Post-HSCT with RSV (n=13) or PIV3 (n=2) Oral RBV (n=15): 10 mg/kg/d in 4 divided doses Escalated by 10 mg/kg/d every 24 to 48 h to maximum of 60 mg/kg/d Treatment continued until symptoms resolved or virus cleared URTI: Final dose median 35 mg/kg/d and median duration 25.5 days LRTI: Final dose 25 mg/kg/d and median duration 15 d 7 All progressed to LRTI before dose escalation 6 LRTI: 2 deaths URTI: 1 death Authors concluded that oral RBV dose was too low for treatment of RSV and suggested 20 mg/kg/d with dose escalation to maximum of 60/mg/kg/d Mori 201119 Japan Case report Late post-HSCT (n=1) 600 mg/d (7.5 mg/kg/d assuming 80 kg patient) 7 days 0 1 No deaths No adverse events Avetisyan 20095 Sweden Retrospective review, case-control HSCT with RSV (n=32) Aerosolized, IV, PO, or combination RBV (n=17) Oral RBV alone (n=11): 15 to 20 mg/kg/d in 3 divided doses All dosage forms: Median 22.5 days 18 (16 received RBV) 14 (12 received RBV) URTI: no progression and all survived LRTI: 5 deaths (RBV route of administration uncertain) Authors concluded that RBV therapy initiated early in the infection improves outcomes Chakrabarti 200113 United Kingdom Prospective observational Inpatient or outpatient BMT with PIV3 (n=5) or RSV (n=5) Oral RBV Asymptomatic/mild symptoms (n=5): 15 mg/kg/d, doubled every week to maximum of 60 mg/kg/d Severe symptoms: Aerosolized RBV x 5 to 7 days LRTI not responding to oral/aerosol: IV RBV x 5 to10 days 15 days for 4 patients, 10 days for 2 patients 3 dose escalations: To 30 mg/kg (n=2) To 45 mg/kg (n=1) Continued on 15 mg/kg (n=2) None No RSV-related deaths, all 5 improved Nausea and anemia in 1 patient Anemia in 3 patients Sparrelid 199714 Sweden Retrospective HSCT with influenza B (n=4), RSV (n=6), parainfluenza (n=3) RSV (n=3 children, n=3 adults) Oral/IV RBV: 15 to 20 mg/kg/d in 3 divided doses Aerosol was given to 4 patients with RSV Not reported 2 2 No URTIs progressed LRTI present in 4 cases (2 as new cases) 2 RSV-related death (both children) Authors concluded that ribavirin has low mortality and minimal severe systemic adverse events and early treatment may help reduce the spread of the virus Lung, heart-lung transplant Li 20127 United States Retrospective analysis Lung or heart-lung transplant >15 years (n=21) Aerosolized (n=15) Oral RBV (n=6): 400 mg 3 times daily x 5 to 10 d (15 mg/kg/day assuming 80 kg patient) 5 to 10 days 2 4 No progression to BOS or death in oral RBV group Authors concluded both routes result in similar outcomes at 6 months post-RSV infection Fuehner 201118 Germany Prospective, observational Lung or heart-lung outpatients with RSV (n=43), hMPV (n=5), and PIV (n=19) RSV only (n=43) Oral RBV (n=24): 15 to 20 mg/kg/d in 2 divided doses x 14 days Control group (n=19): Those with contraindications to RBV 14 days Eliminated virus in 89% of patients 12 (all PV types) 55 (all PV types) New BOS in RSV: 6 Graft function restored in 84% RBV vs 59% nonRBV after 30 d, p=0.02 Pelaez 200911 US Retrospective Lung transplant with LRTI RSV (n=5) adults Oral RBV (n=5):15-20 mg/kg/d in 3 divided doses x 10 days 10 days None 5 No cases of BOS or death up to 1.5 years after therapy Cost $700 per patient, authors conclude this route of administration has many benefits over risks of other routes. Well tolerated and favorable outcomes Immunocompromised patients Marcelin 201420 US Retrospective cohort Adults with moderatea (n=20) and severeb (n=14) immuno-suppression Oral RBV (n=34): 600 mg BID (<75 kg) or 800 mg BID (≥75 kg) x 5 to 10 days (10 mg/kg/d assuming 80 kg patient) 400 mg was used for elderly or mild renal insufficiency Not reported 10, including bronchiolitis 24 No deaths None transitioned to aerosolized or IV RBV 2 patients discontinued treatment due to ADRs (altered mental status; hemolytic anemia and lactic acidosis) Mean 2.7 doses of IVIG in 19 patients Park 201316 Korea Retrospective chart review, including a nonRBV therapy control group Adults with hematologic diseases infected with RSV (n=60), PIV (n=64) or hMPV (n=21) RSV subgroup (n=60) Oral RBV (n=48): 15 to 20 mg/kg/d in 3 divided doses, continued until asymptomatic or virus undetectable NonRBV control (n=12) Median dose 900 mg Median duration 12 days RBV: 13 nonRBV: 6 RBV: 35 nonRBV: 6 RSV-related deaths: 5 (10%) RBV vs 3 (25%) nonRBV URTI independently associated with mortality Hospital LOS: Oral RBV 24 d vs NonRBV 5 d, p=0.002 Authors concluded RBV may NOT improve clinical outcomes in these patients Khanna 200815 Switzerland Retrospective chart review Moderatea and severeb immuno-suppression (n=34) Moderatea: URTI (n=5) or LRTI (n=2) Oral RBV: 10 mg/kg LD, then 400 mg 3 times daily on day 2 and 600 mg 3 times daily on day 3 (15 to 22.5 mg/kg on days 2 to 3, assuming 80 kg patient) Severeb: URTI (n=9): Same as above + PLV Severeb: LRTI (n=9): Same as above, but IVIG every other day, +/- PLV IV RBV for mechanically ventilated Given until asymptomatic and no longer detectable on PCR Moderatea: median 14 days Severeb: median 16 days Moderatea: 10 (5 not treated) Severeb: 12 (3 not treated) Moderatea: 2 Severeb: 10 (1 not treated, 2 RBV + IVIG, 7 RBV + IVIG+ PLV Moderatea : URTI, no progression or death Severeb: LRTI, 5 went to ICU, 4 ventilated, all died. 6 RSV-attributable deaths Hemolysis in 5 patients out of 25 treated Maximum dose of RBV was tolerated, but efficacy not known a Moderate: eg, solid organ transplant >1 year ago, hematologic malignancies with chemotherapy, HSCT >6 months ago, or with GVHD <grade 2, long-term prednisone >20 mg/day, HIV CD4<200 cells/mcL b Severe: eg, HSCT ≤6 months, or GVHD is >6 months, lung transplant within 1 year, or >1 year with augmented immunosuppression. Abbreviations: ADR, adverse drug reactions; BMT, bone marrow transplant; BOS, bronchiolitis obliterans syndrome; GVHD, graft-versus-host-disease; hMPV, human metapneumovirus; HSCT, hematopoietic stem cell transplant; IV, intravenous; IVIG, intravenous immunoglobulin; LD, loading dose; LOS, length of stay; LRTI, lower respiratory tract infection; palivizumab, PLV; PCR, polymerase chain reaction; PIV, parainfluenza virus; PIV3, parainfluenza virus type 3; PV, Paramyxovirus; RBV, ribavirin; RSV, respiratory syncytial virus; URTI, upper respiratory tract infection.
Is there any information regarding reducing the adverse effects from acetylcysteine in acetaminophen overdose?
Is there any information regarding reducing the adverse effects from acetylcysteine in acetaminophen overdose?
Acetaminophen is one of the most commonly used over-the-counter medications to treat pain and fever. Additionally, acetaminophen has consistently ranked in the top 5 for medications implicated in fatal overdoses. In 2012, acetaminophen (alone and in combination) was associated with 11.9% of all fatalities related to medication overdoses.1 Although acetaminophen is safe when used appropriately, acetaminophen is the leading cause of acute liver failure in both Europe and North America.2
Briefly, the toxicity of acetaminophen is a result of a toxic metabolite N-acetyl-p-benzoquinonemine (NAPQI), which is metabolized from acetaminophen by cytochrome P450 (CYP) 2E1.2 NAPQI normally combines with glutathione to form a benign excretable conjugate. However, in the setting of acetaminophen overdose glutathione stores are depleted and the NAPQI metabolite causes hepatotoxicity. Acetylcysteine exerts its therapeutic effect in acetaminophen overdoses primarily by serving as a glutathione precursor to facilitate inactivation of NAPQI. For more information on the mechanism of action and dosing of acetylcysteine, please see a previous Frequently Asked Question on this topic available at: http://dig.pharm.uic.edu/faq/Nov10/apap.aspx.
Acetylcysteine is recognized worldwide as the antidote of choice for acetaminophen overdose; however, adverse reactions are often associated with its use. In the past 30 years, many adverse reactions have been reported, which have ranged in severity from nausea to anaphylactoid reactions to death.2 Side effects such as nausea and vomiting can often delay and/or interrupt therapy resulting in the antidote not being administered in timely fashion. Additionally, much debate still exists on the ideal dose, duration, and route of administration of acetylcysteine. Due to these issues many researchers and clinicians are exploring variations of the approved acetylcysteine dosing regimens.
Adverse Reactions with Acetylcysteine for Acetaminophen Overdose
A literature review by Sandilands and Bateman examined adverse reactions associated with acetylcysteine and identified particular “at risk” groups. 2 Nausea and vomiting (1.5% to 63.1%) and cutaneous anaphylactoid reactions (0.9% to 76.3%) are the most common adverse events associated with intravenous acetylcysteine. The clinical features of anaphylactoid reactions are similar to anaphylactic reactions, but differ in their mechanism. Anaphylactoid reactions are not IgE-mediated and do not require previous exposure to the substance, but histamine does appear to play an important role. Symptoms associated with an anaphylactoid reaction usually appear within the first hour of starting therapy and range from flushing to angioedema and respiratory symptoms. Some studies have shown that acetaminophen may be protective against developing an anaphylactoid reaction, as patients with lower serum concentrations of acetaminophen have shown a higher risk of developing this reaction. Other patient groups that were identified as being “at risk” groups for developing anaphylactoid reactions included females, those with a family history of drug allergy, and asthmatics.
A prospective study by Pakravan et al also examined the rate of occurrence of adverse events with acetylcysteine and possible associated risk factors. 3 The study included 169 patients treated with intravenous acetylcysteine in the setting of acetaminophen overdose. Reported adverse events included nausea (70.4%), vomiting (60.4%), pruritus (20.1%), dyspnea (13.6%), dizziness (7.7%), chest pain (7.1%), wheezing and bronchospasm (7.1%), fever (4.7%), and rash/urticaria (3.6%). More than half of the adverse events (59.8%) reported were minimal with the remaining being moderate and severe (40.1%). Logistic stepwise regression analysis found several variables with a statistically significant correlation with moderate or severe adverse events. This included an inverse correlation with serum acetaminophen concentration (odds ratio [OR] 0.99; 95% confidence interval [CI] 0.99 to1.00; p=0.043], a positive correlation with family history of allergy (OR 2.89; 95% CI 1.39 to 5.99; p=0.004), and an inverse correlation with male gender (OR 0.45; 95% CI 0.22 to 0.92; p=0.028. No significant correlations were seen with age, history of asthma, or previous drug allergy. One limitation of studying adverse events associated with acetylcysteine administration is that these events may not always be solely related to the infusion and could be related to acetaminophen ingestion, ethanol, or coingested drugs. The authors concluded that moderate to severe adverse events reported in this study were consistent with previous reports of 3% to 50%. Due to high rate of adverse effects, which can often interrupt or delay treatment, many clinicians are experimenting with changes in acetylcysteine treatment algorithms in hopes of reducing adverse effects.
A prospective, randomized, factorial study by Bateman et al compared the rates of adverse effects with and without antiemetic pretreatment between a standard acetylcysteine regimen and a shorter modified schedule.4 The hypothesis was that adverse events could be lowered by delivering the same total dose of acetylcysteine, but over a shorter duration and with a lower, slower initial infusion. The acetylcysteine regimens used in this study are provided in the Table. It should be noted, however, that in the United States the initial infusion of 150 mg/kg is infused over 60 minutes as opposed to the 15 minutes in the United Kingdom, the location of the study.5
Table. Acetylcysteine infusion regimens.4 UK Standard Schedule (duration 20 to 25 hours)
- 150 mg/kg in 200 mL over 15 minutes
50 mg/kg in 500 mL over 4 hours
100 mg/kg in 1000 mL over 16 hours
Modified (shorter) protocol (duration 12 hours)
- 100 mg/kg in 200 mL over 2 hours
200 mg/kg in 1000 mL over 10 hours
500 mL of 5% dextrose over 20 to 25 hours
Patients were randomized in a 2×2 factorial design to 1 of 4 groups: ondansetron pretreatment and modified protocol (ondansetron-modified), ondansetron and standard schedule (ondansetron-standard), placebo and modified protocol (placebo-modified), or placebo and standard schedule (placebo-standard). The primary outcome was the proportion of patients who did not vomit or retch and did not require rescue antiemetic drugs within 2 hours of initiation of acetylcysteine. Secondary outcomes included the proportion of patients without nausea, vomiting, or retching for up to 12 hours after initiation of acetylcysteine and occurrence of anaphylactoid reactions. Other prespecified analyses to assess the frequency of hepatotoxicity at the end of treatment included alanine aminotransferase (ALT) increase greater than 50% over baseline or greater than 1000 IU/L and international normalized ratio (INR) greater than 1.3.
A total of 222 patients met inclusion criteria and were randomized to 4 well-balanced groups with respect to baseline characteristics. Patients in the modified acetylcysteine protocol had significantly less vomiting, retching, or use of rescue antiemetic medications within the first 2 hours of treatment (OR 0.26; 97.5% CI 0.13 to 0.52; p<0.0001). This primary outcome was also significantly less in those patients who were pretreated with ondansetron (OR 0.41; 97.5% CI 0.20 to 0.80; p=0.004). The secondary outcome also was less common in patients who received the modified acetylcysteine protocol compared to the standard protocol (OR 0.37; 97.5% CI 0.18 to 0.79; p=0.003) and for those patients who were pretreated with ondansetron (OR 0.35; 97.5% CI 0.17 to 0.74; p=0.002). Anaphylactoid reactions were recorded in 64% of patients overall, with 46% of patients in the modified protocol being anaphylactoid symptom-free compared to 25% in the standard schedule. The OR for a severe reaction with the modified regimen was 0.23 (97.5% CI 0.12 to 0.43; p<0.0001) compared with the standard regimen. A 50% increase in ALT 20 to 25 hours after the start of treatment was reported in 11% of patients. No difference was seen between the modified and standard acetylcysteine regimens. However, this outcome was more common among those patients pretreated with ondansetron (p=0.024). ALT activity greater than 1000 IU/L was seen in 5 of 202 treated patients, and an INR over 1.3 was reported in 25 of 201 patients (p-values not reported).
The results of this study showed that a shorter (12-hour) modified regimen significantly reduced the frequency of both vomiting/retching and anaphylactoid reactions when compared with the UK standard acetylcysteine regimen. However, further clinical trials powered for efficacy and safety are necessary to validate this regimen. Pretreatment with ondansetron reduced vomiting; however, increase in ALT was an unexpected outcome and requires further research.
Nausea, vomiting, and anaphylactoid reactions are common adverse events associated with the administration of intravenous acetylcysteine used to treat acetaminophen overdoses. Additionally, much debate still exists on the appropriate dose, duration, and route of administration of acetylcysteine. 6 The study by Bateman et al demonstrated a reduction of adverse events by shortening the duration of infusion while keeping the total dose equivalent to the standard regimen. One major limitation of this study is that it was not powered for efficacy. Further research is necessary to demonstrate efficacy before shortened protocols can be utilized to reduce adverse events associated with acetylcysteine.
1. Mowry JB, Spyker DA, Cantilena LR et al. 2012 Annual Report of American Association of Poison Control Centers’ National Poison Data System (NPDS): 30 th Annual Report. Clin Toxicol. 2013;51():949-1229.
2. Sandilands EA, Baterman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol 2009; 47(2): 81-88.
3. Pakravan N, Waring WS, Sharma S et al. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol 2008; 46(8): 697-702.
4. Bateman DN, Dear JW, Thanacoody HR et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomized controlled trial. Lancet 2014; 383(9918): 697-704.
5. Acetadote [package insert]. Nashville, TN: Cumberland Pharmaceuticals, Inc; 2013.
6. Heard K. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008; 359(3): 285-292.
Jaime Kimmel, PharmD
University of Illinois at Chicago
- 150 mg/kg in 200 mL over 15 minutes
What are the current guidelines on treatment of hyponatremia with vasopressin antagonists?
What are the current guidelines on treatment of hyponatremia with vasopressin antagonists?
Hyponatremia is the most common electrolyte disorder, commonly defined as a serum sodium of <135 mEq/L, or mmol/L.1 Approximately 15% to 30% of patients hospitalized for either acute or chronic illnesses experience hyponatremia. Hyponatremia has been associated with increased mortality in patients with heart failure or cirrhosis, and in patients with acute hyponatremic encephalopathy. There have been reports of increased falls and fractures in patients deemed “asymptomatic” by lack of findings upon neurological examination. Estimated costs associated with management of hyponatremia and sequelae are $1.6 to $3.6 billion annually.2
The 2007 hyponatremia guidelines published by a United States expert panel were updated at the end of 2013.1,3 The updated guidelines incorporate new information on safety of vasopressin antagonists, or “vaptans,” recommended rates of serum sodium increase, as well as morbidities and mortalities in general for hyponatremia.1 However, these guidelines do not include a scoring system for their recommendations given the limited and weak evidence available on treatment of hyponatremia. This article will briefly review hyponatremia and the recommendations for use of vaptans made by the updated guidelines.
The etiology and classification of hyponatremia dictate treatment, so clinicians must first recognize if hyponatremia is acute or chronic, as well as hypovolemic, euvolemic, or hypervolemic.1,4,5 Definitions, common etiologies, and conventional therapy for each type of hyponatremia are provided in Table 1.
Table 1. Hyponatremia classifications and treatment. 1,4,5 Hyponatremia type Description Etiologies Conventional therapy Hypovolemic Decreased ECF; Loss of Na+ or K+ with secondary water retention
- Vomiting or diarrhea
- Cerebral salt wasting
- Isotonic saline solution
- Hypertonic saline if severe symptoms (coma, seizures, respiratory arrest)
Euvolemic Normal ECF
- Nephrogenic syndrome of inappropriate diuresis
- Glucocorticoid deficiency
- Low solute intake
- Primary polydipsia
- Fluid restriction
Hypervolemic Increased ECF
- Heart failure
- Acute kidney injury; chronic kidney disease; nephrotic syndrome
- Fluid restriction
a Not for use in cirrhosis/liver injury. Abbreviations: ECF, extracellular fluid; SIADH, syndrome of inappropriate antidiuretic hormone.
An elevated level of antidiuretic hormone, or arginine vasopressin (AVP), is a common etiology of hyponatremia.1,4,5 This hormone responds to plasma osmolality and intravascular volume, in turn affecting water reabsorption in the collecting ducts of the kidneys to regulate urine osmolality and dilution. In normal physiology, when plasma osmolality is low, AVP levels decrease and solute-free renal excretion occurs (aquaresis) to compensate. 1,5 Circulating AVP levels are abnormally increased in patients with the syndrome of inappropriate antidiuretic hormone (SIADH), and in patients with heart failure or cirrhosis. Other conditions may result in abnormally elevated AVP as well. In these cases, aquaresis does not occur despite plasma hypoosmolality, in turn leading to abnormal water retention and hyponatremia. When AVP levels are elevated, the first-line treatment strategy is fluid restriction.1 Patients who have severe, symptomatic hyponatremia should first be treated with 3% hypertonic saline to achieve rapid sodium correction and prevent cerebral edema. Patients with euvolemic hyponatremia may benefit from pharmacologic treatment with demeclocycline, urea, or vaptans. Vaptans may also be used in hypervolemic hyponatremia.
Chronicity of hyponatremia will determine the rate at which sodium levels should be corrected.1,4,5 The greatest concern with treatment of chronic hyponatremia is osmotic demyelination syndrome (ODS), which can occur if sodium levels are corrected too rapidly. In ODS, brain cells are unable to uptake organic osmolytes at the same rate at which the hyponatremia is being corrected, resulting in neurological deficits. Risk factors for development of ODS include serum sodium concentration <105 mmol/L, hypokalemia, alcoholism, malnutrition, and liver cirrhosis.1 In acute hyponatremia, the brain has not had time to adapt and patients are at risk for cerebral edema. Because of the brain’s inability to quickly adapt, the risk of ODS with treatment is less for acute hyponatremia.
Correction rate recommendations
The 2013 guidelines recommend a rate of correction for acute hyponatremia of a serum sodium level increase of 6 mmol/L/day, since there is no evidence for improved outcomes at higher rates.1 This is a change from the 2007 guidelines, which recommended to aim for 8 mmol/L/day.3 The current guidelines recommend a rate of correction for chronic hyponatremia of 4 to 8 mmol/L/day, with a decreased goal of 4 to 6 mmol/L/day if a patient has a risk factor for ODS.1 Prior to this, the recommendations were a correction of serum sodium of no more than 10 to 12 mmol/L/day. 3 Greater rates of correction increase the risk for ODS.
Vaptan use in hyponatremia
When elevated AVP is an etiologic factor of hyponatremia, consideration can be made for use of vaptans.1,5 Vaptans exert their mechanism of action by binding to AVP receptors in the kidney, blocking the actions of AVP, in turn promoting electrolyte-free excretion of water, or aquaresis. The negative water balance results in increased plasma osmolality and an increase in serum sodium concentration. The 2 vaptans currently approved in the United States are intravenous conivaptan and oral tolvaptan. They are both approved for use in clinically significant hypervolemic and euvolemic hyponatremia, defined by a serum sodium <125 mEq/mL, or in milder cases after fluid restriction has failed. Conivaptan is an antagonist of both the AVP V1a and V2 receptors, while tolvaptan is specific for V2 receptors, which are located on renal collecting tubules and vascular endothelium. Both medications must be initiated in the hospital, but tolvaptan may be used long-term given its oral formulation. Specific information for each drug is available in Table 2.
Table 2. Vasopressin antagonists. 1,6,7 Conivaptan Tolvaptan Dosing
- Initial: 20 mg IV over 30 minutes (10 mg if CrCl 30 to 60 mL/min or hepatic impairment)
- Maintenance: 20 mg IV over 24 hours (10 mg if CrCl 30 to 60 mL/min or hepatic impairment); may be increased to 40 mg over 24 hours
- Initial: 15 mg orally daily
- Maintenance: May be increased to 30 mg orally after 24 h; maximum 60 mg orally daily
Duration Not to exceed 4 days Not to exceed 30 days Monitor
- Volume status and serum sodium frequently (at least every 6 to 8 h when hospitalized)
- Stop infusion if correction rate exceeds 8 mmol/L/24 h
- Do not restrict fluids for first 24 to 48 h of treatment; the patient’s thirst will compensate for possible overcorrection
Adverse effects Injection site reactions, headache, polyuria, thirst, hypokalemia, orthostatic hypotension Polyuria, thirst, dry mouth, constipation, hyperglycemia Contraindications
- Do not use in anuric patients Coadministration with strong CYP3A4 inhibitorsa as conivaptan concentrations will be increased Known allergy to corn or corn products
Do not use in anuric patients or those with CrCl <10 mL/min Coadministration with strong CYP3A4 inhibitorsa as tolvaptan concentrations will be increased Warnings Data are limited for use in hypervolemic hyponatremia with heart failure Monitor serum sodium and neurologic status to avoid overcorrection
- Initiate in a hospital where serum sodium can be closely monitored ODS if too rapid of serum sodium correction (>12 mmol/L/day)
- Monitor serum potassium in patients with potassium >5 mmol/mL
- Can cause serious and potentially fatal liver injury inhibitor of P-gp; consider dose reduction of tolvaptan if concomitant use
a Strong CYP3A4 inhibitors include drugs such as ketoconazole, itraconazole clarithromycin, and ritonavir. Abbreviations: CrCl, creatinine clearance; CYP3A4, cytochrome P450; IV, intravenous; P-gp, p-glycoprotein; ODS, osmotic demyelination syndrome.
The 2013 hyponatremia guidelines do not make clear recommendations regarding the use of vaptans, but provide considerations and cautions for use. 1 They acknowledge their role in the setting of mild to moderate hyponatremia and also make a statement that despite lack of data for use in asymptomatic severe hyponatremia, they may have a role provided the recommended rate of increase is followed and patients are carefully monitored. However, the SALT-1 and SALT-2 randomized controlled trials that led to the approval of tolvaptan included very few patients with severe hyponatremia (serum sodium level <120 mEq/mL), so use of tolvaptan in this patient population is not evidence-based.8 The guideline panel states that there is a potential for vaptans to replace water restriction as first-line therapy for euvolemic and hypervolemic hyponatremia, but the cost-benefit ratio needs to be further elucidated.
In April 2013 the Food and Drug Administration (FDA) issued a safety warning on the use of tolvaptan given reports of hepatic injury leading to transplant or death.9 They recommend that it not be used for longer than 30 days due to these risks and to avoid use in patients with cirrhosis. The tolvaptan prescribing information was updated to reflect this. However, in trials that assessed the long-term use of tolvaptan for hyponatremia (SALTWATER and EVEREST), liver damage was not reported, even after 30 days of use.10,11 The FDA reports were mostly based off of the TEMPO trial, which assessed tolvaptan at twice the approved maximum dosage (120 mg/day) for use in autosomal dominant polycystic kidney disease, an indication for which it is not currently approved.12
The 2013 guidelines recommend that physicians should use discretion when considering use of tolvaptan for >30 days.1 The most appropriate candidates for long-term use may be patients who are refractory to other hyponatremia therapies and for whom benefits outweigh risks. Liver function tests should be administered every 3 months during extended treatment. Patients with liver impairment should not receive tolvaptan given the inability to differentiate further injury to tolvaptan use. This is an update from the 2007 guidelines.3 Further warnings given for vaptan use include not to use in patients with a diagnosis of hypovolemic hyponatremia; concomitantly with other treatments for hyponatremia; or immediately after other treatments, especially after infusion of 3% hypertonic saline.1
Despite the limited evidence and recent FDA warning, tolvaptan used cautiously and with careful monitoring may play an important role in short and long-term treatment of hyponatremia.1,9 Conivaptan continues to be an option in the inpatient setting as well. Other vaptans are currently approved in Europe and in development, so it will be important to assess these further once efficacy and safety data become available.
1. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-42.
2. Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc. 2006 May 31;4:10.
3. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1-21.
4. Shchekochikhin D, Tkachenko O, Schrier RW. Hyponatremia: an update on current pharmacotherapy. Expert Opin Pharmacother. 2013;14(6):747-755.
5. Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A. Role of vaptans in the management of hyponatremia. Am J Kidney Dis. 2013;62(2):364-376.
6. Samsca [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co.; 2014.
7. Vaprisol [package insert]. Northbrook, IL; Astellas Pharma US; 2012.
8. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
9. FDA Drug Safety Communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death. U.S. Food and Drug Administration website. http://www.fda.gov/drugs/drugsafety/ucm350062.htm. Updated May 6, 2013. Accessed April 30, 2014.
10. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705-712. (SALTWATER)
11. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331.
12. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418.