April 2013 FAQs

What are the differences between the recent American Society of Clinical Oncology (ASCO) guideline on antibiotic use for neutropenia and those from the Infectious Diseases Society of America (IDSA)?

Introduction

In February 2013, the American Society of Clinical Oncology (ASCO) issued their first published guideline on the prevention of infection in neutropenia and febrile neutropenia (FN) in outpatients.1 ASCO has previously published guidelines on the use of hematopoietic colony-stimulating factors, which have included primary prophylaxis of fever and neutropenia.2 The Infectious Disease Society of America (IDSA) has also recently published updated guidelines on the use of antimicrobial agents in neutropenic patients with cancer.3 These guidelines address 12 clinical questions; however, it does not specifically address which patients can be managed as an outpatient for a febrile neutropenic episode (FNE). Both guidelines address which patients should receive antimicrobial prophylaxis, antifungal prophylaxis, and antiviral prophylaxis.2,3 The IDSA guidelines further include appropriate agents to choose for empiric antimicrobial, antifungal, and antiviral treatment. Both also address risk stratification of patients for a severe infection. This review will focus primarily on the similarities and differences between the IDSA and ASCO guidelines focusing specifically on the 3 key questions the ASCO guidelines address.

Guideline Recommendations

The purpose of the ASCO guidelines was to address 3 key questions relating to the outpatient management of FN.2 To address these questions, an expert panel was formed to review the results of a systematic review of published data. Forty-five articles met study criteria and were used to develop the guidelines. In cases where there was no published literature to address part of a key question, the panel relied on expert opinion as the basis of their recommendation. A similar method was used for the IDSA guidelines.3

1. What interventions are appropriate to prevent infections in patients with malignancy, who have received chemotherapy, and are or are anticipated to become neutropenic as an outpatient?

How should we assess risk of developing a febrile neutropenic episode (FNE)?

ASCO2

–   Assessing the risk a FNE should include patient-specific characteristics, underlying malignancy, and the treatment for malignancy. Patient-specific factors associated with an increased risk of FNE include age ≥ 65 years, an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, a decrease in nutritional status (ie, albumin < 35 g/L), an episode of FN in cycle one of chemotherapy, and the presence of one or more comorbidities. The FN rate is higher with hematologic malignancies, such as acute leukemias and myelodysplastic syndrome, whereas patients with solid tumors, such as colorectal, prostate and breast cancer, have a lower rate of FN reported. Patients with advanced cancer stage, those not in remission, and those with a partial tumor response are also at an increased risk of developing FN. Lastly, the risk of FN is higher in patients receiving certain cytotoxic regimens, such as high-dose cisplatin or anthracyclines or higher dose-intensity, or in those with a high degree and duration of myelosuppression or with grade ≥ 3 mucositis. Prophylactic white blood cell (WBC) growth factors can reduce the risk of FN in select patients per the ASCO guidelines on the use of growth factors. Granulocyte colony-stimulating factor (G-CSF) prophylaxis should be given before neutropenia develops in patients that meet the criteria specified in the ASCO WBC growth factors guideline  

IDSA3

–   Patients should be classified as high-risk or low-risk according to either expert opinion or through the use of the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. A low MASCC score (<21) indicates a higher risk of contracting a severe infection.

–   G-CSF can be considered in patients with a 20% or greater risk of neutropenia.

Who should be offered antimicrobial prophylaxis?

ASCO2

–   Antibacterial prophylaxis should be considered in patients expected to experience profound neutropenia likely to last for 7 days or more.

–   Antifungal prophylaxis should be limited to patients receiving chemotherapy, expected to experience prolonged neutropenia for ≥ 7 days, and at a substantial risk (> 6% to 10%) for invasive fungal infections.

–   Antibacterial and antifungal prophylaxis is not recommended for patients with solid tumors receiving conventional-dose chemotherapy with or without biologics.

–   Pneumocystis jirovecii (PJP) prophylaxis should be considered in patients on chemotherapy regimens associated with a greater than 3.5% risk for PJP pneumonia.

–   Antiviral prophylaxis may be used in patients with a substantial risk for reactivation of hepatitis B infection (HBV).

–   Prophylaxis against reactivation of herpes simplex virus (HSV) or varicella-zoster virus (ZVZ) may be considered for select patients.

–   HSV prophylaxis is recommended for seropositive patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), receiving induction, reinduction, or consolidation therapy for acute leukemia, T-cell depleting chemotherapy with alemtuzumab or purine analogs, or receiving bortezomib.

–   The yearly influenza vaccine is recommended for all patients with cancer including all family and household contacts. In certain circumstances, a neuraminidase inhibitor may be offered after proven exposure.

IDSA3

–   Antibacterial prophylaxis should be considered in patients at high-risk who are expected to have prolonged and profound neutropenia (ANC < 100 cells/mm3 for > 7 days).

–   Antifungal prophylaxis should be targeted toward Candida species and is recommended when there is substantial risk of invasive candida infections.

–   Antifungal, mold-active prophylaxis against Aspergillus is recommended in patients with a prior history of invasive aspergillosis, anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HSCT.

–   Prophylaxis against Aspergillus with posaconazole should be considered in patients with a substantial risk of invasive aspergillosis and are undergoing intensive chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

–   Antibacterial and antifungal prophylaxis is not recommended in low-risk patients.

–   Antiviral prophylaxis is recommended for patients that are HSV seropositive and undergoing induction or reinduction therapy for any type of acute leukemia and HSCT.

–   The yearly influenza vaccine is recommended for all patients with cancer including all household members.

What antimicrobial drug classes should be used?

ASCO2

–   Antibacterial: oral fluoroquinolone.

–   Antifungal: oral triazole antifungals or parenteral echinocandins.

o A mold-active triazole is recommended when the risk for invasive aspergillosis is greater than 6%.

–   PJP: trimethoprim-sulfamethoxazole.

–   Antiviral:

o HBV reactivation: lamivudine.

o HSV: nucleoside analog.

IDSA3

–   Antibacterial: fluoroquinolone (levofloxacin or ciprofloxacin).

–   Antifungal: fluconazole, itraconazole, voriconazole, posaconazole, micafungin, caspofungin.

–   Antiviral: acyclovir.

2. Which patients are appropriate candidates to be managed as outpatients for a febrile neutropenia (FN)?

What clinical characteristics define which patients can be managed as outpatients?

ASCO2

–   Inpatient therapy is considered the standard approach.

–   Considerations in the assessment for outpatient therapy:

• Assessing the risk for medical complications associated with FN should be done using a validated tool (either MASCC risk index or Talcott’s rules). However, if a clinician has any doubts regarding the accuracy of the tool for an individual patient, the patient should be hospitalized for management.
  • MASCC is a multinational scoring system to evaluate a patients risk for medical complications associated with FN.4 Patients are classified as being either low-risk for high-risk for medical complications. The maximum score is 26 and characteristics are weighted from 2 to 5. Less crucial factors such as age and outpatient status are given a lower weight of 2 and 3, respectively, versus more important factors, such as lack of symptoms and lack of hypotension, being weight more heavily at 5. Scores ≥ 21 indicate a low-risk for medical complications.
  • Talcott’s rules places patients into 1 of 4 groups to determine which patients are medically stable and thus at lower risk for developing complications associated with FN.5 Groups I through III are patients considered to be at significantly higher risk than those in group IV. Group I includes hospitalized patients, Group II includes outpatients with serious comorbidities (ie, hypotension, inadequate fluid intake, altered mental status); Group III are patients with uncontrolled cancer.
• Patients with signs and symptoms of organ dysfunction or patients with signs and symptoms that should lead to clinical instability should not be managed as an outpatient.
  • Patients with neurologic dysfunction (seizures, altered mental status), cardiovascular dysfunction (accelerated hypertension, uncontrolled heart failure, arrhythmias), renal or hepatic impairment, pulmonary dysfunction (tachypnea, hypopnea, hypoxemia), gastrointestinal dysfunction (unable to swallow oral medications, nausea, vomiting), hematologic dysfunction (severe thrombocytopenia, anemia, thromboembolic events), infectious (evidence of sepsis or allergies to antimicrobials used for outpatients), pregnant or nursing patients, patient requiring parenteral pain medications.
• Patients with a MASCC score < 21 or in Talcott groups I to III or that meet any of the criteria described above should not be managed as an outpatient.

IDSA3

–   Not addressed in the updated guidelines.

Should patients considered low-risk start their initial doses of empiric therapy in the hospital or clinic or receive outpatient therapy after evaluation?

ASCO2

–   Direct comparisons of inpatient and outpatient therapy are lacking.

–   After documented fever in a neutropenic patient, blood samples should be drawn and the first dose of empiric therapy should be given within 1 hour of presentation.

–   Patients at low-risk for medical complications and selected to be managed on an outpatient basis should be observed for at least 4 hours prior to discharge to ensure the patient is stable and tolerability of the regimen.

IDSA3

–   Not addressed in the updated guidelines.

What are the logistic requirements that must be met to permit outpatient management?

ASCO2

–   In order to receive outpatient management, a patient must each of the following criteria:

• Residence ≤ 1 hour or ≤ 30 miles from clinic or hospital.
• Primary care physician or oncologist agree to outpatient management.
• Patient is able to comply with clinic visits.
• 24-hour caregiver present.
• 24-hour access telephone and transportation.
• No history of noncompliance with treatment protocols.

IDSA3

–   Not addressed in the updated guidelines.

3. What interventions are appropriate for managing oncology patients with a FNE outside the hospital?

What antibacterials are recommended in the outpatient setting for empiric therapy?

ASCO2

–   Oral fluoroquinolone (ciprofloxacin or levofloxacin) plus amoxicillin/clavulanate (or plus clindamycin for penicillin-allergic patients).

–   An oral fluoroquinolone is not recommended for empiric therapy in neutropenic patients who develop fever after receiving fluoroquinolone prophylaxis or in areas where the prevalence of fluoroquinolone resistance exceeds 20%.

–   Hospitalized patients who are clinically stable and low-risk patients initially receiving intravenous (IV) antibiotics with unexplained FN may be transitioned to an oral antimicrobial regimen and early discharge with outpatient monitoring.

–   Patients with FN at a high-risk of medical complications should be hospitalized and managed with IV antimicrobial therapy based on the most recent IDSA guidelines.

IDSA3

–   Not addressed in the updated guidelines.

What additional measures are recommended for outpatient management of FN?

ASCO2

–   Patients should be evaluated frequently for at least 3 days in either clinic or at home.

–   To verify fever has resolved, daily or frequent telephone calls should be conducted.

–   Frequent clinic visits and ANC and platelet count monitoring.

–   Evaluation for re-admission due to persistent neutropenic fever syndrome (PNF), fever recurrence, new signs or symptoms of infection, inability to tolerate oral medications, need for change/addition to empiric antimicrobial regimen, or identification of micro-organisms not susceptible to the initial empiric regimen.

IDSA3

–   Not addressed in the updated guidelines.

How should PNF syndrome be managed?

ASCO2

–   If the fever does not defervesce after 2 to 3 days of empiric therapy in low-risk patients, consider hospitalization for re-evaluation.

IDSA3

–   Not addressed in the updated guidelines.

Summary

Based on a systematic review of the literature, the ASCO Panel has produced guidelines on antimicrobial prophylaxis and management of FN, which specifically focus on outpatient management. The guidelines are similar to the current IDSA guidelines in their recommendations on who should receive antimicrobial prophylaxis and the appropriate therapeutic agents. Clinicians can use these ASCO guidelines to assess if their patient can be selected for outpatient management.

References

1. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.

1. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.

1. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-e93.

1. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051.

1. Talcott JA, Siegel RD, Finberg R, et al. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol. 1992;10(2):316-322

Prepared by:
Amanda Seddon, PharmD, PGY-1
University of Illinois at Chicago
March 2013

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What data are available to guide appropriate off-label use of the peripheral mu-opioid receptor antagonists, methylnaltrexone and alvimopan?

Overview of peripheral mu-opioid receptor antagonists

Methylnaltrexone and alvimopan are peripherally-acting mu-opioid receptor antagonists used to prevent or reverse decreased gastrointestinal (GI) motility. 1,2 This may be due to postoperative ileus (POI) or opioid-induced constipation (OIC), both of which may be attributable to endogenous and exogenous agonism of mu-opioid receptors in the GI tract.3,4 Alvimopan and methylnaltrexone antagonize these mu-opioid receptors, thus preventing or reversing the negative consequences of decreased GI motility. However, since neither crosses the blood-brain barrier, the beneficial analgesic effects of opioids are unaffected.

Diseases for which the drugs are indicated occur via similar physiology. While the cause of POI is multifactorial, contributing factors include the release of inflammatory mediators and endogenous opioids after surgery and postoperative use of medications that delay GI transit, such as exogenous opioids.3 Similarly, OIC is an untoward effect of stimulation of GI mu-opioid receptors by opioids, and may affect as many as 80% of these patients. 4,5 The resultant uncoordinated gut motility due to POI and OIC may cause nausea, vomiting, and in severe cases, anorexia, aspiration, or the inability to pass stool.

Despite their similar action and use in similar diseases, a key difference between the drugs is their respective Food and Drug Administration (FDA)-approved indication. Alvimopan is indicated to accelerate the time to GI recovery following partial large or small bowel resection with primary anastomosis, while methylnaltrexone is indicated for the treatment of OIC in patients with advanced illness who are receiving palliative care and have failed laxative therapy.1,2

Off-label use of peripheral mu-opioid antagonists

Because of these similarities, questions arise regarding the appropriate off-label use of alvimopan and methylnaltrexone, particularly their interchangeability in the same indication. However, off-label studies of alvimopan have shown limited and conflicting benefit in OIC. Similarly, methylnaltrexone did not improve recovery of GI function or time to hospital discharge when studied off-label in POI.

Alvimopan

Data for the off-label use of alvimopan in OIC are derived mostly from patients with non-cancer-related pain and results have varied.6-8 Early studies included a single-dose trial of placebo or alvimopan 0.5, 1.5, or 3 mg in 101 patients receiving opioid therapy for chronic pain or opioid addiction.6 Compared to placebo, a significantly greater proportion of patients receiving all alvimopan doses experienced a bowel movement within 12 hours. A dose-response relationship was suggested by the shorter time to laxation with higher doses. In contrast, large randomized controlled trials (RCTs) in OIC reported contrary results and did not support the dose-response relationship.7,8 One trial randomized 518 patients receiving opioids for non-cancer pain to alvimopan 0.5 mg once or twice daily or placebo over 12 weeks. 7 The trial showed significant benefit with alvimopan, but only with twice daily administration. Compared to placebo, a greater proportion of patients receiving this dose achieved restored GI function (72% versus 48%, p<0.001). In contrast, a trial evaluating the same endpoint in 485 patients receiving opioids for non-cancer pain did not replicate the beneficial findings.8 Compared to placebo, a numerically greater proportion of patients assigned to alvimopan 0.5 mg once or twice daily achieved the primary endpoint, but neither represented a statistically significant difference (63% in both alvimopan groups versus 56% placebo). Notably, the magnitude of difference in this trial did not even represent what the authors predefined as a clinically significant difference in response rates (20%), illustrating the inconsistency in the statistically and clinically significant benefit of alvimopan in non-cancer OIC.

Beyond its use in patients with OIC in the setting of non-cancer pain, very limited data are available for alvimopan use in patients with OIC due to opioid dependence. One RCT that included both populations offers little information, as only 20 of 168 total patients received opioids for dependence.9 Compared to placebo, a significantly greater proportion of patients assigned to alvimopan 0.5 or 1 mg daily for 21 days achieved at least 1 bowel movement within 8 hours of administration (43%, 54%, and 29%, respectively; p<0.001 for both comparisons). Unfortunately, patients receiving alvimopan for OIC due to opioid dependence were not analyzed separately.

Studies of alvimopan used in other unlabeled populations include abdominal hysterectomy, which showed positive, albeit limited findings.10-13 Only 1 RCT by Herzog and colleagues exclusively studied patients undergoing total abdominal hysterectomy.12 Of 519 randomized women, those receiving alvimopan experienced significantly accelerated time to the primary composite endpoint (referred to as GI-2), defined by achievement of both tolerance of solid food and passage of stool (hazard ratio [HR] 2.23, p<0.001). Although other clinical trials of alvimopan in POI have included patients undergoing hysterectomy, only one performed a subanalysis of them, the results of which are of limited practicality.13 Contrasting the findings by Herzog, a subanalysis of 97 patients who underwent simple hysterectomy in this trial found no significant difference between alvimopan dosed at either 6 or 12 mg twice daily and placebo for the primary composite outcome (referred to as GI-3), defined by achievement of both tolerance of oral food and the first passage of either stool or flatus. Importantly, GI-3 is considered a weaker endpoint than GI-2, since patients must be aware of and willing to report the passage of flatus. Unfortunately, the authors did not report results for the more meaningful GI-2 endpoint in patients undergoing simple hysterectomy. Other abdominal surgeries in which alvimopan is currently being studied include radical cystectomy, though trial results are not yet available and the other data are based on a hypothetical cost-effectiveness model.14,15

Methylnaltrexone

Similar to alvimopan, off-label studies of methylnaltrexone to reduce the duration of POI have been of limited applicability.16 Two identical placebo-controlled RCTs including 1048 total patients found methylnaltrexone at 12 or 24 mg for up to 10 days after segmental colectomy did not significantly decrease the time to gastrointestinal recovery.

Additionally, methylnaltrexone has been studied in patients with OIC, but in settings other than that approved in the product labeling.2,17,18 Michna and colleagues evaluated methylnaltrexone 12 mg daily or every other day or placebo in 460 patients with OIC in nonmalignant pain.17 Compared to placebo, a significantly greater proportion of patients assigned to both methylnaltrexone groups experienced bowel movement (BM) within 4 hours of the first dose (34.2% both groups, 9.9% placebo; p<0.001). Another trial in patients with methadone-induced constipation suggested benefit, but with important limitations.18 While all 11 patients treated with methylnaltrexone experienced laxation after administration, the sample size was small and the drug was given intravenously rather than subcutaneously, the labeled route of administration. Lastly, methylnaltrexone has shown benefit in OIC in intensive care unit (ICU) patients, but this study was small and retrospective. Of 15 sedated ICU patients with OIC, laxation occurred within 24 hours in 6 of 7 treated with methylnaltrexone versus 0 of 8 treated with sodium picosulfate and glycerin suppositories (p=0.001).19 A prospective trial was planned to explore this use, but its status is unknown.20

Considerations for appropriate use

Because of limited off-label data for alvimopan and methylnaltrexone, determination of patients likely to benefit from their use is warranted. Consideration should be given to the use of concomitant medications, safety concerns, and factors related to response to the drugs.

The benefit of alvimopan in patients receiving concomitant medications is not fully defined. Prospective trials have excluded patients receiving epidural opioid analgesia, which is concerning because opioids are frequently administered via this route after bowel resection. Furthermore, alvimopan has not been studied extensively in conjunction with nonopioid pain medications, which may reduce the amount of required opioids and modify the drug’s effect. Only 1 retrospective review analyzed the effect of concomitant non-steroidal anti-inflammatory drugs (NSAIDs) on outcomes with alvimopan versus historical controls.21 Although NSAID use was not associated with a shorter length of stay, nearly twice as many alvimopan patients received NSAIDs compared to historical controls, which may have favored this group due to potentially lower required opioid doses. Additionally, a post-hoc analysis of an RCT of patients undergoing open abdominal surgery suggests that receipt of opioids via patient-controlled analgesia (PCA) may modify the effect of alvimopan. Alvimopan patients who received opioids via PCA were more likely to achieve the GI-2 outcome compared to placebo (HR 1.39, p=0.023), while for alvimopan patients receiving intermittent bolus opioids, outcomes were not significantly different (HR=1.17, p=0.289).22

The potential for serious adverse events should also be considered, particularly with alvimopan. While safety-related outcomes have generally not differed significantly from placebo with either drug, patients receiving alvimopan who had established cardiovascular disease or underlying risk factors experienced numerically more serious cardiovascular events versus placebo in clinical trials. 23 Combined data showed numerically higher rates of serious cardiovascular events with alvimopan compared to placebo, specifically when used in OIC. Based on this imbalance, the FDA-approved the drug for use only in limited indications and required a Risk Evaluation and Mitigation Strategy; the manufacturer also terminated its further study in OIC. Therefore, it may be appropriate to avoid alvimopan in patients with cardiovascular risk factors. Methylnaltrexone labeling does not contain a warning for such serious adverse events.

Lastly, response-related factors may be considered in the decision to discontinue therapy. A post-hoc analysis of 1methylnaltrexone trial found that an early initial response in OIC predicted response to subsequent doses.24 Of patients who responded to at least 2 of the initial 4 doses, 81% had at least 3 BMs per week throughout the entire 4-week intervention compared to 43% of patients who responded to less than 2 of the initial 4 doses (p<0.0001). Therefore, lack of an initial response to methylnaltrexone in OIC may be a compelling reason to discontinue therapy. Furthermore, methylnaltrexone use has not been studied beyond 4 months, thus lack of a sustained response may also influence considerations to discontinue therapy due to lack of long-term safety data. Likewise, response to alvimopan can aid in the decision to stop therapy. Although the product labeling states it may be used for a maximum of 15 doses or until hospital discharge, some protocols and reviews have specified the drug may be discontinued upon the first BM. 3,11,25

Summary

Although alvimopan and methylnaltrexone have the same pharmacologic action and are used in diseases with similar pathophysiology, they are FDA-approved for different uses. Alvimopan is indicated to accelerate GI recovery following partial large or small bowel resection, whereas methylnaltrexone is indicated to treat OIC in patients with advanced illness receiving palliative care. Data do not strongly support their use outside of these indications and the drugs should not be considered interchangeable. Trials of alvimopan in OIC have shown conflicting and limited benefit, and their safety results led to the inclusion of a warning in the product labeling. Similarly, trials of methylnaltrexone in POI suggest it offers no benefit; furthermore, results supporting its use in OIC due to opioid dependence or in ICU patients have not been replicated. Some data are available to direct appropriate use of these drugs, suggesting the effect of alvimopan may be decreased by intermittent bolus administration of opioids but not by concomitant NSAIDs, and that an early response to methylnaltrexone may predict future response.

References

1. Entereg [package insert]. Exton, PA: Adolor Corp; 2011.

2. Relistor [package insert]. Raleigh, NC: Salix Pharmaceuticals; 2012.

3. Bream-Rouwenhorst HR, Cantrell MA. Alvimopan for postoperative ileus. Am J Health Syst Pharm. 2009;66(14):1267-1277.

4. Gatti A, Sabato AF. Management of opioid-induced constipation in cancer patients: focus on methylnaltrexone. Clin Drug Investig. 2012;32(5):293-301.

5. Portenoy RK, Thomas J, Moehl Boatwright ML, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage. 2008;35(5):458-468.

6. Schmidt WK. Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001;182(Suppl 5A):27S-38S.

7. Jansen JP, Lorch D, Langan J, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):185-193.

8. Irving G, Pénzes J, Ramjattan B, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):175-184.

9. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction–a 21-day treatment-randomized clinical trial. J Pain. 2005;6(3):184-192.

10. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240(4):728-734.

11. Taguchi A, Sharma N, Saleem RM, et al: Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001;345(13):935-940.

12. Herzog TJ, Coleman RL, Guerrieri JP, et al. A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006;195(2):445-453.

13. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48(6):1114–1125.

14. Cubist Pharmaceuticals, Techner L. A Study of Alvimopan for the Management of Postoperative Ileus in Subjects Undergoing Radical Cystectomy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-2013. Available at: http://clinicaltrials.gov/ct2/show/NCT00708201?term=A+phase+4%2C+multicenter%2C+double-blind%2Cplacebo-controlled%2C+parallel+study+of+alvimopan+for+the+management+of+postoperative
+ileus+in+subjects+undergoing+radical+cystectomy&rank=1 NLM Identifier: NCT00708201.

15. Hilton WM, Lotan Y, Parekh DJ, Basler JW, Svatek RS. Alvimopan for prevention of postoperative paralytic ileus in radical cystectomy patients: a cost-effectiveness analysis [published online ahead of print November 21, 2012]. BJU Int. 2012. doi: 10.1111/j.1464-410X.2012.11499.x.

16. Yu CS, Chun HK, Stambler N, et al. Safety and efficacy of methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy: results of two randomized, placebo-controlled phase 3 trials. Dis Colon Rectum. 2011;54(5):570-578.

17. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562.

18. Yuan CS, Foss JF, O'connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283(3):367-372.

19. Sawh SB, Selvaraj IP, Danga A, Cotton AL, Moss J, Patel PB. Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients. Mayo Clin Proc. 2012;87(3):255-259.

20. Whitmer BA; St. John Health System, Michigan. Methylnaltrexone for Treatment of Opiate-Induced Constipation in the Intensive Care Unit (MOVE-IT). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-2013. Available at: http://clinicaltrials.gov/ct2/show/NCT01050595?term=methylnaltrexone&rank=4. NLM Identifier: NCT01050595.

21. Absher RK, Gerkin TM, Banares LW. Alvimopan use in laparoscopic and open bowel resections: clinical results in a large community hospital system. Ann Pharmacother. 2010;44(11):1701-1708.

22. Büchler MW, Seiler CM, Monson JR, et al. Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment Pharmacol Ther. 2008;28(3):312-325.

23. GSK and Adolor announce preliminary results from phase 3 safety study of alvimopan (Entereg/Entrareg). GlaxoSmithKline Web site. http://www.gsk.com/media/press-releases/2007/gsk-and-adolor-announce-preliminary-results-from-phase-3-safety-study-of-alvimopan-enteregentrareg.html. Accessed March 3, 2013.

24. Michna E, Weil AJ, Duerden M, et al. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis. Pain Med. 2011;12(8):1223-1230.

25. Thompson M, Magnuson B. Management of postoperative ileus. Orthopedics. 2012;35(3):213-217.

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What are the risk factors associated with supratherapeutic dosing of acetaminophen in hospitalized patients?

Background

Acetaminophen (Tylenol) is one of the most commonly prescribed pain medications in the United States.1 It is found in single ingredient preparations as well as multi-symptom combination products.2 Many combination product names do not indicate that acetaminophen is a component of these medications, which can lead to confusion for patients and providers. Acetaminophen is also the leading cause of acute liver failure (ALF) in the United States.3,4 Doses of acetaminophen that exceed 4 g per day can lead to elevated liver enzymes, ALF or death. Although ALF is a known adverse effect of high dose acetaminophen, reports of liver damage continue to occur. One study reported that acetaminophen-related ALF increased from 28% in 1998 to 51% in 2003.5 The Food and Drug Administration has implemented a number of strategies to reduce the risk of acetaminophen toxicity, including limiting the dose to 325 mg and requiring boxed warnings to alert consumers to the risks of liver damage.6

The majority of clinical trials that evaluate supratherapeutic doses of acetaminophen have been conducted in ambulatory populations.7-9 These trials theorized that patients had limited knowledge about appropriate per day doses of acetaminophen and errors could occur resulting in overdose. The improper use of acetaminophen in hospitals was thought to be less of a risk since healthcare providers are monitoring the prescribing and administration of the drug. This document reviews a trial that evaluates the risks of acetaminophen use in hospitalized patients.

Literature Review

This retrospective trial evaluated acetaminophen use in adult patients at 2 hospitals in Boston, MA over a 3-month period in 2010.10 The patients’ electronic medical records were obtained to determine if supratherapeutic doses of acetaminophen were given during hospitalization. Supratherapeutic doses were defined as doses of acetaminophen >4 g per day or >3 g per day in patients with chronic liver disease (CLD). The patient’s primary diagnosis, liver function tests, and patient demographics were collected. The primary outcomes were acetaminophen exposure and the rate of supratherapeutic dosing in this population. Risk factors for excessive acetaminophen dosing were also evaluated.

During the study period, 14,411 patients received acetaminophen at 1 of the 2 study sites.10 The average age of the patients in the trial was 55.4 years although 35.1% were over age 65. The majority of the patients were white (78.4%) and female (58%). A total of 955 patients (6.6%) exceeded a dose of 4 g per day (9.6% at Hospital A and 4.2% at Hospital B). Approximately 22% of patients over age 65 and 18% of patients with CLD received supratherapeutic doses.

Almost half of all supratherapeutic doses were >5 g per day. Surgical and intensive care units (ICU) had a higher risk of excessive dosing (odds ratio (OR) = 2.9 [95% confidence interval (CI): 2.5 to 3.3] and OR = 1.3 [95% CI: 1.1 to 1.6], respectively). Although there was no statistically significant difference in the rate of excessive dosing when single-drug products were compared to multi-ingredient products, a higher risk of supratherapeutic dosing was associated with the acetaminophen only products (OR = 3.4 [95% CI: 2.5 to 4.6]). Patients who received products with 500 mg of acetaminophen per dose had a higher risk of supratherapeutic dosing (OR = 10.7 [95% CI: 9.3 to 12.2]). In addition, patients who had standing orders for acetaminophen had increased risk (OR = 29.3 [95% CI: 24.5 to 35.11]). A diagnosis of osteoarthritis was associated with a higher risk of excessive dosing (OR, 4.2 [95% CI, 3.6-5.0]). Approximately 40% of patients received excessive doses of acetaminophen for >3 days and 4% received excessive doses for >10 days.

There was a difference in supratherapeutic acetaminophen dosing between the study facilities, so the patient characteristics were evaluated.10 Hospital A had a higher number of standing orders (25.3% vs. 15.9%; p<0.001), more 500 mg doses given (19.1% vs. 5.1%; p<0.001), more female patients (62.9% vs. 53.9%; p<0.001), fewer ICU patients (27.4% vs. 51.8%, p<0.001) and fewer patients with osteoarthritis 7.2% vs. 9.6%; p<0.001). Hospital B had more patients who received combination products (44.8% vs. 4.7%; p<0.001) and more patients who received multiple products (23.2% vs. 3.2%; p<0.001).

Conclusion

Although the electronic medical record was able to accurately document excessive acetaminophen dosing, it did not prevent supratherapeutic dosing of acetaminophen. These occurrences were reported at both institutions over a 3 month period and were not isolated incidents. Patient characteristics that were identified as risk factors included a diagnosis of osteoarthritis, and those who were older. Other risk factors identified were potentially controllable, including the use of 500 mg doses, scheduled vs. as needed doses, the use of multiple formulations containing acetaminophen and location in an ICU or surgical unit.

Recommendations

Hospital pharmacists are in a position to reduce the risk of supratherapeutic acetaminophen dosing. Although there are many uncontrollable risk factors, there are some specific policy changes that hospital pharmacists can implement to reduce the risk of supratherapeutic doses of acetaminophen. These include:

• Avoid use of scheduled doses of acetaminophen at doses >325 mg.
• Avoid use of multiple products that contain acetaminophen.
• Implementation of clinical alerts at the bedside that indicate when the maximum daily dose is about to be exceeded.
• Educate healthcare providers on the maximum daily doses of acetaminophen.

References

1. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344.
2. Wickersham RM, ed.. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2013.
3. Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am. 2008;92(4):761-794.
4. Lee WM. Acetaminophen-related acute liver failure in the United States. Hepatol Res. 2008;38 (Suppl 1):S3-S8
5. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364-1372..
6. US FDA Drug Safety Communication: prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. US Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Accessed February 28, 2013.
7. Stumpf JL, Skyles AJ, Alaniz C, Erickson SR. Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population. J Am Pharm Assoc. 2007;47(1):35-41.
8. Heaton PC, Cluxton Jr. RJ, Moomaw CJ. Acetaminophen overuse in the Ohio Medicaid population. J Am Pharm Assoc. 2003;43(6):680-684.
9. Albertson TE, Walker Jr. VM, Stebbins MR, Ashton EW, Owen KP, Sutter ME. A population study of the frequency of high-dose acetaminophen prescribing and dispensing. Ann Pharmacother. 2010;44(7-8):1191-1195.
10. Zhou L, Maviglia SM, Mahoney LM, et al. Supratherapeutic dosing of acetaminophen among hospitalized patients. Arch Intern Med. 2012;172(22):1721-1728.

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