April 2017 FAQs

What evidence is available for the use of aprepitant (Emend) compared to other antiemetics for the prevention of postoperative nausea and vomiting?

Introduction

Postoperative nausea and vomiting

Postoperative nausea and vomiting (PONV) refers to nausea, vomiting, or retching, an involuntary effort to vomit, that occurs within 24 hours postoperatively and is frequently rated by patients as worse than postoperative pain.^1,2 Nausea and vomiting after surgery affects approximately 75 million patients annually with an overall incidence of approximately 30%, however, the estimated incidence can be as high as 80% in patients at high risk of PONV.^3,4 Complications in postoperative recovery or additional problems such as wound dehiscence, esophageal rupture, aspiration, dehydration, increased intracranial pressure, and pneumothorax can present in patients who experience PONV. The Apfel risk score identifies female gender, nonsmoking status, history of PONV, and the use of postoperative opioids as risk factors for PONV. Table 1 provides additional risk predictors related to the development of PONV. The presence of all 4 risk factors correlates with a ~80% risk for PONV. Dopamine (D₂), muscarinic, histamine (H₁), serotonin (5-HT₃), and neurokinin-1 (NK₁) receptors are involved in the signaling of emesis. The NK₁ receptor acts in the central and peripheral nervous systems and mediates the effects of substance P, whose presence can lead to emesis.

Table 1. Postoperative nausea and vomiting risk predictors.^3,4

Numerous pharmacological treatment options such as antihistamines, 5-HT₃ antagonists, NK₁receptor antagonists, haloperidol, metoclopramide, scopolamine, and corticosteroids can be recommended for the prevention of PONV, although not all agents have a Food and Drug Administration (FDA)-approved indication.^4,5 Also, strategies to minimize the occurrence of PONV can also be implemented to decrease baseline risk (Table 2). In patients with moderate to high risk of PONV, the use of PONV prophylaxis should be considered with either monotherapy or combination therapy. The Society for Ambulatory Anesthesiology guidelines for the management of PONV – available here –  provides a list of recommended prophylactic doses and timing for antiemetics.⁴ Based on evidence from multiple randomized controlled trials, the recommended dose of aprepitant is 40 mg at anesthesia induction.

Table 2. Strategies to reduce baseline risk⁴

Aprepitant

Aprepitant (Emend^®) is a highly selective NK₁ receptor antagonist that decreases substance P resulting in an anti-emetic effect.⁶ Aprepitant is available in both oral capsule and suspension formulations, however, only the oral capsule is FDA-approved for the prevention of PONV.² The dose of aprepitant capsules for PONV is 40 mg by mouth within 3 hours prior to the induction of anesthesia.⁶ It is not excreted by the kidneys and is primarily metabolized by the liver. The elimination half-life is 9 to 13 hours.

Literature review

This article reviews evidence on the use of aprepitant for the prevention of PONV in the non-oncological surgery setting.

Reviews/meta-analyses

According to meta-analyses, aprepitant has been found to be effective for PONV for patients undergoing different types of surgeries in a number of trials.^7,8 A meta-analysis by Liu et al included 14 trials that evaluated whether NK₁ receptor antagonists, including aprepitant, were effective in preventing PONV in patients who underwent surgery and received general anesthesia.⁸ Ten trials included the use of aprepitant in doses ranging from 40 mg to 125 mg, of which 7 trials were included in the network meta-analysis. The authors did not find a significant difference in the incidence of vomiting amongst the 3 doses (40 mg, 80 mg, and 125 mg) of aprepitant when compared to each other. In addition, no difference was found when aprepitant was compared to ondansetron 4 mg, except with the aprepitant 125 mg dose (odds ratio [OR] 7.07; 95% confidence interval [CI], 1.52 to 18.19). Aprepitant did not demonstrate a dose-related effect in preventing PONV. Aprepitant was effective in reducing the incidence of postoperative vomiting at all 3 doses, but not the rate of nausea. The authors concluded that overall NK₁ receptor antagonists, including aprepitant, help prevent PONV.

A meta-analysis by Singh et al., which included 15 trials, looked specifically at aprepitant compared to traditionally used antiemetics (eg, ondansetron, dexamethasone, etc.) in patients undergoing surgery.⁷Aprepitant was studied at doses of 40 mg, 80 mg, and 125 mg and was primarily compared to ondansetron or dexamethasone. The likelihood of vomiting was significantly lower with the use of aprepitant at different doses compared to active control drugs on postoperative day (POD) 1 (49.1% vs. 41.3%; OR 0.44; 95% CI, 0.32 to 0.61), and POD 2 (6.8% vs. 12.8%; OR 0.54; 95% CI, 0.40 to 0.72). Patients were also approximately twice as likely to achieve a complete response, no nausea or vomiting, on POD 1 with aprepitant. Since most of the studies included used aprepitant 40 mg, there were insufficient data to demonstrate a difference amongst different aprepitant doses in preventing PONV. As a result, recommendations on the optimal dose of aprepitant for PONV cannot be established at this time.

Table 3. Summary of trials evaluating use of aprepitant to prevent PONV.

Recommendations for clinical practice

According to the guidelines for the management of PONV, there is a lack of evidence to suggest the use of prophylactic antiemetic therapy for all surgical patients, but it is recommended for moderate to high risk patients.⁴ The literature demonstrates that aprepitant 40 mg, 80 mg, and 125 mg may be more effective than ondansetron in reducing postoperative vomiting at multiple time intervals up to 48 hours postoperation, however, there are insufficient data to determine an optimal aprepitant dose.^4,7In addition, complete response and reduced rates of nausea were not consistently achieved. Based on the review of current data of non-oncological operations and unless future data suggests otherwise, aprepitant 40 mg oral dose within 3 hours of induction of anesthesia may be considered, either alone or as part of a multimodal regimen, for the prevention of PONV for patients who are at high risk of emesis.

References:

1. UpToDate [database online]. Waltham, MA: Wolters Kluwer; 2017. http://uptodate.com Accessed March 22, 2017.

2. Diemunsch P, Joshi GP, Brichant JF. Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting. Br J Anaesth. 2009;103(1):7-13.

3. Collins AS. Postoperative nausea and vomiting in adults: implications for critical care. Crit Care Nurse.2011;31(6):36-45.

4. Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118(1):85-113.

5. Apfelbaum JL, Silverstein JH, Chung FF, et al. Practice guidelines for postanesthetic care: an updated report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. Anesthesiology. 2013;118(2):291-307.

6. Emend [package insert]. Athlone, Ireland: Alkermes Pharma Ireland Limited; 2017.

7. Singh PM, Borle A, Rewari V, et al. Aprepitant for postoperative nausea and vomiting: a systematic review and meta-analysis. Postgrad Med J. 2016;92:87-98.

8. Liu M, Zhang H, Du BX, et al. Neurokinin-1 receptor antagonists in preventing postoperative nausea and vomiting: a systematic review and meta-analysis. Medicine (Baltimore). 2015;94(19):1-15.

9. Trimas SJ, Trimas MD. Use of aprepitant and factors associated with incidence of postoperative nausea and vomiting in patients undergoing facial plastic surgery. JAMA Facial Plast Surg. 2015;17(4):251-255.

10. Ham SY, Shim YH, Kim EH, et al. Aprepitant for antiemesis after laparoscopic gynaecological surgery: A randomised controlled trial. Eur J Anaesthesiol. 2016;33:90-95.

11. Green MS, Green P, Malayaman SN, et al. Randomized, double-blind comparison of oral aprepitant alone compared with aprepitant and transdermal scopolamine for prevention of postoperative nausea and vomiting. Br J Anaesth. 2012;109:716-722.

Prepared by

Sarah Hausner, PharmD

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

Edited by: Yesha Patel, PharmD, BCPS

April 2017

The information presented is current as of February 9, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

What handling precautions should be taken when preparing monoclonal antibody drugs?

Introduction

While the hazards of exposure to traditional antineoplastic drugs is widely accepted, the hazardous potential of other drug classes that do not fall into this category is less clear.¹ Some of these drugs include non-antineoplastic medications that meet one or more of the National Institute for Occupational Safety and Health (NIOSH) criteria for hazardous drugs.² Risks associated with such drugs may be reproductive in nature, and some healthcare workers have expressed concern regarding the risk of long-term monoclonal antibody (mAbs) exposure on women who are or may become pregnant.³ Many mAbs, which are used in chemotherapy regimens but are not always directly mutagenic may generate questions regarding their safe handling during preparation and administration, including the use of personal protective equipment (PPE).

Hazardous drugs

The NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings is published periodically and lists drug products meeting the organization’s definition of hazardous.² It defines hazardous drugs as those with one or more of the following properties: carcinogenicity, teratogenicity or other developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, and structure and toxicity profiles of new drugs that mimic existing drugs categorized as hazardous by the preceding criteria. Hazardous drugs include those used for cancer chemotherapy, antiviral drugs, hormones, some bioengineered drugs, and other miscellaneous drugs. Many cancer chemotherapy drugs interfere with the function of DNA or RNA, and when their effects are nonselective, they may result in toxic side effects in healthcare workers exposed to such drugs. For this reason, a mAb conjugated to a traditional chemotherapy agent, ado-trastuzumab emtansine, is included in the NIOSH list of hazardous drugs, while its non-conjugated counterpart (trastuzumab), which is not directly mutagenic, is omitted. The only non-conjugated mAb included in the NIOSH list of hazardous drugs is pertuzumab because of its risk of embryo-fetal toxicity. Importantly, the NIOSH definition of hazardous drugs may not accurately indicate the risk associated with newer-generation pharmaceutical products (ie, bioengineered drugs targeting specific sites in the body like mAbs), which may or may not be hazardous to healthcare workers. Research into this risk is ongoing.

Data on toxicity of mAbs

Little is known regarding the effects of low-level, continuous exposure to mAbs when handled by healthcare practitioners.¹ For example, a 2016 literature review found that many international guidelines on handling of cytotoxic or hazardous substances did not fully address mAbs. Not surprisingly, there is no broad consensus on exactly how they should be handled.

The risks of exposure to mAbs are considered in light of the normal properties of these drugs.¹ Because of their large molecular size, mAb exposure via the skin is considered unlikely. However, local reactions such as irritation and allergic reaction may occur with a compromised skin barrier. When preparing mAbs from powder or aerosolized particles, inhalational or mucosal absorption may occur. Oral absorption via hand-to-mouth exposure may occur, but decomposition by digestive enzymes would likely mitigate systemic exposure. While the amount of exposure is difficult to quantify, it is considered a possibility, as some nurses have described the ability to taste mAbs while reconstituting them.³ A difficulty in evaluating risk of exposure to new mAb drug products may also lie in the many mAb approvals via accelerated pathways, which may provide little insight regarding long-term exposure and hazardous potential.⁴

Beyond the risk of exposure to mAbs, the sequelae may include formation of neutralizing antibodies.¹These may cross-react with endogenous proteins, cause anaphylaxis, or reduce future clinical response in a patient requiring treatment with a mAb to which they were previously exposed. Although the clinical significance of neutralizing antibody production is uncertain, immunologic and allergic reactions may occur with exposure below normal therapeutic doses.

Recommendations for handling mAbs

Because mAbs represent a heterogeneous group of medications with unique toxicity profiles, it is unlikely that any overarching handling requirements will meet the needs of all products. The new draft of chapter 800 of the United States Pharmacopeia (USP), which will take effect in July 2018, addresses handling of hazardous drugs in healthcare settings.^5,6 It states that every institution should maintain a list of hazardous drugs, including those listed by NIOSH, and should update such a list at least annually. USP 800 recommends the criteria from the NIOSH list be used to identify hazardous drugs. While it does not provide recommendations specifically for mAbs, the chapter states that when information on a drug is insufficient to make an informed decision, it should be considered hazardous until more information is available.

Currently, and similarly to USP 800 recommendations, experts recommend handling mAbs in accordance with established procedures for cytotoxic or biohazardous medications, utilizing PPE such as gloves and masks.^1,5,7 This also entails potentially segregating storage for specific mAbs, preparation within a biological safety cabinet, and the use of a closed system drug-transfer device. USP 800 states that gloves, gowns, and head, hair, and shoe covers are required during compounding of sterile and nonsterile hazardous drugs, while gloves and gowns may be required when administering injectable antineoplastic hazardous drugs; PPE that is required for other activities should be delineated in an institution’s standard operating procedures based on the risk of exposure.⁵ Safe handling practices of mAbs should also be incorporated into healthcare staff training programs regarding their storage, preparation, and distribution, and consideration can be given to occupational health screening for mAb exposure because of the risk for antibody formation.¹

Insight into current practices of handling mAbs is provided by one survey of healthcare professionals.⁸The 2013 survey identified that among 222 Australian clinicians, only 43% reported access to institutional mAb handling guidelines. Results indicated that the most common strategies utilized to reduce occupational exposure risk included education and training (71%), spill and waste management (71%), procedures for transportation of mAbs (57%), and restricted handling (50%). When asked about a group of mAbs chosen to represent a variety of dosage forms and administration techniques (bevacizumab, brentuximab vedotin, cetuximab, denosumab, rituximab, and trastuzumab), responses varied across medications in the use of PPE such as gloves, goggles, protective coveralls and boots, and respiratory masks.

Conclusion

Because many mAbs are not directly mutagenic as are traditional chemotherapy drugs, they may not appear in the NIOSH list of hazardous drugs unless they are conjugated. Nonetheless, occupational exposure remains a concern and research is ongoing regarding the risk of long-term, low-level exposure among healthcare workers. Current recommendations are generally to handle mAbs consistent with drugs considered hazardous, which requires the use of PPE.

References

1.         Rinehart JR, Jorgenson JA. Considerations for handling monoclonal antibodies. Pharm Purchasing Prod. 2015;12(5):S6-S8.

2.         Anonymous. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. Centers for Disease Control and Prevention website. https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf. Published September 2016. Accessed March 17, 2017.

3.         South Australian Health. Safe handling of cytotoxic drugs and related wastes: Guidelines for South Australian health services 2012. South Australian Health website. http://www.uhb.nhs.uk/Downloads/pdf/CancerPbPreparationOfMonoclonalAntibodies.pdf. Published July 2012. Accessed March 17, 2017.

4.         Anonymous. Hematology/oncology (cancer) approvals & safety notifications. US Food and Drug Administration website. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Updated March 23, 2017. Accessed March 25, 2017.

5.         <800> Hazardous drugs – handling in healthcare settings. In: USP 40-NF 35. 40th ed. Baltimore, MD: United Book Press, Inc; 2016: 727-746.

6.         Anonymous. Frequently asked questions: <800> hazardous drugs—handling in healthcare settings. U.S. Pharmacopeial Convention website. http://www.usp.org/frequently-asked-questions/hazardous-drugs-handling-healthcare-settings. Accessed March 27, 2017.

7.         Vizcarra C. Biologic therapy. In: Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R, eds. Infusion nursing: An evidence-based approach. 3rd ed. St. Louis, MO: Saunderes/Elsevier; 2010: 299-315.

8.         Alexander M, King J, Lingaratnam S, et al. A survey of manufacturing and handling practices for monoclonal antibodies by pharmacy, nursing and medical personnel. J Oncol Pharm Pract. 2016;22:219-227.

April 2017

The information presented is current as of March 22, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

What are the American Heart Association’s recommendations for managing NOACs in acute care and peri-procedurally?

The use of non-vitamin K antagonist oral anticoagulants (NOACs) is becoming more widespread but methods for managing patients who are actively bleeding, at risk of bleeding or undergoing surgical procedures are still unclear. A recent scientific statement released in March 2017 from the American Heart Association (AHA) helps clarify some of these unanswered questions.¹

NOAC reversal

The currently available NOACs include dabigatran, rivaroxaban, apixaban, and edoxaban.¹ Except for dabigatran which is a direct thrombin inhibitor, all the other agents are factor Xa inhibitors. Regular monitoring of the anticoagulant effect of these agents is not required due to their predictable pharmacokinetics and anticoagulant effects. Although these agents do affect certain coagulation tests, it is not in a predictable manner that can be used to quantify the anticoagulation effect. Although this is an advantage for routine care, it is also a challenge in certain situations in which the desired effect of the NOAC needs to be reversed or stopped such as in serious bleeding or an urgent surgical procedure. An assessment of time of last ingestion and renal function can help determine the best methods for NOAC reversal. Table 1 provides a summary of the coagulation tests that are affected by the NOACs and the recommended method of reversal. For dabigatran reversal, hemodialysis is listed as an alternative option. According to the AHA statement, this can be considered when creatinine clearance (CrCl) is less than 30 mL/min chronically or in patients who develop acute kidney injury. Approximately 50% of dabigatran would be expected to be removed with hemodialysis within 4 hours. Hemodialysis is not recommended for reversal of the factor Xa inhibitors due to high protein binding of these agents. Activated charcoal is mentioned as a potential method for recent (within 1 to 2 hours) ingestion of large doses of dabigatran, rivaroxaban, and apixaban; however, there is risk of aspiration in patients with reduced consciousness and vomiting induced by activated charcoal can increase intracranial pressure in patients presenting with intracranial hemorrhage. It is important to note that the methods listed by the AHA for reversal of the factor Xa inhibitors are based on either case reports or in vitro studies. There currently is no evidence of a NOAC reversal method that demonstrates control of bleeding as the studies to date have focused on normalization of coagulation tests.

Investigation of the safety and efficacy of andexanet alfa, a recombinant human factor Xa decoy protein, for reversal of factor Xa inhibitors is ongoing.¹ An interim analysis of an open-label trial evaluating its reversal effects in patients with acute hemorrhage receiving apixaban, rivaroxaban, edoxaban, or enoxaparin demonstrated an approximate 90% reduction in anti-factor Xa activity for patients on apixaban or rivaroxaban. Additionally, 37 out of 47 patients (79%) achieved excellent or good clinical hemostasis. Ciraparantag (PER 977) is a synthetic molecule that is also under investigation as an antidote for edoxaban-associated bleeding. It has been shown to bind heparin, factor Xa inhibitors, and direct thrombin inhibitors and has demonstrated normalization of clotting time within 10 to 30 minutes of administration. Neither agent is approved for use as studies are ongoing.

Table 1. Coagulation tests affected by NOACs and methods for reversal of major bleeding.^1-5

Major bleeding and acute care

Depending on the condition of the patient some general measures for managing major, life-threatening bleeding in patients on NOACs may include mechanical compression (if compressible) of the bleeding area, use of tourniquets, resuscitation, intravenous (IV) fluids, packed red blood cells (RBCs), and/or plasma expanders.¹ Table 2 below provides recommendations for NOAC management of specific types of bleed. Table 3 provides a summary of the AHA’s guidance of management in NOAC overdose, acute kidney injury, and ischemic stroke.

Table 2. Major bleeding and NOAC management.^1,6

Table 3. Acute care scenarios and NOAC management.^1-7

Periprocedural management of NOACs

For patients on NOACs who require a surgical procedure, the AHA provides guidance on assessing the bleeding risk of the procedure and the risk of thromboembolism (TE) based on patient factors. Bridging and interruption of NOAC therapy is not considered necessary in patients undergoing a procedure with low bleeding risk which includes minor dental, minor dermatologic, ophthalmologic, and endoscopic (without biopsy) procedures. On the other hand, interruption of therapy and/or bridging may become necessary in procedures classified as having a moderate to high bleeding risk. Procedures categorized as having a moderate bleeding risk include supraventricular tachycardia (SVT) ablation, implantable cardioverter-defibrillator (ICD) implant, endoscopy with biopsy, prostate biopsy, and cardiac catheterization via the radial artery. High bleeding risk procedures include cardiovascular/thoracic surgery, intra-abdominal/pelvic surgery, major orthopedic surgery, neurosurgery, and cardiac catheterization via the femoral artery. For these types of procedures, assessment of the patient’s thromboembolic (TE) risk is required.

A commonly used tool to assess stroke risk in patients with nonvalvular atrial fibrillation is the CHA₂DS₂VASc score.⁶ A score is assigned for each of the risk factors associated with stroke and include congestive heart failure, hypertension, age 75 years or greater, diabetes, history of stroke, transient ischemic attack (TIA) or TE, vascular disease such as peripheral arterial disease or myocardial infarction (MI), age 65 to 74 years, and female gender. Most factors are assigned a score of 1 except previous stroke and age 75 years and greater which are given a score of 2. The higher the score, the greater the risk of stroke. The maximum score is 9. Patients are considered to have a low TE risk if their CHA₂DS₂VASc score is less than or equal to 1, have not had a TE event in the last 3 months, and if they are heterozygous for Factor V Leiden or a prothrombin (PT) gene mutation.¹ A moderate to high TE risk is defined as a CHA₂DS₂VASc score greater than 2, a TE event in the last 3 months, protein C, S or antithrombin deficiency and/or antiphospholipid syndrome.

If the TE risk is low to moderate and less than the bleeding risk, the NOAC should be stopped prior to the procedure.¹ The timeframe for discontinuation varies amongst the NOACs. For patients receiving dabigatran with a CrCl of 50 mL/min or greater, the drug should be discontinued for 24 to 48 hours before the procedure.^1,2 If CrCl is less than 50 mL/min, dabigatran should be discontinued for 3 to 5 days before the procedure. The other agents (rivaroxaban, apixaban, edoxaban) should be held for at least 24 to 48 hours (for apixaban) before the procedure.^1,3-5  In patients with a low to moderate TE risk, no bridge therapy is necessary.¹ On the other hand, if the TE risk is high and greater than the bleeding risk, the NOAC should be stopped and bridge therapy should be considered if a TE event has occurred within 6 weeks. The AHA provides recommendations for specific types of procedures and these are summarized in Table 4.

Table 4. Periprocedural NOAC management.^1,8

References

1. Raval AN, Cigarroa JE, Chung MK, et al.  Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation. 2017;135(10):e604-e633.
2. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.;2015.
3. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;2016.
4. Eliquis [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company;2016.
5. Savaysa [package insert]. Parsipanny, NJ: Daiichi Sankyo, Inc.;2016.
6. UpToDate [database online]. Waltham, MA: Wolters Kluwer, 2017. https://www.uptodate.com/contents/search. Accessed March 21, 2017.
7. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
8. Narouze S, Benzon HT, Provenzano DA, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med.2015;40(3):182-212.

April 2017

The information presented is current as of March 7, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.