Antiemetic Therapy

Number: 0724

Policy

This policy is based in part on antiemetic practice guidelines from the National Comprehensive Cancer Network (NCCN) and the American College of Obstetrics and Gynecology (ACOG) practice guidelines on nausea and vomiting of pregnancy.

  1. Cancer Chemotherapy

    Aetna considers palonosetron (Aloxi) or fosaprepitant dimeglumine (Emend) antiemetic therapy medically necessary for either of the following indications:

    1. the prevention of acute nausea or vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy, including high-dose cisplatin; or
    2. for treatment of chemotherapy-induced nausea or vomiting from low or minimally emetogenic cancer chemotherapy in persons who have an inadequate response or contraindication to intravenous granisetron (Kytril) or ondansetron (Zofran) at the Food and Drug Administration (FDA) recommended dose (see table in Appendix).

    Aetna considers granisetron (Kytril), extended-release granisetron (Sustol) and ondansetron (Zofran) antiemetic intravenous therapy medically necessary for the following indications:

    1. prevention of acute and delayed nausea and/or vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy including high-dose cisplatin; and
    2. for treatment of chemotherapy-induced nausea and/or vomiting of low or minimally emetogenic cancer chemotherapy in persons who have an inadequate response or contraindication to oral granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose (see table in Appendix).

    Aetna considers combined palonosetron (Aloxi) and fosaprepitant dimeglumine (Emend) medically necessary for individuals with high emetic risk who have failed previous therapy with a steroid plus 5-HT3 antagonist.

    Aetna considers use of rolapitant (Varubi) or aprepitant (Cinvanti) in combination with dexamethasone and a serotonin receptor antagonist (5-HT3), administered before intravenous antineoplastic therapy, medically necessary in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy with moderate or high emetic risk (see table in Appendix).

    Aetna considers intravenous dolasetron (Anzemet) experimental and investigational for prevention of nausea or vomiting from cancer chemotherapy.

    Aetna considers Akynzeo injection (fosnetupitant/palonosetron) in combination with dexamethasone medically necessary in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.  (Note: Akynzeo injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy).

  2. Radiotherapy

    Aetna considers dolasetron mesylate (Anzemet), medically necessary for the prevention of radiation-induced nausea or vomiting secondary to total body irradiation (TBI) when intravenous antiemetic therapy with granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated.

    Aetna considers intravenous granisetron (Kytril) or intravenous ondansetron (Zofran) medically necessary for the prevention of radiation-induced nausea and/or vomiting secondary to TBI when oral granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated.

    Aetna considers intravenous palonosetron (Aloxi) and fosaprepitant dimeglumine (Emend) experimental and investigational for the prevention of radiation-induced nausea and vomiting because there is insufficient evidence of their effectiveness for this indication.

  3. Post-Operative

    Aetna considers intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend) medically necessary for the prevention or treatment of post-operative nausea or vomiting when intravenous granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated.

    Aetna considers intravenous granisetron (Kytril) or ondansetron (Zofran) medically necessary for the prevention or treatment of post-operative nausea or vomiting when oral granisetron (Kytril) or ondansetron (Zofran) has failed or is contraindicated. 

    Note: As with other antiemetics, routine prophylaxis is not recommended for individuals in whom there is little expectation that nausea and/or vomiting will occur post-operatively.

  4. Pregnancy

    Aetna considers intravenous granisetron (Kytril) or ondansetron (Zofran) antiemetic intravenous therapy medically necessary for severe, intractable, persistent nausea or vomiting during pregnancy when clinical signs of dehydration are present or nausea and vomiting have persisted for more than 3 weeks and all of the following conditions are met:

    1. Conservative treatment has failed (e.g., dietary changes, ginger, multi-vitamin, vitamin B6 (pyridoxine) with or without doxylamine (Unisom)); and
    2. Oral, sublingual, or rectal antiemetics have failed or are contraindicated including 2 or more of the following:

      1. Dimenhydrinate (Dramamine); and
      2. Ondansetron (Zofran) or granisetron (Kytril); and
      3.  Promethazine (Phenergan); and
      4. Trimethobenzamide (Tigan); and

    3. Other injectable/intravenous antiemetics have failed or are contraindicated including all of the following:

      1. Dimenhydrinate (Dramamine); and
      2. Promethazine (Phenergan).

      Aetna considers intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend) medically necessary for severe, intractable, persistent nausea or vomiting during pregnancy when clinical signs of dehydration are present or nausea and vomiting have persisted for more than 3 weeks and intravenous granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated.

  5. Motion Sickness

    Aetna considers 5-HT3 receptor antagonist antiemetic intravenous therapy experimental and investigational for motion-induced nausea and vomiting (motion-sickness).

  6. Other Indications

    Aetna considers granisetron (Kytril) or ondansetron (Zofran) antiemetic intravenous therapy medically necessary for refractory cases of nausea or vomiting for other indications (e.g., bulimia nervosa, cyclic vomiting syndrome, HIV) when oral granisetron (Kytril) or ondansetron (Zofran) has failed or is contraindicated.

    Aetna considers intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend) medically necessary for refractory cases of nausea or vomiting for other indications (e.g., bulimia nervosa, cyclic vomiting syndrome, HIV) when intravenous granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated.

    Aetna considers aprepitant experimental and investigational for the treatment of gastroparesis because there is insufficient evidence of its effectiveness for this indication.

    Aetna considers aromatherapy experimental and investigational for the treatment of post-operative nausea and vomiting because there is insufficient evidence of its effectiveness for this indication.

See also Pharmacy Clinical Policy Bulletin (PCPB): Antiemetics.

See also

Note: This policy does not address the use of 5-HT3 receptor antagonists in the emergency room.  Serotonin 3 receptor antagonists have been used in the management of acute toxicities (e.g., acetaminophen, theophylline).

Background

Serotonin 3 (5-HT3) receptor antagonists [(i.e., palonosetron (Aloxi), dolasetron mesylate (Anzemet), granisetron (Kytril), and ondansetron (Zofran)] are used for the treatment and prevention of post-operative nausea and vomiting as well as nausea and vomiting caused by cancer chemotherapy, radiotherapy, and pregnancy.  5-HT3 receptor antagonists work by blocking serotonin binding at vagal afferents in the gut and in regions of the central nervous system (CNS) involved in emesis. 

Antiemetic practice guidelines from the National Comprehensive Cancer Network (NCCN, 2008) recommend antiemetic regimens based upon the emetogenic potential of the chemotherapy drug as well as individual risk factors.  The antiemetic regimen for highly emetogenic drugs includes aprepitant, dexamethasone, and a 5-HT3 antagonist with or without lorazepam.  The antiemetic regimen for moderately emetogenic drugs includes dexamethasone and a 5-HT3 antagonist (palonosetron is preferred) with or without lorazepam; consider adding aprepitant for select patients (those receiving carboplatin, cyclophosphamide, doxorubixin, epirubicin, ifosfamide, irinotecan, or methotrexate).  The antiemetic regimen for low emetogenic drugs includes the following non-5-HT3 anatgonists: dexamethasone with or without lorazepam, prochlorperazine, spansule, or metoclopramide with or without diphenhydramine.  For minimal risk chemotherapy, the NCCN guidelines recommend that no routine prophylactic treatment be given. 

According to NCCN, the basic strategy of any antiemetic regimen is to prevent nausea/vomiting from occurring, thus, prophylactic antiemetics should be administered before chemotherapy begins and for patients receiving high or moderate emetogenic chemotherapy, antiemetics should continue for at least 4 days.  Although oral and intravenous (I.V.) antiemetics have equivalent efficacy, patients who are unable to swallow or digest tablets because of emesis, should be given I.V. antiemetics (NCCN).  Breakthrough nausea/vomiting induced by high, moderate and low emetic risk chemotherapy can be very difficult to treat.  Adding an additional agent from a different drug class is the general management approach recommended by NCCN as well as adjusting either the intensity or frequency of dosing.  Dopamine antagonists, metoclopramide, thiethylperazine, butyrophenones (e.g., halpreridol), corticosteroids, and agents such as lorazepam may be required.  Routine around-the-clock administration should be considered, rather than as needed.  Also, while not likely to be effective, anecdotal evidence suggests that switching to a different 5-HT3 may be efficacious (NCCN). 

Studies have demonstrated that all of the 5-HT3 antagonists are effective and have mild, infrequent side effects, although optimal antiemetic therapy requires concomitant dexamethasone or methylprednisolone, unless the patient can not tolerate corticosteroids (NCCN).  According to the NCCN guidelines, dolasetron mesylate, granisetron, and ondansetron are effective in preventing acute emesis but are less effective for delayed emesis compared with palonosetron.  Palonosetron is effective for preventing both delayed and acute emesis and is the preferred medication for patients undergoing moderate emetic risk chemotherapy (NCCN).  In the trial data submitted to the Food and Drug Adminsitration (FDA) for licensure, palonosetron achieved equivalent or superior results compared to the control arms (ondansetron and dolasetron), especially with regard to delayed nausea.  The side effect and safety profile of palonosetron has been demonstrated to be the same as dolasetron mesylate and ondansetron but it has a slightly higher tissue binding affinity for the 5-HT3 receptor and a significantly longer serum half-life than other 5-HT3 antagonists.  Palonosetron is administered intravenously and is approved by the FDA as a single dose of 0.25 mg I.V. over 30 seconds on day 1, approximately 30 mins before chemotherapy.  Higher doses (e.g., 0.75 mg) were studied and were no more effective than the 0.25 mg dose.  Repeat dosing of palonosetron in the days following chemotherapy (e.g., day 2 to 3) or in the setting of multi-day chemotherapy regimens is not supported by the scientific literature.

In December 2010, the FDA released a special announcement that the injection form of dolasetron mesylate (Anzemet) should no longer be used to prevent nausea and vomiting associated with chemotherapy-induced nausea and vomiting (CINV) in pediatric and adult patients.  New data demonstrated that intravenous dolasetron can increase the risk of developing an abnormal heart rhythm (torsade de pointes) which can be fatal.

The Multinational Association of Supportive Care in Cancer (MASCC) International Consensus Conference (2005) classified the risk of radiotherapy-induced emesis as follows:
  1. high - total body irradiation,
  2. moderate - upper abdomen,
  3. low - lower thorax, pelvis, cranium (radiosurgery) and craniospinal,
  4. minimal risk - head and neck, extremities, cranium and breast (Maranzano et al, 2005).
NCCN (2006) antiemesis guidelines for the use of antiemetics in radiotherapy are based on the site of radiation and whether radiotherapy is combined with chemotherapy; when radiotherapy is combined with chemotherapy, prophylaxis is dictated by the emetogenic potential of the chemotherapy regimen.  For total body irradiation, NCCN guidelines recommend pretreatment for each day of radiation treatment with either oral ondansetron or oral / I.V. granisetron.  For upper abdomen radiation, NCCN guidelines recommend pretreatment for each day of radiation treatment with either oral ondansetron or oral granisetron.  NCCN guidelines do not recommend primary treatment for patients receiving radiation to other sites.

Nausea and vomiting are common in pregnancy.  Approximately 70 to 85 % of pregnant women experience nausea and/or vomiting.  Hyperemesis gravidarum, a severe and intractable form of nausea and vomiting during pregnancy, may result in weight loss, nutritional deficiencies, and dehydration.  The peak incidence occurs at 8 to 12 weeks of pregnancy, and symptoms usually resolve by week 16.  The American College of Obstetrics and Gynecology (ACOG) (2004) recommend a step-wise approach to alleviating nausea and vomiting in pregnancy, beginning with prevention at the time of conception.  Two studies found that women who take a multi-vitamin at the time of conception were less likely to need medical attention for vomiting.  While there is little published evidence regarding the efficacy of dietary changes for prevention or treatment of nausea and vomiting of pregnancy, a small study showed that protein meals were more likely to relieve nausea and vomiting of pregnancy than carbohydrate and fatty meals.  Other conservative treatments recommended by ACOG included ginger capsules and electrical stimulation or acupressure at the P6 (or Neguian) point on the inside of the wrist.  Women with more complicated nausea and vomiting of pregnancy may need pharmacologic therapy.  While many conventional antiemetics have been used for nausea and vomiting of pregnancy, it is important to note that no drug has been approved by the FDA for the treatment of nausea and vomiting in pregnancy since Benedictine (an antiemetic no longer available in the U.S. but still widely used in Europe). 

According to ACOG guidelines, pharmacologic treatment of nausea and vomiting of pregnancy should begin with pyridoxine (vitamin B6).  If there is no improvement, doxylamine (Unisom) should be added with the pyridoxine.  A 70 % reduction in nausea and vomiting has been reported with this combination.  Doxylamine and pyridoxine are currently available separately without a prescription in the U.S.  Several studies involving more than 170,000 exposures have found this combination to be safe with regard to fetal exposure.  If this is unsuccessful, adding or switching to antiemetics and antihistamines may be necessary.  Medications for which there are some safety data but no conclusive evidence of efficacy include anticholinergics and metoclopramide (Reglan) (ACOG, 2004). 

Evidence is limited on the safety and efficacy of ondansetron injectable for treatment of pregnancy-related nausea and vomiting.  However, this medication is being prescribed as an off-label use for the treatment of nausea and vomiting of pregnancy due to its reported effectiveness in reducing chemotherapy-induced emesis (ACOG, 2004).  In a limited comparative study with other antiemetics, no increased risks of major malformations were reported (Einarson et al, 2004).  In a small trial of I.V. therapy in women with hyperemesis gravidarum, no increased benefit was demonstrated with ondansetron over promethazine (Sullivan et al, 1996).  However, according to ACOG’s step-wise approach to managing nausea and vomiting of pregnancy, ondansetron may be tried in refractory cases as a last resort.  When indicated, ACOG guidelines recommend 8 mg of ondansetron over 15 mins every 12 hrs I.V.

According to the peer-reviewed medical literature, selective 5-HT3 receptor antagonists have been proven safe and effective for the management of post-operative nausea and vomiting (Loewen et al, 2000; Kovac, 2000; Fuji, 2005).

Ondansetron for bulimia nervosa was reported to be effective in 3 small trials by one group of investigators, and may be an option after failure of traditional therapies (Fung and Ferrill, 2001).  Additionally, some studies on bulimia nervosa recommend short-term use of antiemetics at the onset of a patient's treatment.  Antiemetics are thought to reduce a patient's stimuli to vomit and help patients through the few weeks it takes for antidepressants to become fully effective (Moreno, 2005). 

A Prodigy Clinical Practice Recommendation (SCHIN, 2006) on palliative care - nausea/vomiting/malignant bowel obstruction.stated, “[o]ndansetron, tropisetron, granisetron, and dolasetron are rarely indicated in the palliative care setting.  Their use is limited to chemotherapy and radiotherapy induced nausea…[t]he role of somatostatin analogues in the relief of nausea and vomiting due to malignant bowel obstruction is not clear.”

In a single-blind, randomized controlleds tudy, Yonemura et al (2009) evaluated the non-inferiority of 1-mg to 3-mg granisetron (GRN) injection for the treatment of acute CINV and assessed the tolerability of GRN given at 1-mg in Japanese cancer patients.  Patients with cancer receiving highly emetogenic chemotherapy were enrolled in this study.  Patients were randomly assigned to receive GRN at a single dose of 1-mg or 3-mg.  The primary endpoint was the rate of complete protection from emetic events (no vomiting, no retching and no need for rescue medication) during the first 24 hrs following the initiation of chemotherapy.  There were 89 patients in the 1-mg group and 90 patients in the 3-mg group.  Complete protection was achieved in 70 patients (78.7 %) in the 1-mg group and 73 (81.1 %) patients in the 3-mg group.  The 1-sided test did not reveal non-inferiority of either dose of GRN to the other at a 5 % significance level.  The authors concluded that these findings failed to show the non-inferiority of 1-mg of GRN to 3-mg of GRN administered as a single dose.  However, the rate of complete protection from nausea and vomiting was similar in the 2 groups.  They stated that given the recommended dosage in the guidelines and the economic need for reduction of medical care expenses in Japan, prophylactic administration of GRN at 1-mg may be an appropriate, alternative treatment for acute CINV in cancer patients.

Results of clinical trials indicated that 5-HT3 receptor antagonists for the reduction of motion sickness have not been proven effective (Levine et al, 2000; Reid et al, 2000).

Broder et al (2014) noted that individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for CINV on cost and utilization, but no synthesis of the findings exists.  These investigators systematically reviewed published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs.  PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (i.e., Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of "ondansetron", "granisetron", "palonosetron", "dolasetron mesylate", "costs", "cost analysis" and "economics".  These researchers included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV.  Of the 434 identified studies, 32 were included in the current analysis: 7 studies reported costs, 18 reported utilization, and 7 studies reported both.  The costs were reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies).  The studies varied in designs, patients, 5-HT3RA regimens, and the definition of outcomes.  The US studies reported higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs.  Fewer patients receiving palonosetron versus with ondansetron or other 5-HT3RAs required rescue medication or used outpatient or inpatient care.  In Europe and in Canada, the total pharmacy costs and use of rescue medications reported were lower for patients receiving prophylaxis with palonosetron.  The authors concluded that the findings of this analysis showed that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs in the United States.  They stated that the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.

Zhou and co-workers (2015) discussed existing and emerging therapeutic options, and examined studies focusing on palonosetron with regards to efficacy, pharmacology, tolerability, safety, and patient-derived outcomes.  These investigators performed a literature search using Ovid MEDLINE and EMBASE to identify relevant studies using palonosetron alone or in combination with other anti-emetics.  Studies were extracted if they included complete response (CR), complete control (CC), no nausea, no vomiting, and no rescue medications as an end-point.  Studies were also included if safety end-points were examined.  Palonosetron alone has been shown to improve CR and CC rates for patients receiving low, moderate, or high emetogenic chemotherapy.  Rates were further improved with the addition of dexamethasone.  Furthermore, the addition of neurokinin-1 receptor antagonists, such as netupitant markedly improved efficacy profiles compared to palonosetron alone.  Aprepitant is an anti-emetic that has exhibited positive results in combination with palonosetron.  Recently, a new drug consisting of netupitant and palonosetron (NEPA) has demonstrated significantly more effective prevention of CINV.  Regardless of the combination, palonosetron has been well-tolerated.  The most common adverse events were constipation, headache, fatigue, and dizziness, with the majority of patients describing them as only mild or moderate.  The authors concluded that palonosetron, alone or with other anti-emetics, has improved CINV treatment due to its ability to significantly reduce delayed phases of CINV, compared to similar 5-HT3RAs.  They stated that palonosetron is both more effective than first generation 5-HT3RAs and safer, as it results in a smaller prolongation of the QTc interval, compared to other 5-HT3RAs.

Tricco and colleagues (2015a) noted that patients may experience nausea and vomiting when undergoing chemotherapy or surgery requiring anesthesia.  Serotonin 5-hydroxytryptamine 3 receptor antagonists are effective anti-emetics, yet may cause adverse cardiac events, such as arrhythmia.  These investigators identified interventions that mitigate the cardiac risk of 5-HTRAs.  Electronic databases, trial registries, and references were searched.  Studies on patients undergoing chemotherapy or surgery examining interventions to monitor cardiac risk of 5-HT3 receptor antagonists were included.  Search results were screened and data from relevant studies were abstracted in duplicate.  Risk of bias of included studies was assessed using the Cochrane Effective Practice and Organization of Care (EPOC) group's risk-of-bias tool.  Due to a dearth of included studies, meta-analysis was not conducted.  A total of 2 randomized clinical trials (RCT) and 1 non-randomized clinical trial (NRCT) were included after screening 7,637 titles and abstracts and 1,554 full-text articles.  Intravenous administration of different dolasetron doses was examined in the NRCT, while dolasetron versus ondansetron and palonosetron versus ondansetron were examined in the RCT.  Electrocardiogram (ECG) was the only intervention examined to mitigate cardiac harm.  No differences in ECG evaluations were observed between dolasetron or palonosetron versus ondansetron after 15 minutes, 24 hours, and 1 week post-administration in the 2 RCTs.  Four deaths were observed in 1 RCT, which were deemed unrelated to palonosetron or ondansetron administration.  Minor increases in PR and QT intervals were observed in the NRCT for dolasetron dosages greater than 1.2 mg/kg 1 to 2 hours post-administration, but were deemed not clinically relevant.  The authors concluded that ECG monitoring of chemotherapy patients administered with 5-HT3RAs did not reveal clinically significant differences in arrhythmia between the medications at the examined time periods.  The usefulness of ECG to monitor chemotherapy patients administered with 5-HT3RAs remains unclear, as all patients received ECG monitoring.

Tricco and associates (2015b) stated that 5-HT3 receptor antagonists are commonly used to decrease nausea and vomiting for surgery patients, but these agents may be harmful.  These researchers conducted a systematic review on the comparative safety of 5-HTRAs.  Searches were done in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify studies comparing 5-HT3 receptor antagonists with each other, placebo, and/or other anti-emetic agents for patients undergoing surgical procedures.  Screening search results, data abstraction, and risk of bias assessment were conducted by 2 reviewers independently.  Random-effects pairwise meta-analysis and network meta-analysis (NMA) were conducted.  Overall, 120 studies and 27,787 patients were included after screening of 7,608 citations and 1,014 full-text articles.  Significantly more patients receiving granisetron plus dexamethasone experienced an arrhythmia relative to placebo (odds ratio (OR) 2.96, 95 % confidence interval [CI]: 1.11 to 7.94), ondansetron (OR 3.23, 95 % CI: 1.17 to 8.95), dolasetron (OR 4.37, 95 % CI: 1.51 to 12.62), tropisetron (OR 3.27, 95 % CI: 1.02 to 10.43), and ondansetron plus dexamethasone (OR 5.75, 95 % CI: 1.71 to 19.34) in a NMA including 31 RCTs and 6,623 patients of all ages.  No statistically significant differences in delirium frequency were observed across all treatment comparisons in a NMA including 18 RCTs and 3,652 patients.  The authors concluded that granisetron plus dexamethasone increases the risk of arrhythmia.

Aloxi

Aloxi (palonosetron) is a selective serotonin‐3 5‐HT3‐receptor antagonist. It has minimal or no affinity for other receptor types.5‐HT3 receptors are present on vagal nerve terminals peripherally and centrally in the chemoreceptor trigger zone; cytotoxic agents induce emesis by releasing 5‐HT3 from intestinal enterochromaffin cells, with subsequent 5‐HT3binding to (activation of) vagal afferents. An advantage of Aloxi (palonosetron) over other 5‐HT3 antagonists is its longer elimination half‐life which allows for less frequent dosing.

Aloxi (palonosetron) injection for intravenous use is indicated for moderately emetogenic cancer chemotherapy and highly emetogenic cancer chemotherapy used for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses. Aloxi (palonosetron) is also indicated for the prevention of acute nausea and vomiting in pediatric patients associated with repeat courses of emetogenic chemotherapy, including highly emetogenic chemotherapy. This formulation is also indicated for the prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been established.

Palonosetron is available as Aloxi Intravenous Solution:

  • 0.25 mg/5mL (CINV)
  • 0.075 mg/1.5mL (PONV).

Recommended Dosing:

  • Chemotherapy‐induced nausea and vomiting, Acute, associated with moderately/highly emetogenic chemotherapy; Prophylaxis: 0.25 mg IV as a single dose 30 min prior to the start of chemotherapy.
  • Chemotherapy‐induced nausea and vomiting, Delayed, associated with moderately emetogenic chemotherapy; Prophylaxis: 0.25 mg IV as a single dose 30 min prior to the start of chemotherapy.
  • Postoperative nausea and vomiting; Prophylaxis: 0.075 mg IV as a single dose immediately before induction of anesthesia.

Aloxi (palonosetron) may not be used concurrently [other 5‐HT3 RA drugs should generally not be used within 2 days following an Aloxi (palonosetron) dose] with other 5‐HT3 antagonists unless a change of therapy is warranted.

According to the 2012 NCCN Practice Guidelines in Oncology for Antiemesis, Aloxi (palonosetron) was comparable to a single IV dose of dolasetron for the prevention of acute CINV; however, palonosetron was superior to dolasetron in preventing delayed emesis. Aloxi (palonosetron) had similar safety and side effect profiles to other 5‐HT3 receptor antagonists. Aloxi (palonosetron) has a 100‐fold higher binding affinity for the 5‐HT3 receptor than other serotonin antagonists and has a mean elimination half‐life of 40 hours. Repeat dosing of Aloxi (palonosetron) in the days after chemotherapy (Days 2 or 3) is likely to be safe. However in the setting of multi‐day chemotherapy, the need for repeat dosing with Aloxi (palonosetron) is not yet known and increased efficacy has not been established. One study in patients receiving highly emetogenic multiday cisplatin based chemotherapy for testicular cancer received multiple daily dosing of Aloxi (palonosetron) and dexamethasone, which prevented nausea and emesis.

According to a consensus statement published by the International Anesthesia Research Society, there is no difference in the efficacy and safety profiles of the serotonin receptor antagonists in the prophylaxis of Postoperative Nausea and Vomiting (PONV), and these drugs are most effective when given at the end of surgery. Cost effectiveness must also be taken into consideration and the panel agreed that with equivalent efficacy and safety profiles, acquisition cost was the primary factor that differentiated the 5‐HT3 receptor antagonists from one another.

For information on Pediatric Dosing and Administration, please refer to the Prescribing Information.

Aloxi (palonosetron) should not be used in persons with hypersensitivity to Aloxi (palonosetron) or any component of the product.

Emend

Aprepitant is a selective high‐affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant inhibits emesis via central actions. Aprepitant crosses the blood brain barrier and occupies brain NK1 receptors. Fosaprepitant is a prodrug that is converted into aprepitant.

Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high dose cisplatin. Aprepitant is also indicated for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Lastly, Aprepitant is indicated for the prevention of postoperative nausea and vomiting.

Aprepitant is available as Emend 40 mg, 80 mg, and 125 mg capsules and as a unit‐of-use tri‐fold pack containing one 125 mg and two 80 mg capsules. Fosaprepitant is available as Emend 115 mg and 150 mg powder for injection.

The recommended dosing of fosaprepitant:

  • Chemotherapy‐induced nausea and vomiting, due to moderately and highly emetogenic chemotherapy; Prophylaxis: fosaprepitant 150 mg IV administered over 20‐30 minutes, 30 min prior to chemotherapy on Day 1 only in combination with dexamethasone 12 mg orally administered 30 min prior to chemotherapy on day 1 and dexamethasone 8 mg orally administered day 2 and dexamethasone 8 mg orally, twice daily on days 3‐4 and ondansetron IV 32 mg administered 30 to 60 min prior to chemotherapy on Day 1. No capsules of aprepitant are administered on Day 2 or Day 3.
  • Chemotherapy‐induced nausea and vomiting, due to highly emetogenic chemotherapy including high‐dose cisplatin; Prophylaxis: fosaprepitant 115 mg IV 30 min prior to chemotherapy on Day 1 only, then aprepitant (80 mg) orally daily in the morning on Day 2 and Day 3; in combination with ondansetron 32 mg IV 30 minutes prior to chemotherapy on Day 1 only and dexamethasone 12 mg orally 30 min prior to chemotherapy on Day 1 and 8 mg ORALLY daily in the morning on Days 2, 3, and 4.
  • Chemotherapy‐induced nausea and vomiting, due to moderately emetogenic chemotherapy; Prophylaxis: fosaprepitant 115 mg IV 30 min prior to chemotherapy on Day 1 only, then aprepitant (80 mg) orally once daily in the morning on day 2 and day 3; in combination with dexamethasone 12 mg orally administered 30 min prior to chemotherapy on day 1 and ondansetron 8 mg orally administered 30 to 60 min prior to chemotherapy and 8 mg orally administered 8 hours after the first dose on Day 1.

Emend (fosaprepitant) therapy is not indicated for persons not receiving concurrent moderate to highly emetogenic chemotherapy. Fosaprepitant is only indicated for prevention of chemotherapy induced nausea at this time

Emend IV is not indicated for concurrent use with oral Emend (aprepitant) capsules if taking the 150 mg dose.

Emend IV (fosaprepitant) is not indicated as monotherapy; Emend should be used in conjunction with a 5‐HT3 antagonist and dexamethasone.

Per ASCO recommendations, only the established dose and schedule of Emend (fosaprepitant) should be used.

Emend (Aprepitant) has only shown proven efficacy when used in combination with a 5HT3 antagonist and dexamethasone.

Studies show that Emend (aprepitant) augments the antiemetic activity of the 5‐HT3 receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phase of cisplatin‐induced emesis.

Emend (aprepitant) has not been studied in the treatment of established nausea and vomiting.

Emend (aprepitant) should be used with caution in members receiving concomitant orally administered medicinal products, including chemotherapy agents, which are primarily metabolized through CYP3A4.Inhibition of CYP3A4 by Emend (aprepitant) could result in elevated plasma concentrations of these concomitant medicinal products.The effect of Emend (aprepitant) on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of Emend (aprepitant) on the pharmacokinetics of intravenously administered CYP3A4 substrates.

Chronic continuous use of Emend (aprepitant) for the prevention of nausea and vomiting is not recommended because this has not been studied and because the drug interaction profile may change with chronic continuous use.

The efficacy of hormonal contraceptives may be reduced during coadministration of Emend (aprepitant) and for 28 days after the last dose of aprepitant.

Coadministration of Emend (aprepitant) with warfarin may result in clinically significant decrease in international normalized ration (INR) or prothrombin time.

For the 115mg strength only, member should have confirmed access to the Day 2 and 3 oral dose prior to initiating Day 1 IV dose of Emend/fosaprepitant.

Emend IV (fosaprepitant) should not be utilized in the following:

  • Members on concurrent pimozide, terfenadine, astemizole, or cisapride; CYP3A4 inhibition by aprepitant could result in toxicity and potentially serious or life-threatening reactions.
  • Members with hypersensitivity to fosaprepitant dimeglumine, aprepitant, polysorbate 80, or any other component of the product.
  • Safety and efficacy not established in members under 18 years of age.

Anzemet

Anzemet (dolasetron) is a 5‐HT3 antagonist. These medications act as receptor antagonists at the 5‐hydroxytryptamine‐3 receptor (5‐HT3 receptor), a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. 5‐HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by chemotherapy, and are considered the gold standard in this setting.

Anzemet (dolasetron) is indicated for the prophylaxis of chemotherapy induced nausea and vomiting, post operative nausea and vomiting, and radiation induced nausea and vomiting in adults and children 2 years and older. At equivalent doses for the prevention of acute emesis, 5‐HT3 serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably.

Dolasetron is available as Anzemet in 50mg and 100mg tablets in addition to a 12.5mg/0.625ml and 20mg/ml solutions for injection.

Anzemet (dolasetron) injection should not be administered for the prevention of CINV. The recommended dose in this setting has been linked to abnormal heart rhythms (torsade de pointes). Specifically, Anzemet (dolasetron) causes a dose-dependent prolongation in the QT, PR and QRS intervals. Members with underlying structural heart disease or preexisting arrhythmias are at greater risk.Anzemet (dolasetron) tablets may be considered medically necessary in this setting. However the use of tablets is not without increased risk.

The incidence and severity of Chemotherapy Induced Nausea and Vomiting (CINV) are affected by multiple factors such as the chemotherapeutic agent, the schedule are route of administration of the agent, and individual member variability. Antiemetic therapy regimens should be chosen based on the drug with the highest emetic risk as well as member specific risk factors.

Radiation‐Induced Nausea and Vomiting occurs most commonly in members receiving whole body or upper abdominal radiation therapy.

According to the 2014 NCCN guidelines for Antiemesis, antiemetic therapy should be initiated before chemotherapy and continued for the same length of time as the duration of the emetic activity of the chemotherapeutic agent being used. When compared with other routes of administration, oral formulations of antiemetic agents are equally effective, safe, more convenient, and less costly. Many clinical trials comparing ondansetron, granisetron, dolasetron, and palonosetron have been conducted. These trials have used various doses, routes, and schedules of administration and have found no difference in efficacy between ondansetron, granisetron, and dolasetron. Ondansetron, granisetron, and dolasetron and effective in preventing acute emesis but appear to be less effective for delayed emesis.

The American Society of Clinical Oncology (ASCO) updated the antiemetic guidelines for oncology in 2006 and identified 5HT3 receptor antagonists as having equivalent safety and efficacy and states they can be used interchangeably for the treatment of acute emesis. These agents share similar adverse effect profiles and dose‐limiting effects are rare.

The International Anesthesia Research Society has developed guidelines regarding the management of postoperative nausea and vomiting (PONV). When making a recommendation for postoperative treatment, must consider member’s level of PONV risk, potential morbidity associated with PONV, efficacy of antiemetics, cost of antiemetic therapy and increase healthcare costs associated with PONV. The panel agreed that not all members should receive PONV prophylaxis and there is not evidence of any difference in the efficacy or safety profiles of 5HT3 receptor antagonists. In addition, 5HT3 receptor antagonists are more effective when give at the end of surgery. Cost effectiveness must also be taken into consideration and the panel agreed that with equivalent efficacy and safety profiles, acquisitioncost was the primary factor that differentiated the 5HT3 receptor antagonists from one another.

No dosage adjustments are necessary in members with hepatic or renal impairment.

Sustol

Sustol (granisetron extended release) injection is the first extended-release 5-HT3 receptor antagonist approved for the prevention of acute and delayed nausea and vomiting associated with both moderately emetogenic chemotherapy and anthracycline and cyclophosphamide combination chemotherapy regimens  A standard of care in the treatment of breast cancer and other cancer types, AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens as defined by both the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO).

Combined Palonosetron (Aloxi) and Fosaprepitant Dimeglumine (Emend)

National Comprehensive Cancer Network’s clinical practice guideline on “Antiemesis” (Version 2.2015) states that “As per high emetic risk (greater than 90 % frequency of emesis) prevention, aprepitant or fosaprepitant should be added (to dexamethasone and a 5-HT3 antagonist regimen) for select patients with additional risk factors or who have failed previous therapy with a steroid + 5-HT3 antagonist alone”.

Transdermal Granisetron

Coluzzi and Mattia (2016) noted that granisetron transdermal delivery system (GTDS) is the first 5-HT3 drug to be transdermally delivered and represents a convenient alternative to oral and intravenous anti-emetics for the treatment of CINV.  GTDS is effective and well-tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy.  In this setting non-inferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron.  GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias.  The authors concluded that GTDS has been examined for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

Doggrell (2017) stated that CINV has a negative impact on the lives of subjects receiving chemotherapy.  In 2009, the 2nd generation 5-HT3-receptor antagonist, palonosetron, which is longer-acting than granisetron, was shown, as part of dual therapy with dexamethasone, to be superior to intravenous granisetron in the delayed phase of CINV.  In an attempt to maintain plasma levels of granisetron during the delayed phase of CINV, longer-acting preparations of granisetron have been manufactured . In addition to comparing intravenous/oral granisetron with palonosetron, the author considered the new longer-acting preparations of granisetron (transdermal and subcutaneous) with emphasis on whether they are effective in the delayed phase of CINV.  Comparison of intravenous/oral granisetron and palonosetron, as part of triple therapy against the delayed phase of CINV, did not give clear-cut results as to non-inferiority or superiority of either agent.  Subcutaneous granisetron is more convenient to use than transdermal granisetron, and has been shown to be non-inferior to palonosetron, as part of dual therapy, in the treatment of the acute and delayed phases of CINV.  The author concluded that it appeared likely that there will be ongoing roles for intravenous and subcutaneous granisetron in CINV, but more data are needed to determine the future of transdermal granisetron.

In an observational case-series study, Le and co-workers (2017) reviewed the effectiveness of anti-emetic therapy (no emesis/retching episodes and no rescue medication use) when granisetron is administered via a transdermal patch system (TDS) in women who are 6 to 14 weeks pregnant when compared with oral ondansetron by evaluating the frequency of the use of rescue medications for control of nausea/vomiting of pregnancy (NVP). These researchers examined the potential benefits of granisetron TDS compared with oral ondansetron for management of NVP in pregnant patients during the 1st trimester.  Dates of data collection were September 1, 2014, through December 31, 2015.  There was no direct contact with patient.  The oral ondansetron and granisetron TDS patients were matched by age, 4:1.  The proportion of patients who received rescue anti-emetics was calculated from those patients who continued to experience NVP.  Risk factors for NVP were identified and compared between groups.  Descriptive statistics were used to describe study results.  Patients were prescribed rescue anti-emetics in 0/3 patients in the granisetron TDS group compared with 2/12 patients in the oral ondansetron group.  The authors concluded that prospective efficacy studies on the use of granisetron TDS for management of NVP are needed to confirm this clinical observation.

Rolapitant (Varubi)

On October 25, 2017, TESARO, Inc. announced the U.S. FDA approval of Varubi (rolapitant) IV, a substance P/neurokinin 1 (NK1) receptor antagonist, to be used in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy (TESARO, 2017).

In two multicenter, randomized, double-blind, parallel group, controlled clinical trials (HEC1 and HEC2), the clinical profile of Varubi in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed. Both trials met their primary endpoint of complete response (CR), which was defined as no emetic episodes and no rescue medication, and demonstrated statistical superiority of rolapitant (180 mg oral) compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase (25–120 hours) of chemotherapy-induced nausea and vomiting (CINV). In HEC1, 264 patients received rolapitant and 262 received active control. The proportion of patients achieving a CR was 72.7% vs. 58.4% (p=<0.001). In HEC2, 271 patients received rolapitant and 273 received active control. The proportion of patients achieving a CR was 70.1% vs. 61.9% (p=0.043). The most common adverse reactions (≥3%) among patients receiving cisplatin-based chemotherapy were neutropenia (9% Varubi vs. 8% control), hiccups (5% vs. 4%), and abdominal pain (3% vs. 2%) (Rapoport et al., 2015).

A Phase 3 trial was also conducted to evaluate rolapitant (180 mg oral) compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant compared to active control (5-HT3 receptor antagonist plus dexamethasone) in the delayed phase of CINV. The proportion of patients achieving a CR was 71.3% vs 61.6% (p=<0.001). The most common adverse reactions (≥3%) among patients receiving these chemotherapies were decreased appetite (9% VARUBI vs. 7% control), neutropenia (7% vs. 6%), dizziness (6% vs. 4%), dyspepsia (4% vs. 2%), urinary tract infection (4% vs. 3%), stomatitis (4% vs. 2%), and anemia (3% vs. 2%).

In addition, a bioequivalence study was conducted to compare the exposure of the 166.5 mg dose of IV rolapitant to the exposure of a 180 mg dose of oral rolapitant. Study participants were randomized to receive a single dose of either 166.5 mg of intravenous rolapitant administered over 30 minutes (n=61) or 180 milligrams of oral rolapitant (n=62). The primary endpoint of this pivotal study was bioequivalence, defined by estimating whether the 90% confidence intervals (CI) for the ratio of the area under the curves (AUCs) of the two formulations are entirely included within the acceptance range of 80% to 125%. Safety and tolerability were also assessed for both formulations. The safety profile was consistent with previous clinical trials with oral rolapitant, except for infusion-site reactions observed with the IV formulation (TESARO, 2017).

Dosing Recommendations for Varubi per Prescribing Information (TESARO, 2017):

  • Varubi is available as a ready-to-use, single-dose vial emulsion injectable for intravenous (IV) administration, or as tablets for oral use.
  • Tablets: 90 mg rolapitant. The recommended dosage is 180 mg as a single dose.
  • Injectable emulsion: The recommended dosage is 166.5 mg/92.5 mL administered as an intravenous infusion over 30 minutes.
  • Varubi is to be administered either orally or intravenously in combination with a 5-HT3 receptor antagonist and dexamethasone on Day 1 within two hours prior to initiation of each chemotherapy cycle, but at no less than 2 week intervals.
  • No dosage adjustment is required for dexamethasone, a CYP3A4 substrate. Varubi does not contain polysorbate 80.
  • Administer a dexamethasone dose of 20 mg on Day 1, 30 minutes prior to initiation of chemotherapy; then 8 mg twice daily on Day 2, 3 and 4.

Rolapitant is a moderate inhibitor of CYP2D6 and is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide. Varubi can significantly increase the plasma concentrations of thioridazine and pimozide, which may result in QT prolongation and Torsades de Pointes.

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics compendium (2017) recommends use of Varubi (rolapitant) in combination with dexamethasone and a serotonin receptor antagonist before intravenous antineoplastic therapy with either a high emetic risk or moderate emetic risk. NCCN recommendation includes that Varubi may be used with or without lorazepam, histamine-2 blockers, or proton pump inhibitors.

Aprepitant (Cinvanti)

On November 9, 2017, Heron Therapeutics, Inc. announced the U.S. FDA approval of Cinvanti (aprepitant) injectable substance P/neurokinin-1 (NK1) receptor antagonist, to be used in combination with other antiemetic agents in adults, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin and nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Approval was based on data from 2 pivotal randomized, cross-over bioequivalence studies of Cinvanti and Emend IV (fosaprepitant). Subjects receiving Cinvanti reported fewer adverse events than those receiving Emend IV, including substantially fewer infusion-site reactions (Heron, 2017).

In a randomized, parallel, double-blind, active-controlled study, 150 mg fosaprepitant as a single IV infusion (N = 1147) was compared to a 3-day oral aprepitant regimen (N = 1175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m2). All patients in both groups received dexamethasone and ondansetron. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%). The efficacy of fosaprepitant was evaluated based on the primary and secondary endpoints (complete response, delayed phase, no vomiting and overall post-initiation of cisplatin chemo) and was shown to be non-inferior to that of the 3-day oral aprepitant regimen with regard to complete response in each of the evaluated phases (Heron, 2017).

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, a 3-day oral aprepitant regimen was compared with a standard of care therapy in patients receiving a MEC regimen that included cyclophosphamide or cyclophosphamide, and doxorubicin or epirubicin. Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). Patient ages ranged from 25 to 78 years of age, with mean age of 53 years. The primary endpoint was complete response, defined as no emetic episodes and no use of rescue therapy in the overall phase (0 to 120 hours post-chemotherapy). A statistically significantly (p = 0.015) higher proportion of patients receiving the oral aprepitant regimen in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy, and (76%) had no vomiting compared with patients receiving standard therapy (62%) (Heron, 2017).

As of November 27, 2017, the National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (2017) had not included Cinvanti as an antiemetic option.

Dosing Recommendations for Cinvanti (aprepitant) per Prescribing Information (Heron, 2017):

  • Highly emetogenic cancer chemotherapy (HEC), single dose regiment: adults – 130 mg on Day 1 as an intravenous (IV) infusion over 30 minutes approximately 30 minutes prior to chemotherapy, and
     
    • Dexamethasone 12 mg orally on Day 1, 8 mg orally on Day 2, and 8 mg orally twice a day on Day 3 and 4, and
    • 5-HT3 antagonist (refer to selected 5-HT3 antagonist prescribing information for recommended dosage).
       
  • Moderately emetogenic cancer chemotherapy (MEC), 3-day regimen: adults – 100 mg on Day 1 as an IV infusion over 30 minutes approximately 30 minutes prior to chemotherapy. Aprepitant capsules (80 mg) are given orally on Days 2 and 3, and
     
    • Dexamethasone 12 mg orally on Day 1, and
    • 5-HT3 antagonist (refer to selected 5-HT3 antagonist prescribing information for recommended dosage).
       
  • Cinvanti is part of a regimen that includes a corticosteroid and a 5-HT3 antagonist.
  • Cinvanti has not been studied for the treatment of established nausea and vomiting.
  • Cinvanti is polysorbate 80-free.

Most common adverse reactions with single-dose Cinvanti (≥2%) were: headache and fatigue. Most common adverse reactions with the 3-day oral aprepitant regimen inconjunction with MEC (≥1% and greater than standard therapy) were: fatigue and eructation (Heron, 2017).

Treatment of Gastroparesis

Fahler and co-workers (2012) reported a case of refractory nausea in a patient with idiopathic gastroparesis successfully treated with aprepitant.  A 41-year old woman with idiopathic gastroparesis demonstrated by a delayed gastric emptying time experienced significant nausea, vomiting, and abdominal pain.  This resulted in numerous hospital admissions and regular out-patient intravenous fluid administration.  Over a 3-year period the patient had been treated with numerous agents for nausea and vomiting, including metoclopramide 10 mg thrice-daily, ondansetron 8 mg twice-daily, and promethazine (various doses from 12.5 to 25 mg orally up to thrice-daily).  No treatment tried was either tolerated or effective.  As a last option before considering gastric pacing the patient was started on aprepitant 40 mg daily.  The patient had a dramatic response to aprepitant and reported that her nausea had decreased significantly after 48 hours of starting the medication (2 doses).  She was able to tolerate oral feeding and her need for out-patient intravenous hydration abated.  Over the course of 2 months while using aprepitant her gastroparesis symptoms continued to improve.  She reported no adverse effects attributable to aprepitant.  After the first 2 months of aprepitant treatment, the patient was unable to continue the medication due to cost.  Although her symptoms did worsen after discontinuation, they did not return to their initial severity.  At 4 months after the trial of aprepitant, she continued to have improved symptoms.  She claimed not to have daily nausea or vomiting, but still required high-dose promethazine and occasional out-patient intravenous fluids.  At that point, she had gained 7.2 kg from the time that she had started aprepitant.  The authors concluded that aprepitant is approved in the U.S. for nausea and vomiting associated with surgery and cancer chemotherapy.  To the authors’ knowledge, this was the 2nd reported case of its use in gastroparesis-induced nausea.  This patient reported relief of nausea and vomiting despite existing evidence showing that aprepitant had no significant effect on accelerating gastric emptying.  Despite its acquisition cost, this patient avoided hospital admission and the administration of intravenous hydration, suggesting aprepitant may be cost-effective in this case.  These investigators stated that aprepitant may have some utility in treating refractory nausea caused by gastroparesis.  This case suggested that the drug's anti-emetic effect may be successfully used in areas not approved by the FDA; a controlled trial examining aprepitant in patients with such challenging clinical conditions may be warranted.

Fountoulakis and colleagues (2017) noted that people with gastroparesis who develop refractory disease pose a difficult challenge, especially in the setting of end-stage renal disease (ESRD) or post pancreas transplant.  Aprepitant is licensed for the short-term treatment of chemotherapy-induced nausea.  There is lack of information on its long-term safety and efficacy in people with diabetic gastroparesis.  These researchers reported 2 cases in which long-term aprepitant treatment proved effective in alleviating severe symptoms of gastroparesis that had failed conventional 1st-line medical treatments.  Case 1 was 73-year old man with type 2 diabetes of 25 years' duration and ESRD requiring dialysis.  He was referred to the authors’ unit as his severe symptoms of gastroparesis had failed to respond to multiple medications and resulted in frequent hospital admissions.  Aprepitant resulted in significant improvement in his symptoms of nausea and vomiting within weeks, and he remained on this long-term (18 months) with continued benefits and had no further gastroparesis-related hospital admissions.  Case 2 was a 44-year old man with type 1 diabetes of 41 years' duration with a history of severe hypoglycemic events that required a pancreas transplant.  Despite normoglycemia, his symptoms of gastroparesis persisted and failed to respond to multiple medications and frequent botulinum toxin injections.  He was given aprepitant with significant improvement in symptoms and has remained on treatment for 12 months with sustained benefits.  The authors concluded that the findings of these 2 cases highlighted the need for novel treatments for managing refractory diabetic gastroparesis.  These preliminary findings need to be validated by well-designed studies.

Pasricha and associates (2018) stated that there are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes.  These investigators performed a randomized trial of the ability of aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome.  They conducted a 4-week multi-center, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months.  Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63).  The primary outcome from the intention-to-treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity.  These researchers calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis.  Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46 % reduction in the VAS score in the aprepitant group versus 40 % reduction in the placebo group; relative risk [RR], 1.2; 95 % CI: 0.8 to 1.7) (p = 0.43).  However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0 to 5 Gastroparesis Clinical Symptom Index) for nausea (1.8 versus 1.0; p = 0.005), vomiting (1.6 versus 0.5; p = 0.001), and overall symptoms (1.3 versus 0.7; p = 0.001).  Adverse events (AEs), predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35 % versus 11 of 63, 17 % in the placebo group; p = 0.04).  The authors concluded that in a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome.  However, aprepitant had varying effects on secondary outcomes of symptom improvement.  These researchers stated that these findings supported the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant.

Furthermore, an UpToDate on “Treatment of gastroparesis” (Camilleri, 2018) states that “While transdermal scopolamine, neurokinin receptor-1 antagonist aprepitant, and synthetic cannabinoid dronabinol have been used to treat gastroparesis, there are no randomized trials to support their use”.

Akynzeo Injection (Fosnetupitant/Palonosetron)

Schwartzberg and colleagues (2018) stated that NEPA was the first fixed anti-emetic combination to have been approved.  A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline-cyclophosphamide (AC) and non-AC HEC showed superior prevention of CINV over palonosetron (PALO) plus DEX for 5 days post-chemotherapy.  The safety of NEPA was well-established in the phase II/III clinical program in 1,169 NEPA-treated patients.  An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed.  In a randomized, multi-national, double-blind, stratified (by sex and country) phase-III clinical trial in chemotherapy-naïve patients with solid tumors, these investigators examined the safety of a single-dose of i.v. NEPA infused over 30 mins before initial and repeated cycles of HEC.  Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1 to 4.  Safety was assessed primarily by treatment-emergent adverse events (AEs) and ECG.  A total of 404 patients completed 1,312 cycles.  The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity.  There was no increased incidence of AEs in subsequent cycles in either group.  The incidence of treatment-related AEs was similar and relatively low in both groups (12.8 % i.v. NEPA and 11.4 % oral NEPA during the entire study), with constipation being the most common (6.4 % i.v. NEPA, 6.0 % oral NEPA).  No serious treatment-related AEs occurred in either group.  No infusion site or anaphylactic reactions related to i.v. NEPA occurred.  No clinically relevant changes in heart rate corrected QT (QTc) and no cardiac safety concerns were observed.  The authors concluded that intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

On April 19, 2018, the FDA approved Akynzeo injection (fosnetupitant/palonosetron) for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (FDA, 2018). 

The prescribing Information of Akynzeo (fosnetupitant/palonosetron) for injection states that it is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (Helsinn Therapeutics, 2018). Furthermore, it states that Akynzeo for injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.

Aromatherapy

In a Cochrane review, Hines and associates (2018) examined the  safety and efficacy of aromatherapy comparable to standard pharmacological treatments for PONV in adults and children.  These investigators searched CENTRAL; Medline; Embase; CINAHL; CAM on PubMed; Informit; LILACS; and ISI Web of Science as well as grey literature sources and the reference lists of retrieved articles up to March 2017.  The original search was performed in August 2011.  They included all randomized RCTs and controlled clinical trials (CCTs) where aromatherapy was used to treat PONV.  Interventions were all types of aromatherapy compared to placebo or with standard antiemetics.  Primary outcomes were severity and duration of PONV.  Secondary outcomes were adverse reactions, use of rescue anti-emetics and patient satisfaction.  Two review authors independently evaluated risk of bias in the included studies and extracted data.  For dichotomous outcome variables, these investigators used a random-effects model and calculated RR with associated 95 % CI.  For continuous outcome variables, they used a random-effects model and calculated standardized mean difference (SMD) with associated 95 % CI.  They used the GRADE software to compile “Summary of findings” tables.

These researchers included 7 new studies with 663 subjects in the 2017 update; 5 RCTs and 2 CCTs.  These were added to the 9 previously included studies (6RCTs and 3e CCTs with a total of 373 subjects) for a total of 16 included studies and 1,036 subject in this updated review.  The mean age and range data for all subjects were not reported for all studies.  These investigators identified 2 registered trials that met the inclusion criteria for this review; however there were no results for these studies yet.  Overall, the GRADE assessment of evidence quality ranged from moderate-to-very low.  The method of randomization in 11 of the 12 included RCTs was explicitly stated and adequate.  Incomplete or methodologically diverse reporting of data affected the completeness of the analysis.  Data on additional aromatherapies were added in the 2017 update (blended aromatherapy products, and peppermint products).  Heterogeneity of outcome measures and time-points between studies affected the completeness of the analysis.  In the summary of the findings of 6 studies, these researchers did not find aromatherapy to be effective in reducing nausea severity in comparison to placebo (SMD -0.22, 95 % CI: -0.63 to 0.18, p = 0.28, 241 participants, level of evidence: low).  Those participants receiving aromatherapy were no more likely to be free of nausea at the end of the treatment period than those receiving placebo (RR 3.25, 95 % CI: 0.31 to 34.33, p = 0.33, 4 trials, 193 participants, evidence level: very low), however they were less likely to require rescue anti-emetics (RR 0.60, 95 % CI: 0.37 to 0.97, p = 0.04, 7 trials, 609 participants, evidence level: low).  There were no data reported on AEs or patient satisfaction for this comparison.  A specific comparison of peppermint aromatherapy to placebo did not show evidence of an effect on nausea severity at 5 mins post-treatment in the pooled results (SMD -0.18, 95 % CI: -0.86 to 0.49, p = 0.59, 4 trials, 115 participants, evidence level: low).  There were no data reported on nausea duration, use of rescue anti-emetics, AEs or patient satisfaction for this comparison.  When these investigators pooled studies comparing isopropyl alcohol to standard anti-emetic treatment in a GRADE summary of findings, in terms of nausea duration, there was a significant effect on the time in minutes to a 50 % reduction in nausea scores (SMD -1.10, 95 % CI: -1.43 to -0.78, p < 0.00001, 3 trials, 176 participants, evidence level: moderate).  Fewer participants who received isopropyl alcohol required rescue anti-emetics (RR 0.67, 95 % CI: 0.46 to 0.98, p = 0.04, 215 participants, 4 trials, evidence level: moderate).  Two studies with 172 participants measured patient satisfaction; there were high levels of satisfaction across both aromatherapy and standard treatment groups and no differences found (evidence level: low).  There were no data reported on nausea severity or AEs for this comparison.  There was no difference in effectiveness between isopropyl alcohol vapor inhalation and placebo for reducing the proportion of participants requiring rescue anti-emetics (RR 0.39, 95 % CI: 0.12 to 1.24, p = 0.11, 291 participants, 4 trials, evidence level: very low).  There were no data reported on nausea severity, nausea duration, AEs or patient satisfaction for this comparison.  The authors concluded that for nausea severity at the end of treatment, aromatherapy may have similar effectiveness to placebo and similar numbers of participants were nausea-free.  However, this finding was based on low-quality evidence and thus, very uncertain.  Also, these researchers stated that low-quality evidence suggested that participants who received aromatherapy may need fewer anti-emetic medications, but again, this was uncertain.  Participants receiving either aromatherapy or anti-emetic medications may report similar levels of satisfaction with their treatment, according to low-quality evidence.

In a systematic review, Asay and colleagues (2020) examined the use of aromatherapy on the incidence of nausea and vomiting post-operatively.  The literature search was focused on aromatherapy and the effect on PONV in adult surgical patients.  These investigators searched Medline, PubMed, Cumulative Index of Nursing and Allied Literature, and Cochrane Database of Systematic Reviews using specific inclusion and exclusion criteria; and the search yielded 5 RCTs.  The overall synthesis of evidence supports the use of aromatherapy in PONV.  Aromatherapy has a positive effect on PONV, and thus should be considered as a complementary therapy or as an adjunct to anti-emetic medications.  The authors concluded that aromatherapy is one modality that should be considered as treatment for PONV in adult surgical patients.  However, these researchers stated that more research should be conducted to provide additional support in the use of aromatherapy for PONV; and future research should aim at standardizing a nausea scale that would provide more reliable and valid results in studies that research PONV.

Appendix

Table: Emetogenic Potential of Intravenous and Oral Antineoplastic Agents
Emetic Risk Without Prophylaxis Agents

High-risk (greater than 90% frequency of emesis)Footnotes for proportion of patients*
  • AC combination defined as either doxorubicin or epirubicin with cyclophosphamide
  • Altretamine (oral)
  • Carboplatin AUC ≥ 4
  • Carmustine > 250 mg/m2
  • Cisplatin ≥ 50 mg/m2
  • Cyclophosphamide > 1,500 mg/m2
  • Dacarbazine
  • Doxorubicin ≥ 60 mg/m2
  • Epirubicin > 90 mg/m2
  • Estramustine (oral)
  • Etoposide (oral)
  • Ifosfamide ≥ 2 g/m2 per dose
  • Lomustine (single day) (oral)
  • Mechlorethamine
  • Procarbazine (oral)
  • Streptozocin
  • Temozolamide > 75 mg/m2/day (oral)

Moderate-risk (30 - 90 % frequency of emesis)Footnotes for proportion of patients*
  • Aldesleukin > 12 - 15 million IU/m2
  • Altretamine (oral)
  • Amifostine > 300 mg/m2
  • Arsenic trioxide
  • Azacytidine
  • Bendamustine
  • Busulfan ≥ 4 mg/day (oral)
  • Carboplatin
  • Carmustine ≤ 250 mg/m2
  • Ceritinib (oral)
  • Cisplatin < 50 mg/m2
  • Clofarabine
  • Crizotinib (oral)
  • Cyclophosphamide ≤ 1,500 mg/m2
  • Cyclosphosphamide ≥ 100 mg/m2/day (oral)
  • Cytarabine > 200 mg/m2
  • Dabrafenib (oral)
  • Dactinomycin
  • Daunorubicin
  • Dinutuximab
  • Doxorubicin < 60 mg/m2
  • Dual-drug liposomal encapsulation of cytarabine and daunorubicin
  • Enasidenib (oral)
  • Epirubicin ≤ 90 mg/m2 
  • Estramustine (oral)
  • Etoposide (oral)
  • Idarubicin
  • Ifosfamide < 2 g/m2 per dose
  • Interferon alfa ≥ 10 million IU/m2
  • Irinotecan
  • Irinotecan (liposomal)
  • Lenvatinib (oral)
  • Lomustine (single day) (oral)
  • Melphalan 
  • Methotrexate ≥ 250 mg/m2
  • Midostaurin (oral)
  • Mitotane (oral)
  • Olaparib (oral)
  • Oxaliplatin
  • Temozolomide 
  • Procarbazine (oral) 
  • Rucaparib (oral)
  • Temozolomide > 75 mg/m2/day (oral)
  • Trabectedin
  • Trifluridine/tipiracil (oral)

Low-risk (10 - 30 % frequency of emesis)
  • Abemaciclib (oral)
  • Acalabrutinib (oral)
  • Ado-trastuzumab emtansine
  • Afatinib (oral)
  • Aldesleukin ≤ 12 million IU/m2
  • Alectinib (oral)
  • Amisfostine ≤ 300 mg
  • Axicabtagene ciloleucel
  • Axitinib (oral)
  • Belinostat
  • Bexarotene (oral) 
  • Binimetinib (oral)
  • Bosutinib (oral)
  • Brentuximab vedotin
  • Brigatinib (oral)
  • Cabazitaxel
  • Cabozantinib (oral)
  • Capecitabine (oral)
  • Carfilzomib
  • Cobimetinib (oral)
  • Copanlisib
  • Cytarabine (low-dose) 100 - 200 mg/m2
  • Dacomitinib (oral)
  • Dasatinib (oral)
  • Docetaxel
  • Doxorubicin (liposomal)
  • Duvelisib (oral)
  • Encorafenib (oral)
  • Eribulin
  • Etoposide
  • Everolimus (oral)
  • 5-Fluorouracil 
  • Floxuridine
  • Fludarabine (oral and intravenous)
  • Gemcitabine
  • Gemtuzumab ozogamicin
  • Gilteritinib (oral)
  • Glasdegib (oral)
  • Ibrutinib (oral)
  • Idelalisib (oral)
  • Inotuzumab ozogamicin
  • Interferon alfa >5 - <10 million IU/m2
  • Ivosidenib (oral)
  • Ixabepilone
  • Ixazomib (oral)
  • Larotrectinib (oral)
  • Lorlatinib (oral)
  • Methotrexate > 50 mg/m2 - < 250 mg/m2
  • Mitomycin
  • Mitoxantrone
  • Necitumumab
  • Neratinib (oral)
  • Olaratumab
  • Omacetaxine
  • Osimertinib (oral)
  • Paclitaxel
  • Paclitaxel-albumin
  • Palbociclib (oral)
  • Panobinostat (oral)
  • Pemetrexed
  • Pentostatin
  • Pomalidomide (oral)
  • Ponatinib (oral)
  • Pralatrexate
  • Regorafenib (oral)
  • Ribociclib (oral)
  • Romidepsin
  • Ruxolitinib (oral)
  • Sonidegib (oral)
  • Talazoparib tosylate (oral)
  • Talimogene laherparepvec
  • Thiotepa
  • Tisagenlecleucel
  • Topotecan
  • Trametinib (oral)
  • Vemurafenib (oral)
  • Venetoclax (oral)
  • Vismodegib (oral)
  • Vorinostat
  • Ziv-aflibercept

Minimal-risk (less than 10% frequency of emesis)Footnotes for proportion of patients*
  • Alemtuzumab
  • Asparaginase
  • Atezolizumab
  • Avelumab
  • Bevacizumab
  • Bleomycin
  • Blinatumomab
  • Bortezomib
  • Busulfan < 4 mg/day (oral)
  • Cetuximab
  • Chlorabmucil (oral)
  • Cladribine (2-chlorodeoxyadenosine)
  • Cyclophosphamide < 100 mg/m2/day (oral)
  • Cytarabine < 100 mg/m2
  • Daratumumab
  • Decitabine
  • Denileukin diftitox
  • Dexrazoxane
  • Durvalumab
  • Elotuzumab
  • Erlotinib (oral)
  • Fludarabine
  • Gefitnib (oral)
  • Hydroxyurea (oral)
  • Imatinib (oral)
  • Interferon alfa ≤ 5 million IU/m2
  • Ipilimumab
  • Lapatinib (oral)
  • Lenalidomide (oral)
  • Melphalan (oral)
  • Mercaptopurine (oral)
  • Methotrexate (oral)
  • Methotrexate ≤  50 mg/m2
  • Nelarabine
  • Nilotinib (oral)
  • Nivolumab
  • Obinutuzumab
  • Ofatumumab
  • Pazopanib (oral)
  • Panitumumab
  • Pegaspargase
  • Peginterferon
  • Pembrolizumab
  • Pertuzumab
  • Ramucirumab
  • Rituximab
  • Rituximab and hyaluronidase human injection for SQ use
  • Siltuximab
  • Sorafenib (oral)
  • Sunitinib (oral)
  • Temozolamide ≤ 75 mg/m2/day (oral)
  • Temsirolimus
  • Thalidomide (oral)
  • Thioguanine (oral)
  • Topotecan (oral)
  • Trastuzumab
  • Tretinoin (oral)
  • Valrubicin
  • Vandetanib (oral)
  • Vinblastine
  • Vincristine
  • Vincristine (liposomal)
  • Vinorelbine
  • Vorinostat (oral)

Footnotes for proportion of patients* Proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis

Note: National Comprehensive Cancer Network guidelines on antiemesis lists the emetogenic potential of additional cancer drugs; these guidelines are available at the following web address (fee registration required).

Source: NCCN, 2019

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to this CPB:
77371 - 77425 Radiation treatment delivery
96401 - 96549 Chemotherapy administration

HCPCS codes covered if selection criteria are met:
J0185 Injection, aprepitant, 1 mg
J1260 Injection, dolasetron mesylate, 10 mg
J1453 Injection, fosaprepitant, 1 mg
J1454 Injection, fosnetupitant 235 mg and palonosetron 0.25 mg
J1626 Injection, granisetron HCl, 100 mcg
J2405 Injection, ondansetron HCl, per 1 mg
J2469 Injection, palonosetron HCl, 25 mcg
J2797 Injection, rolapitant, 0.5 mg
J8670 Rolapitant, oral, 1 mg

HCPCS codes not covered for indications listed in the CPB:
Aromatherapy - no specific code

HCPCS codes related to High Emetic Risk Without Prophylaxis (greater than 90% frequency of emesis):
J1627 Injection, granisetron, extended-release, 0.1 mg
J8530 Cyclophosphamide, oral, 25 mg
J8700 Temozolomide, oral, 1 mg
J9000 Injection, doxorubicin HCl, 10 mg
J9050 Injection, carmustine, 100 mg [> 250mg/m2]
J9070 Cyclophosphamide, 100 mg [> 1,500 mg/m2]
J9130 Dacarbazine, 100 mg
J9178 Injection, epirubicin HCl, 2 mg
J9230 Injection, mechlorethamine HCl, (nitrogen mustard), 10 mg
J9320 Injection, streptozocin, 1 g
Q2050 Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg
S0182 Procarbazine HCl, oral, 50 mg

HCPCS codes related to Moderate Emetic Risk Without Prophylaxis (30-90% frequency of emesis):
J0207 Injection, amifostine, 500 mg [> 300]
J0594 Injection, busulfan, 1 mg [> 4 mg/d]
J1627 Injection, granisetron, extended-release, 0.1 mg
J8510 Busulfan; oral, 2 mg [> 4 mg/d]
J8560 Etoposide, oral, 50 mg
J8600 Melphalan, oral, 2 mg [> 50 mg/m2]
J8610 Methotrexate, oral, 2.5 mg [250 - > 1,000 mg/m2]
J8700 Temozolomide, oral, 5 mg
J9000 Injection, doxorubicin HCl, 10 mg
J9015 Injection, aldesleukin, per single use vial [Interleukin-2] [> 12-15 million units/m2]
J9017 Injection, arsenic trioxide, 1 mg
J9025 Injection, azactidine, 1 mg
J9045 Injection, carboplatin, 50 mg
J9050 Injection, carmustine, 100 mg [< 250mg/m2]
J9060 Injection, cisplatin, powder or solution, per 10 mg [< 50 mg/m2]
J9070 Cyclophosphamide, 100 mg [< 1,500 mg/m2]
J9098 Injection, cytarabine liposome, 10 mg [> 1 g/m2]
J9100 Injection, cytarabine, 100 mg [> 1 g/m2]
J9120 Injection, dactinomycin, 0.5 mg
J9150 Injection, daunorubicin, 10 mg
J9151 Injection, daunorubicin citrate, liposomal formulation, 10 mg
J9178 Injection, epirubicin HCl, 2 mg
J9206 Injection, irinotecan, 20 mg
J9208 Injection, ifosfamide, 1 g
J9211 Injection, idarubicin HCl, 5 mg
J9245 Injection, melphalan HCI, 50 mg [> 50 mg/m2]
J9250 Methotrexate sodium, 5 mg [250 - > 1,000 mg/m2]
J9260 Methotrexate sodium, 50 mg [250 - > 1,000 mg/m2]
J9263 Injection, oxaliplatin, 0.5 mg [> 75 mg/m2]
Q2050 Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg
S0178 Lomustine, oral, 10 mg

HCPCS codes related to Low Emetic Risk Without Prophylaxis (10-30% frequency of emesis):
J0207 Injection, amifostine, 500 mg [< 300 mg]
J1627 Injection, granisetron, extended-release, 0.1 mg
J8520 Capecitabine, oral, 150 mg
J8521 Capecitabine, oral, 500 mg
J8560 Etoposide, oral, 50 mg
J8610 Methotrexate, oral, 2.5 mg [> 50 mg/m2 < 250 mg/m2]
J8700 Temozolomide, oral, 5 mg
J8705 Topotecan, oral, 0.25 mg
J9000 Injection, doxorubicin HCl, 10 mg [liposomal]
J9041 Injection, bortezomib, 0.1 mg
J9055 Injection, cetuximab, 10 mg
J9098 Injection, cytarabine liposome, 10 mg [low dose] [100-200 mg/m2]
J9100 Injection, cytarabine, 100 mg [low dose] [100-200 mg/m2]
J9171 Injection, docetaxel, 1 mg
J9181 Injection, etoposide, 10 mg
J9185 Injection, fludarabine phosphate, 50 mg [oral]
J9190 Injection, fluorouracil, 500 mg
J9201 Injection, gemcitabine HCl, 200 mg
J9250 Methotrexate sodium, 5 mg [> 50 mg/m2 < 250 mg/m2]
J9260 Methotrexate sodium, 50 mg [> 50 mg/m2 < 250 mg/m2]
J9264 Injection, paclitaxel protein-bound particles, 1 mg
J9265 Injection, paclitaxel, 30 mg
J9267 Injection, paclitaxel, 1 mg
J9268 Injection, pentostatin, 10 mg
J9280 Injection, mitomycin, 5 mg
J9291 Mitomycin, 40 mg
J9293 Injection, mitoxantrone HCI, per 5 mg
J9305 Injection, pemetrexed, 10 mg
J9307 Injection, pralatrexate, 1 mg
J9315 Injection, romidepsin, 1 mg
J9328 Injection, Temozolomide, 1 mg [Temodar]
J9340 Injection, thiotepa, 15 mg
J9351 Injection, topotecan, 0.1 mg
J9355 Injection, trastuzumab, 10 mg
Q2050 Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg

HCPCS codes related to Minimal Emetic Risk Without Prophylaxis (< 10% frequency of emesis):
J0202 Injection, alemtuzumab, 1 mg
J0594 Injection, busulfan, 1 mg
J1190 Injection, dexrazoxane HCl, per 250 mg
J8510 Busulfan, oral, 2mg
J8565 Gefitinib, oral, 250 mg
J8600 Melphalan, oral, 2 mg [low-dose]
J8610 Methotrexate, oral, 2.5 mg [< 50 mg/m2]
J9020 Injection, asparaginase, not otherwise specified, 10,000 units
J9035 Injection, bevacizumab, 10 mg
J9040 Injection, bleomycin sulfate, 15 units
J9065 Injection, cladribine, per 1 mg
J9185 Injection, fludarabine phosphate, 50 mg
J9212 Injection, interferon alfacon-1, recombinant, 1 mcg
J9213 Injection, interferon alfa-2A, recombinant, 3 million units
J9214 Injection, interferon alfa-2B, recombinant, 1 million units
J9215 Injection, interferon alfa-N3, (human leukocyte derived), 250,000 IU
J9228 Injection, ipilimumab, 1 mg
J9245 Injection, melphalan HCI, 50 mg [oral low-dose]
J9250 Methotrexate sodium, 5 mg [< 50 mg/m2]
J9260 Methotrexate sodium, 50 mg [< 50 mg/m2]
J9300 Injection, gemtuzumab ozogamicin, 5 mg
J9302 Injection, ofatumumab, 10 mg
J9306 Injection, pertuzumab, 1 mg
J9312 Injection, rituximab, 10 mg
J9357 Injection, valrubicin, intravesical, 200 mg
J9360 Injection, vinblastine sulfate, 1 mg
J9370 Vincristine sulfate, 1 mg
J9390 Injection, vinorelbine tartrate, per 10 mg
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
S0088 Imatinib, 100 mg
S0172 Chlorambucil, oral, 2 mg
S0176 Hydroxyurea, oral, 500 mg

Other HCPCS codes related to this CPB:
A9153 Multiple vitamins, with or without minerals and trace elements, oral, per dose, not otherwise specified
C8957 Intravenous infusion for therapy/diagnosis; initiation of prolonged infusion (more than 8 hours), requiring use of portable or implantable pump
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1mg
J1240 Injection, dimenhydrinate, up to 50 mg
J2550 Injection, promethazine HCl, up to 50 mg
J3250 Injection, trimethobenzamide HCl, up to 200 mg
J3415 Injection, pyridoxine HCl, 100 mg
Q0083 - Q0085 Chemotherapy administration
Q0162 Ondansetron 1 mg, oral, FDA-approved presecription anti-emetic, for use as a complete therapeutic substitute for an IV anti-emetic at the time of chemotherapy treatment, not to exceed a 48 hour dosage regimen
Q0166 Ganisetron HCl, 1 mg, oral, FDA approved prescription anti-emetic, for use as a complete therapeutic substitute for an IV anti-emetic at the time of chemotherapy treatment, not to exceed a 24-hour dosage regimen
Q0169 Promethazine HCl, 12.5 mg, oral, FDA approved prescription anti-emetic, for use as a complete therapeutic substitute for an IV anti-emetic at the time of chemotherapy treatment, not to exceed a 48-hour dosage regimen
Q0180 Dolasetron mesylate, 100 mg, oral, FDA approved prescription anti-emetic, for use as a complete therapeutic substitute for an IV anti-emetic at the time of chemotherapy treatment, not to exceed a 24-hour dosage regimen
S0091 Ganisetron HCl, 1 mg (for circumstances falling under the Medicare statute, use Q0166)
S0119 Ondansetron , oral, 4 mg (for circumstances falling under the medicare statute, use Q0162)
S0174 Dolasetron mesylate, oral, 50 mg (for circumstances falling under the Medicare statute, use Q0180)
S9351 Home infusion therapy, continuous or intermittent anti-emetic infusion therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and visits coded separately), per diem
S9370 Home therapy, intermittent antiemetic injection therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem [covered for high or moderate emetic risk only]

ICD-10 codes covered if selection criteria are met:
B20 Human immunodeficiency virus [HIV] disease
F50.2 Bulimia nervosa
O21.0 - O21.9 Excessive vomiting in pregnancy [when clinical signs of dehydration are present or nausea and vomiting have persisted more than 3 weeks and criteria A,B, and C are met]
R11.0 Nausea
R11.10 - R11.14 Vomiting
R11.10 Vomiting, unspecified [cyclical]
R11.11 Vomiting without nausea
R11.12 Projectile vomiting
R11.2 Nausea with vomiting, unspecified
T45.1X5+ Adverse effect of antineoplastic and immunosuppressive drugs [not covered for Anzemet]
T66.xxx+ Radiation sickness, unspecified [nausea or vomiting secondary to total body irradiation]
Z51.0 Encounter for antineoplastic radiation therapy [for total body radiation when oral antiemetic therapy has failed or is contraindicated]
Z51.11 - Z51.12 Encounter for antineoplastic chemotherapy and immunotherapy [for total body radiation when oral antiemetic therapy has failed or is contraindicated]

ICD-10 codes not covered for indications listed in the CPB:
K31.84 Gastroparesis
T75.3xxA - T75.3xxS Motion sickness

The above policy is based on the following references:

  1. Aapro MS. Palonosetron as an anti‐emetic and anti‐nausea agent in oncology. Ther Clin Risk Manag. 2007;3(6):1009‐1020.
  2. Abbott B, Ippoliti C, Bruton J, et al. Antiemetic efficacy of granisetron plus dexamethasone in bone marrow transplant patients receiving chemotherapy and total body irradiation. Bone Marrow Transplant. 1999;23(3):265-269.
  3. Aguilar AE, Figueiras CM, Cortes-Funes H, et al. Clinical practice guidelines on antiemetics in oncology. Expert Rev Anticancer Ther. 2005;5(6):963-972.
  4. Alhashimi D, Alhashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database Syst Rev. 2006;(4):CD005506.
  5. Alon E, Himmelseher S. Ondansetron in the treatment of postoperative vomiting: A randomized, double-blind comparison with droperidol and metoclopramide. Anesth Analg. 1992;75(4):561-565.
  6. American College of Obstetrics and Gynecology (ACOG). Nausea and vomiting of pregnancy. ACOG Practice Bulletin No. 52. Washington, DC: ACOG; April 2004.
  7. Aouad MT, Siddik-Sayyid SM, Taha SK, et al. Haloperidol vs. ondansetron for the prevention of postoperative nausea and vomiting following gynaecological surgery. Eur J Anaesthesiol. 2007;24(2):171-178.
  8. Asay K, Olson C, Donnelly J, Perlman E. The use of aromatherapy in postoperative nausea and vomiting: A systematic review. J Perianesth Nurs. 2019;34(3):502-516.
  9. Aubin CD. Toxicity, theophylline. eMedicine Pediatrics Topic 2725. Omaha, NE: eMedicine.com; updated August 2, 2004. Available at: http://www.emedicine.com/ped/topic2725.htm. Accessed March 29, 2006.
  10. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29(31):4189-4198.
  11. Bashiri A, Neumann L, Maymon E. Hyperemesis gravidarum: Epidemiologic features, complications and outcome. Eur J Obstet Gynecol Reprod Biol 1995;63(2):135-138.
  12. Benline TA, French J, Poole E. Anti-emetic drug effects on pilot performance: Granisetron vs. ondansetron. Aviat Space Environ Med. 1997;68(11):998-1005.
  13. Broder MS, Faria C, Powers A, et al. The impact of 5-HT3RA use on cost and utilization in patients with chemotherapy-induced nausea and vomiting: Systematic review of the literature. Am Health Drug Benefits. 2014;7(3):171-182.
  14. Camilleri M. Treatment of gastroparesis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2018.
  15. Cancer Care Ontario, Systemic Treatment Disease Site Group. Use of 5-HT3 receptor-antagonists in patients receiving moderately or highly emetogenic chemotherapy. Practice Guidelines Report #12-3. Cancer Care Ontario Practice Guidelines Initiative. Toronto, ON: Cancer Care Ontario; updated January 2003.
  16. Carlisle JB, Stevenson CA. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2006;(3):CD004125. 
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