Antiemetic Therapy - Medical Clinical Policy Bulletins (2024)

Number:0724

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses antiemetic therapy.

1. Medical Necessity

   Aetna considersthe following interventions medically necessary:

   1. Cancer Chemotherapy

      1. Palonosetron (Aloxi) or fosaprepitant dimeglumine (Emend) antiemetic therapyfor 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);

      2. Granisetron (Kytril), extended-release granisetron (Sustol) and ondansetron (Zofran) antiemetic intravenous therapyfor 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)
      3. Combined palonosetron (Aloxi) and fosaprepitant dimeglumine (Emend) for individuals with high emetic risk who have failed previous therapy with a steroid plus 5-HT3 antagonist;
      4. Use of rolapitant (Varubi) or aprepitant (Cinvanti) in combination with dexamethasone and a serotonin receptor antagonist (5-HT3), administered before intravenous antineoplastic therapy, 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);
      5. Akynzeo injection (fosnetupitant/palonosetron) 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;

   2. Radiotherapy

      1. Dolasetron mesylate (Anzemet), 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;
      2. Intravenous granisetron (Kytril) or intravenous ondansetron (Zofran) 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;

   3. Postoperative

      1. Intravenous amisulpride (Barhemsys) for members 18 years of age or older for either of the following:

         1. Prevention of postoperative nausea and vomiting (PONV)

            A single 5 mg intravenous dose at the time of induction of anesthesia for the prevention of PONV, administered alone or in combination with a non-dopaminergic antiemetic (e.g., ondansetron,dexamethasone or betamethasone); or

         2. Treatment of PONV

            A single 10 mg intravenous dose for treatment of PONV in adult members who have received antiemetic prophylaxis with a non-dopaminergic antiemetic (e.g., ondansetron, dexamethasone or betamethasone) or had not received prophylaxis;

      2. Intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend) for the prevention or treatment of postoperative nausea or vomiting when intravenous granisetron (Kytril) or ondansetron (Zofran) at the FDA recommended dose has failed or is contraindicated;
      3. Intravenous granisetron (Kytril) or ondansetron (Zofran) for the prevention or treatment of postoperative 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 postoperatively.

   4. Pregnancy

      1. Intravenous granisetron (Kytril) or ondansetron (Zofran) antiemetic intravenous therapy 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);

      2. Intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend) 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. Other Indications

      1. Granisetron (Kytril) or ondansetron (Zofran) antiemetic intravenous therapy 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;
      2. Intravenous palonosetron (Aloxi), dolasetron mesylate (Anzemet) or fosaprepitant dimeglumine (Emend)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.

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

   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).

2. Experimental, Investigational, or Unproven

   The following interventions are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. Cancer Chemotherapy

      Intravenous dolasetron (Anzemet) for prevention of nausea or vomiting from cancer chemotherapy;

   2. Radiotherapy

      Intravenous palonosetron (Aloxi) and fosaprepitant dimeglumine (Emend) for the prevention of radiation-induced nausea and vomiting because there is insufficient evidence of their effectiveness for this indication;

   3. Motion Sickness

      5-HT3 receptor antagonist antiemetic intravenous therapy for motion-induced nausea and vomiting (motion-sickness);

   4. Other Indications

      1. Aprepitant for the treatment of gastroparesis because there is insufficient evidence of its effectiveness for this indication;
      2. Aromatherapy for the treatment of post-operative nausea and vomiting because there is insufficient evidence of its effectiveness for this indication.

3. Related Policies

   • CPB 0020 - Injectable Medications
   • CPB 0676 - Electrical Stimulation for Nausea, Vomiting and Motion Sickness (PrimaBella and ReliefBand) and Other Selected Indications

   See also:

   1. Pharmacy Clinical Policy Bulletin (PCPB): Antiemetics.

Background

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.

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 withchemotherapy-induced nausea and vomiting (CINV) in pediatric and adult patients. New data demonstrated thatintravenous dolasetroncan increase the risk of developing an abnormal heart rhythm (torsade de pointes) which can be fatal.

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 in3 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 the2 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 wassuperior 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.

Barhemsys

Amisulpride injection is branded as Barhemsys (Acacia Pharma Inc.).Amisulpride is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated for the prevention or treatment of postoperative nausea and vomiting (PONV) in adults.D2 receptors are located in the chemoreceptor trigger zone (CTZ) and respond to thedopamine released from the nerve endings. Activation of CTZ relays inhibitory stimuli to thevomiting center which is involved in emesis.Antagonism of D3 receptors in the area postrema also plays a role in inhibitingemesis.

In February 2020, the U.S. Food and Drug Administration (FDA) approved Barhemsys for (i)treatment of PONV in adult patients who have received antiemetic prophylaxis with an agent of a different class or who have not received prophylaxis, and (ii)prevention of PONV in adults, either alone or in combination with an antiemetic of a different class. Approval was based on evidence from 4 clinical trials of 2323 patients undergoing surgery or experiencing nausea and vomiting after the surgery. The trials were conducted at 80 sites in the United States, Canada and Europe.

The prevention of PONV was evaluated intworandomized, double-blind, placebo-controlled, multi-center trials in adult patientsundergoing general anesthesia and elective surgery (Study 1 and Study 2). In Study1 (NCT01991860), 176 out of 342 patients (age 21 to 88 years) received 5 mg intravenous (IV) monotherapy with Barhemsys compared to placebo (n=166). In Study2 (NCT02337062), 572 out of 1147 patients (age 18 to 91 years) received Barhemsys in combination with one otherintravenously administered, non-dopaminergic antiemetic (ondansetron,dexamethasone or betamethasone) compared to placebo (n=575). In both trials, patients were administeredBarhemsys at the induction of anesthesia. The primary efficacy endpoint of both trials were complete response (defined as absence of any episode of emesis or use of rescue medication within the first 24 hours postoperatively). In Study 1, 78 patients (44%) achieved complete response compared to placebo (n=54; 33%). In Study 2, 330 patients (58%) achieved complete response compared to placebo (n=268; 47%).

The treatment of PONV was evaluatedas a single 10 mg IV dose in tworandomized, double-blind, placebo-controlled, multi-center trials in adult patientsexperiencing PONV after general anesthesia and elective surgery (Study 3 andStudy 4). Study 3 (NCT02449291) enrolled 369 patients (age 19 to 82 years) who had not received priorPONV prophylaxis, whereas Study 4 (NCT02646566) included 465 adult patients (age 18 to 85 years) who hadreceived and failed PONV prophylaxis with an antiemetic of another class compred to placebo. Patientswere excluded if they had received a D2 receptor antagonist antiemetic.For both trials, the primary efficacy endpoint was complete response defined asabsence of any episode of emesis or use of rescue medication within the first 24hours after treatment (excluding emesis within the first 30 minutes). In Study 3, 59 out of 188 patients (31%) achieved complete response compared to placebo (39 out of 181 patients; 22%). In Study 4, 96 out of 230 patients (42%) achieved complete response compared to placebo (67 out of 235 patients; 29%).

Barhemsys carries labeled warnings for QT prolongation.Barhemsys may cause dose- and concentration-dependent prolongation of the QT interval. The recommended dosage is 5 mg or 10 mg as a single IV dose infused over 1 to 2 minutes. It is advised to avoid use in patients with congenital long QT syndromeand in patients taking droperidol. ECG monitoring is recommendedin patients with pre-existing arrhythmias/cardiac conductiondisorders; electrolyte abnormalities (e.g., hypokalemia orhypomagnesemia); congestive heart failure; and in patients takingother medicinal products (e.g., ondansetron) or with other medicalconditions known to prolong the QT interval.

The most common adverse reactions (2% or more) include the following:

• Prevention of PONV: increased blood prolactin concentrations,chills, hypokalemia, procedural hypotension, and abdominaldistension.
• Treatment of PONV: infusion site pain.

Per the label, available data with amisulpride use in pregnant women are insufficient to establish adrug associated risk of major birth defects, miscarriage or adverse maternal or fetaloutcomes; however, a lactating woman may pump and discard breast milk for48 hours after Barhemsys administration.

Barhemsys is not approved for oral dosing or chronic use.

There is no specific antidote for amisulpride overdose. Management includes cardiacmonitoring and treatment of severe extrapyramidal symptoms.Since amisulpride is weakly dialyzed, hemodialysis should not be used to eliminatethe drug.

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 mgorally administered 30 min prior to chemotherapy on day 1 and dexamethasone 8 mgorally 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 mgorally 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 mgorally administered 30 min prior to chemotherapy on day 1 and ondansetron 8 mgorally administered 30 to 60 min prior to chemotherapy and 8 mgorally administered 8 hours after the first dose on Day 1.

Emend (fosaprepitant) therapy isnot indicated for personsnot 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 pharmaco*kinetics of orally administered CYP3A4 substrates is greater than the effect of Emend (aprepitant) on the pharmaco*kinetics 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) injectionis 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)

• 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)

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.

Schwartzberg et al (2020) stated that NEPA, a combination anti-emetic of a neurokinin-1 (NK1) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5-HT3RA [palonosetron] offers 5-day CINV prevention with a single-dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase-III clinical trial of patients receiving cis-platin found no infusion-site or anaphylactic reactions related to IV NEPA. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, especially fosaprepitant in patients receiving anthracycline-cyclophosphamide (AC)-based chemotherapy. In a phase-IIIb, multi-national, randomized, double-blind study, these researchers examined the safety and effectiveness of IV NEPA in the AC setting. This trial enrolled women with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30-min infusion of IV NEPA or single oral NEPA capsule on day 1 before AC-based chemotherapy, in repeated (up to 4) cycles. Oral dexamethasone was administered to all patients on day 1 only. A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral NEPA and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment-related AEs in both groups. There was no treatment-related injection-site AE and no report of hypersensitivity or anaphylaxis. The effectiveness of IV and oral NEPA were similar, with high complete response (no emesis/no rescue) rates observed in cycle-1 (overall [0 to 120 hours] 73.0 % IV NEPA, 77.3 % oral NEPA) and maintained over subsequent cycles. The authors concluded that IV NEPA was safe and effective with no associated hypersensitivity and injection-site reactions in patients receiving AC-based 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.

Dexamethasone-Sparing Regimens with Netupitant/Palonosetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Older Patients (> 65 Years) Fit for Cisplatin

Celio et al (2023) noted that they recently demonstrated the non-inferiority of 2 DEX-sparing regimens with an oral fixed-combination of netupitant and palonosetron (NEPA) versus the guideline-recommended DEX use for cisplatin-induced nausea and vomiting. Since prevention of chemotherapy-induced nausea and vomiting is critical in older patients, these researchers retrospectively examined the effectiveness of the DEX-sparing regimens in this subset. Chemo-naive patients aged over 65 years of age were treated with high-dose cisplatin (70 mg/m2 or greater) were eligible. Patients received NEPA and DEX on day 1 and were randomized to receive either no further DEX (DEX1), oral low-dose DEX (4 mg) on days 2 to 3 (DEX3), or the guideline-recommended standard DEX (4 mg twice-daily) on days 2 to 4 (DEX4). The primary effectiveness endpoint of the parent study was CR (no vomiting and no use of rescue medication) during the overall phase (days 1 to 5). No significant nausea (NSN; none or mild nausea) and the proportion of patients reporting no impact on daily life (NIDL) which was evaluated by the Functional Living Index-Emesis questionnaire on day 6 (overall combined score greater than 108), were secondary endpoints. Among the 228 patients in the parent study, 107 were over 65 years of age. Similar CR rates (95 % CI) were observed in patients over 65 years across treatment groups [DEX1: 75 % (59.7 % to 86.8 %); DEX3: 80.6 % (62.5 % to 92.6 %); DEX4: 75 % (56.6 % to 88.5 %)] as well as versus the total study population. NSN rates were also similar in older patients across treatment groups (p = 0.480) but were higher compared with the total population. Similar rates of NIDL (95 % CI) were reported in the older-patient subset across treatment groups [DEX1: 61.5 % (44.6 % to 76.6 %); DEX3: 64.3 % (44.1 % to 81.4 %); DEX4: 62.1 % (42.3 % to 79.3 %); p = 1.0] during the overall phase, as well as versus total population. A similar proportion of older patients across treatment groups experienced DEX-related side effects. The authors concluded that this analysis showed that older-patients who were fit for cisplatin benefited from a simplified regimen of NEPA plus single-dose DEX with neither loss in anti-emetic effectiveness nor the adverse impact on patient daily functioning.

Palonosetron as Prophylaxis for Post-Discharge Nausea and Vomiting

Moraitis et al (2023) stated that about 25 % of ambulatory surgery patients experience post-discharge nausea and vomiting (PDNV). In a prospective, randomized, double-blind, placebo-controlled study, these investigators examined if palonosetron would lower the incidence of PDNV in high-risk patients. A total of 170 male and female patients undergoing ambulatory surgery under general anesthesia, with a high predicted risk for PDNV, were randomized to receive either IV palonosetron 75 μg (n = 84) or normal saline (n = 86) before discharge. During the first 3 post-operative days (PODs), these investigators measured outcomes using a patient questionnaire. The primary outcome was the incidence of a CR (no nausea, vomiting, or use of rescue medication) until POD 2. Secondary outcomes included the incidence of PDNV each day until POD 3. The incidence of a CR until POD 2 was 48 % (n = 32) in the palonosetron group and 36 % (n = 25) in the placebo group (OR 1.69; 95 % CI: 0.85 to 3.37; p = 0.131). No significant difference in the incidence of PDNV was observed between the 2 groups on the day of surgery (47 % versus 56 %; p = 0.31). Significant differences in the incidence of PDNV were found on POD 1 (18 % versus 34 %; p = 0.033) and POD 2 (9 % versus 27 %; p = 0.007). No differences were observed on POD 3 (15 % versus 13 %; p = 0.700). The authors stated that compared with placebo, palonosetron did not reduce the overall incidence of PDNV up to POD 2. The lower incidence of PDNV on POD 1 and POD 2 in the palonosetron group requires further investigation.

Appendix

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 availableat the following web address(fee registration required).

Source: NCCN, 2019

References