Serotonin Receptor Antagonists
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Serotonin receptor antagonists (5HT3-RA) work by inhibiting the activation of ligand-gated cation channels located peripherally in the gastrointestinal tract and centrally in the chemoreceptor trigger zone of the postrema. Emesis during chemotherapy and radiation therapy appears to be associated with the release of serotonin from enterochromaffin cells in the small intestine. Blocking these nerve endings in the intestine prevents signals to the central nervous system and decreases the vomiting reflex.
Clinical practice guidelines support the use of serotonin receptor antagonists (5HT3-RA) for the prevention of chemotherapy-induced nausea and vomiting , radiation-induced nausea and vomiting, and postoperative nausea and vomiting. Since efficacy between agents is generally considered equal, selection of a 5HT3-RA is based on patient specific factors (e.g., age; risk of QT, PR, or QRS prolongation; concomitant drugs), patient or provider dosage form preference, or cost.
FDA-Approved Age Groups of Serotonin Receptor Antagonists for Nausea/Vomiting Prophylaxis Indications
All 5HT3-RAs are indicated for the prevention of chemotherapy-induced nausea and vomiting (CINV) except IV dolasetron, which is contraindicated for the prevention of CINV due to a dose dependent QT-interval prolongation in this patient population. In general, the efficacy of ondansetron and granisetron for CINV appear similar, although IV palonosetron was found to be superior to first-generation 5HT3-RAs in a meta-analysis of 8 randomized, double-blind trials. Too few randomized comparative studies evaluating the efficacy of dolasetron were available to determine equivalence in meta-analyses. The American Society of Clinical Oncology (ASCO) clinical practice guidelines recommend that adult patients who are treated with moderate to high-emetic-risk chemotherapy agents should be offered a 3-drug combination of a 5-HT3-RA, a neurokinin 1 (NK1) receptor antagonist, and dexamethasone; olanzapine is also added to the 3-drug combination during use of high-emetic-risk agents.
The ASCO and Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Clinical Oncology (ESMO) guidelines both recommend that children receiving moderate to high-emetic-risk agents should be offered a 2-drug combination of a 5-HT3-RA and dexamethasone; aprepitant is also added to the 2-drug combination during the use of high-emetic-risk agents.
The ASCO guidelines recommend that adult patients who are treated with high-emetic-risk radiation therapy (XRT) should be offered a 2-drug combination of a 5-HT3-RA and dexamethasone before each fraction and on the day after each fraction if XRT is not planned for that day. Patients who are treated with moderate-emetic-risk XRT should be offered a 5-HT3-RA receptor antagonist before each fraction, with or without dexamethasone before the first 5 fractions.
IV dolasetron is the only 5HT3-RA indicated for the treatment of PONV in both adults and children 2 years and older. Efficacy of 5HT3-RAs for the prevention of PONV appears to be similar. For patients with a moderate or high risk for developing PONV, the Society of Ambulatory Anesthesia (SAMBA) guidelines recommend prophylaxis using 1 or more agents with different mechanism of actions, including a 5HT3-RA, given at the end of surgery. For children with a moderate or high risk for developing PONV, the SAMBA guidelines recommend prophylaxis using 2 or 3 agents with different mechanism of actions, including a 5HT3-RA (drugs of first choice for prophylaxis).
Serotonin Receptor Antagonists Comparative Efficacy Trials
Meta-analysis from 16 randomized clinical trials (n = 7808) for acute and delayed CINV prevention of highly emotogenic chemotherapy
9 trials evaluated ondansetron and granisetron
Granisetron vs ondansetron
Absence of acute vomiting: OR = 0.89; 95% CI, 0.78-1.02
Absence of acute nausea:OR = 0.97; 95% CI, 0.85-1.1
Absence of delayed vomiting: OR = 1; 95% CI, 0.74-1.34
Absence of delayed nausea: OR = 0.96; 95% CI, 0.75-1.24
Ondansetron and granisetron appear equivalent; both drugs had comparable incidence of adverse effects but ondansetron had less constipation
No definitive conclusion regarding equivalence of dolasetron or palonosetron compared with other 5HT3-RAs due to small number of studies
Jordan et al. Support Care Cancer. 2007;15:1023-1033.
Meta-analysis from 44 randomized clinical trials (n = 12,343) for acute CINV prevention in patients receiving cisplatin vs. non-cisplatin based regimens
27 trials evaluated ondansetron and granisetron
Nausea/vomiting in first 24 hours: OR = 1.033; 95% CI, 0.935-1.142
Granisetron 2 or 3 mg vs ondansetron 24 or 32 mg (IV or PO)
Nausea/vomiting in first 24 hours: OR = 1.053; 95% CI, 0.916-1.21
Granisetron 3 mg IV vs ondansetron 8 mg IV
Nausea/vomiting in first 24 hours: pooled results, OR = 0.877; 95% CI, 0.699-1.102; non-cisplatin studies, OR = 0.453; 95% CI, 0.239-0.857
Ondansetron and granisetron appear equivalent
Granisetron 3 mg IV was superior to ondansetron 8 mg IV in non-cisplatin studies
Granisetron 2 mg or 3 mg resulted in similar efficacy as ondansetron 24 mg or 32 mg
Likun et al. The Oncologist. 2011;16:207-216.
Meta-analysis from 8 randomized, double-blind trials for prevention of acute and delayed CINV for moderately or highly emetogenic chemotherapy (n = 3592)
Palonosetron vs first-generation 5-HT3 -receptor antagonist
Acute emesis: OR = 0.76; 95% CI, 0.66-0.88
Delayed emesis: OR = 0.62; 95% CI, 0.54-0.71
Overall emesis: OR = 0.64; 95% CI, 0.56-0.74
Palonosetron 0.25 mg or 0.75 mg IV was superior compared with first-generation 5-HT3-RAs
The addition of dexamethasone to palonosetron significantly reduced the risk of delayed and overall CINV
Constipation occurred significantly more often with palonosetron 0.75 mg compared with other 5HT3-RAs
Abbreviations: 5HT3-RAs = serotonin 5-hydroxytryptamine-3-receptor antagonists; OR = odds ratio
QT-interval prolongation has been reported with dolasetron, granisetron, ondansetron, and palonosetron. Additionally, torsade de pointes has been reported with dolasetron and ondansetron. Dolasetron also causes a dose dependent PR- and QRS-interval prolongation; second or third degree atrioventricular block, cardiac arrest, and serious ventricular arrhythmias (some fatal) have been reported in pediatrics and adults. ECG monitoring is recommended in select patient populations with increased risk who receive dolasetron or ondansetron.
Serotonin receptor antagonists may cause hypersensitivity reactions including anaphylaxis, facial edema, and urticaria. Antagonism of serotonin receptors and the subsequent increased levels of serotonin have been hypothesized to increase the risk of developing bronchospasm and/or vasoconstriction. Cross-sensitivity between the other drugs in the class is possible.
The serotonin receptor antagonists (5HT3-RA) are metabolized by cytochrome P450 isoenzymes; therefore, inducers or inhibitors of these enzymes may change the pharmacokinetic parameters of these agents. Patients should be monitored for changes in safety or efficacy.
Use caution when administering 5HT3-RAs known to prolong the QT interval (especially dolasetron, granisetron, and ondansetron) with other agents that prolong the QT interval, agents that may cause hypokalemia or hypomagnesemia, and antiarrhythmic agents. Electrocardiogram monitoring is recommended in patients receiving dolasetron or ondansetron in combination with another agent that prolongs the QT-interval.
Use caution when administering dolasetron with other agents that prolong the PR (e.g., verapamil) or QRS (e.g., flecainide, quinidine) intervals. Electrocardiogram monitoring is recommended in patients receiving dolasetron in combination with another agent that prolongs the PR or QRS interval.
Coadministration of ondansetron and apomorphine is contraindicated due to reports of severe hypotension and loss of consciousness when these agents are administered together.
All of the 5HT-3 RAs can prolong the QT interval, although the manufacturers recommend different levels of monitoring for each drug. Dolasetron also prolongs the PR and QRS intervals. The manufacturers of palonosetron and granisetron do not provide specific precautions or monitoring recommendations within the package labeling, while ondansetron and dolasetron's manufacturers recommend caution and monitoring in patients with any condition or concomitant drug that can prolong the risk of QT interval prolongation. Additionally, the manufacturer of dolasetron recommends caution and monitoring in patients with any condition or concomitant drug that can prolong the PR or QRS intervals.
Patient Populations in which EKG Monitoring is Recommended
Ondansetron clearance is decreased 2- to 3-fold and the half life is prolonged in patients with severe hepatic impairment; therefore, the ondansetron maximum daily dose should not exceed 8 mg in patients with severe hepatic impairment.
Patients with phenylketonuria should be informed that ondansetron (Zofran) oral disintegrating tablets (ODT) contain phenylalanine (< 0.03 mg phenylalanine in 4- and 8-mg ODT).
The use of serotonin receptor antagonists in patients with chemotherapy-induced nausea and vomiting or following abdominal surgery may mask a progressive ileus and/or gastric distention.
Anzemet (dolasetron mesylate) tablets package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2014 Sept.
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.
Dupuis LL, Sung L, Molassiotis A, et al. 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 2017;25:323–331.
Feyer PC, Maranzano E, Molassiotis A, et al. Radiotherapy-induced nausea and vomiting (RINV): MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer 2011;19 Suppl 1:S5-14.
Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg 2007;105(6):1615-1628.
Billio A, Morello E, and Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst Rev. 2010;(1):CD006272.
Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. Support Care Cancer 2007;15(9):1023-1033.
Likun Z, Xiang J, Yi B, et al. A systematic review and meta-analysis of intravenous palonosetron in theprevention of chemotherapy-induced nausea and vomiting in adults. Oncologist 2011;16(2):207-216.
Le TP and Gan TJ. Update on the management of postoperative nausea and vomiting and postdischargenausea and vomiting in ambulatory surgery. Anesthesiol Clin 2010;28(2):225-249.
Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017;35:3240-61.
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