5-HT3 Antagonists

5-HT3 Antagonists

The 5-HT3 antagonists inhibit the action of serotonin in the GI tract and the CNS and thereby block the transmission of emetic signals to the VC. Serotonin antagonists are both highly effective and have minimal side effects. Several agents in this class are now available: ondansetron, granisetron, dolasetron, and palonosetron. Dosages of these agents are shown in Table 7-3. These agents have been widely studied and some 

commonalities have emerged. All of these agents have a threshold effect and so a sufficiently large dose must be given to block the relevant receptors. The dose-response curve is relatively flat, such that escalating doses do not enhance efficacy. When given in appropriate doses, all of these agents have similar efficacy for acute CINV, with response rates ranging from about 60% to 80%, depending on study design.^{11,14,17,18,19} The effectiveness of each of these agents is enhanced by the addition of dexamethasone. The response rate increases by about 15% to 20% in regimens that include dexamethasone and a 5-HT3 antagonist.^20,21 Oral and IV 5-HT3 administration are equally effective assuming the patient can take oral medications. The side effects of the 5-HT3 antagonists are similar and fairly mild and include headache, constipation, diarrhea, and transient elevations of liver function tests. These agents are one component of optimal antiemetic prophylaxis for acute CINV, but are not more effective than agents from other classes (notably dexamethasone, aprepitant, or prochlorperazine) for delayed CINV.^22,23,24,25 Serotonin antagonists, therefore, are not recommended for delayed CINV.

Palonosetron, the newest member of the serotonin antagonist family, is distinguished by its longer elimination half-life than others in its class. Palonosetron was compared with single doses of ondansetron or dolasetron in two trials of moderately emetogenic chemotherapy and in one trial of highly emetogenic chemotherapy.^26,27,28 In each of these trials, palonosetron resulted in the same or higher complete response rate (no emesis and no use of rescue medication in the acute or delayed phase) than that of the comparator agents, but methodologic concerns limit the conclusions. In two of these trials, corticosteroid administration was allowed, but not required, although dexamethasone is recommended for prophylaxis for moderately and highly emetogenic chemotherapy. Prophylaxis with dexamethasone for delayed symptoms was not included. These trials essentially compared palonosetron with placebo for the delayed phase, because the comparator was not continued for the 3 days. Palonosetron has not been compared with other serotonin antagonists where dexamethasone dosing was included for both the acute and delayed phase.¹⁴ In addition, it has not been compared with regimens containing other 5-HT3 antagonists (in the delayed setting), dexamethasone, and aprepitant. One group of researchers described a three-drug combination of palonosetron, dexamethasone, and aprepitant in a noncomparative, phase II study, and found that the three-drug combination was safe and effective.²⁹ Whether palonosetron is equivalent or superior to other 5-HT3 antagonists will be determined by trials that compare palonosetron with a 5-HT3 antagonist, with both treatment arms consisting of dexamethasone and aprepitant in the acute and delayed phases.

Table 7-3 Antiemetic Agents for Chemotherapy-Induced Nausea and Vomiting (CINV)

Medication (Trade name) Class Indication/Phase Dose in Adults (doses should be given 30–60 minutes before chemotherapy) Dose in Pediatrics Aprepitant (Emend) NK-1 antagonist Acute/Delayed 125 mg PO on day 1, 80 mg PO on days 2,3 Dexamethasone (Decadron) Corticosteroid Acute (high emetogenicity) 12 mg (if with aprepitant) or 20 mg IV or PO Acute (moderate emetogenicity) 8 mg IV or PO Acute (low emetogenicity) 4–8 mg IV or PO Delayed 8 mg PO daily days 2–4 (when with aprepitant) Dolasetron Serotonin antagonist Acute IV: 100 mg or 1.8 mg/kg PO: 100–200 mg 1.8 mg/kg IV or PO Dronabinol (Marinol) Cannabinoid Breakthrough 2.5–10 mg PO TID to QID Droperidol (Inapsine) Butyrophenone Breakthrough 0.625–1.25 mg IV Q 4–6 h PRN 50–60 mcg/kg/dose Granisetron (Kytril) Serotonin antagonist Acute IV:1 mg or 0.01 mg/kg PO: 2 mg 0.01 mg/kg/dose Haloperidol (Haldol) Butyrophenone Breakthrough 0.5–1 mg PO, IV, or IM Q 6 h PRN Metoclopramide (Reglan) Dopamine antagonist Breakthrough 10–20 mg PO or IV Q 6 h PRN 0.1 mg/kg/dose Lorazepam (Ativan) Benzodiazepine Breakthrough 0.5–2 mg PO, IV, IM, or SL Q 6 h PRN 0.05 mg/kg/dose Nabilone (Cesamet) Cannabinoid Refractory CINV 1–2 mg PO BID (max 2 mg PO TID) Olanzapine (Zyprexa) Serotonin/dopamine antagonist Acute/delayed/breakthrough 2.5–10 mg PO QHS Ondansetron (Zofran) Serotonin antagonist Acute (moderate or high emetogenicity) IV: 8–12 mg or 0.15 mg/kg PO: 16–24 mg PO 0.15 mg/kg Q 4 h ×3 doses or 0.45 mg/kg single dose Palonosetron (Aloxi) Serotonin antagonist Acute/delayed IV: 0.25 mg Prochlorperazine (Compazine) Dopamine antagonist Breakthrough 5–10 mg (up to 20 mg) PO, IV, IM Q 4–6 h PRN >2 yo: 0.1–0.15 mg/kg/dose Promethazine Dopamine antagonist Breakthrough 12.5–25 mg PO, IV, IM, PR Q 4–6 h PRN >2 yo: 0.25–1 mg/kg/dose BID, twice daily; IM, intramuscular; IV, intravenous; PO, oral; PR, rectal; PRN, as needed; QHS, every night; QID, four times daily; TID, three times daily. Adapted from references 11, 14, 16, with permission.

Palonosetron is normally administered as a single 0.25 mg IV dose before chemotherapy. Repeated dosing within 1 week is not approved by the U.S. Food and Drug Administration (FDA). With its long elimination half-life, palonosetron should be effective for at least a few days, but little data are published regarding repeated doses. Palonosetron has been studied in a three-dose regimen (administration on days 1, 3, 5) for multiday chemotherapy in a noncontrolled trial published only in abstract form.³⁰ This regimen appeared to be safe and effective, but was not compared with any other regimen.

Other serotonin antagonists, including tropisetron, ramosetron, lerisetron, and others,^31,32 are under development and study.

It is difficult to identify the serotonin antagonist with the highest overall cost-effectiveness because drug acquisition costs vary between the inpatient and outpatient clinics and from institution to institution. Costs of the different agents should be compared at each practice site to determine the preferred agent.

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