Antiemetics, Selective 5-HT3 Antagonists

Jonathan Theriot; Harrison Wermuth; John Ashurst

Antiemetics, Selective 5-HT3 Antagonists

Author: Jonathan Theriot Author: Harrison R. Wermuth Editor: John V. Ashurst Updated: 4/19/2024 2:50:13 PM

Indications

The 5-HT3 receptor antagonists available on the US market include dolasetron, granisetron, palonosetron, and ondansetron.[1] Dolanestron, granisetron, and ondansetron are first-generation 5-HT3 receptor antagonists. Palonosetron is a second-generation 5-HT3 receptor antagonist.[2] Tropisetron and ramosetron are not available in the US.[1]

Serotonin binding to 5-HT3 receptors triggers nausea and vomiting.[3] Serotonin 5-hydroxytryptamine-3 (5-HT3) receptor antagonists exert their activity on receptors located peripherally on gastrointestinal (GI) vagal nerve terminals and centrally in the chemoreceptor trigger zone (CTZ).[4]

Chemotherapy-induced nausea and vomiting (CINV) may be acute or delayed.[5] Acute CINV usually starts within 2 hours of chemotherapy administration and may last up to 24 hours. Delayed CINV starts 24 hours or more and lasts up to 5 days after chemotherapy administration.[5][6] Breakthrough CINV starts 5 days after chemotherapy administration.[7] Serotonin can trigger acute CINV.[5] Therefore, All 5-HT3 receptor antagonists are effective in preventing acute CINV.[8] Other neurotransmitters may be involved in the pathophysiology of delayed CINV, which explains the limited efficacy of 5-HT3 receptor antagonists in preventing delayed CINV.[5] However, ondansetron and palonosetron prevent delayed CINV in addition to acute CINV.[8][9] Palonosetron is more effective than ondansetron in preventing delayed CINV.[8] Granisetron extended-release subcutaneous formulation is indicated for acute and delayed CINV.[10] Granisetron extended-release subcutaneous formulation is associated with less unscheduled rescue hydration to treat breakthrough CINV compared to palonosetron.[11]

FDA-Approved Indications

Prevention of chemotherapy-induced nausea and vomiting and radiation-induced nausea and vomiting

Dolanestron
Granisetron
Ondansetron
Palonosetron [1]

The manufacturer's labeling for dolasetron, granisetron (excluding extended-release subcutaneous formulation), or ondansetron does not specify if the indication is to prevent acute or delayed CINV. Palonosetron's manufacturer labeling specifies its indication to prevent acute and delayed CINV.[8] Granisetron (extended-release subcutaneous) is indicated for the prevention of acute and delayed CINV.[11]

Prevention of postoperative nausea and vomiting

Granisetron
Ondansetron
Palonosetron [1]

Off-label Uses

Ondansetron is used to treat nausea and vomiting associated with pregnancy, but data to support its safety is limited.[12] The risk of fetal cleft palate is increased 2-fold with the use of ondansetron in the first trimester.[13]

Mechanism of Action

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Mechanism of Action

Gastric irritation or cellular damage triggers the intestinal release of 5-HT, which binds to 5-HT3 receptors in the GI tract. The activation of the 5-HT3 receptors triggers nausea and vomiting.[1] Serotonin 5-HT3 receptor antagonists inhibit the activation of the 5-HT3 receptors peripherally and centrally, resulting in antiemetic effects.[1] Palonosetron has a higher binding affinity to the 5-HT3 receptors than the first-generation 5-HT3 receptor antagonists.[3] Additional receptors that trigger nausea and vomiting include dopamine D2 receptors, muscarinic M1 cholinergic receptors, histamine H1 receptors, cannabinoid receptors, and neurokinin-1 (NK1) receptors. Therefore, 5-HT3 receptor antagonists do not treat all causes of emesis. Antiemetics with different mechanisms of action target the other receptors.[1]

Pharmacokinetics

Absorption: Ondansetron, granisetron, and dolasetron have a rapid and complete absorption following oral administration.[14][15][16]

Distribution: Ondansetron has a wide volume of distribution and is about 70% bound to plasma proteins.[14] Granisetron has a high volume of distribution.[15]

Metabolism: Different enzymes of the CYP-450 enzyme system metabolize each of the 5-HT3 receptor antagonists.[3] Patients with high CYP2D6 enzyme activity are less responsive to 5-HT3 receptor antagonists. Ondansetron undergoes hepatic metabolism by CYP3A4, CYP2D6, and CYP1A2. Granisetron undergoes first-pass metabolism by CYP2D6.[3] Ondansetron and granisetron have a bioavailability of 60%.[14][15] The bioavailability of ondansetron in cancer patients is slightly higher.[14][15] Smoking induces the metabolism of granisetron.[17] Dolasetron is a prodrug that undergoes hepatic metabolism to an active metabolite, hydrodolasetron.[16][18] Hydrodolasetron undergoes metabolism by CYP 2D6.[3] Polanosetron undergoes hepatic metabolism and has a bioavailability of about 97% after oral administration.[19]

Elimination: Ondansetron undergoes extensive hepatic metabolism to inactive metabolites.[14] The elimination half-life for ondansetron is about 4 hours. Granisetron undergoes 12% renal excretion.[15] The elimination half-life for granisetron is about 4 to 6 hours. Dolasetron has a half-life of less than 10 minutes, while hydrodolasetron has a half-life of about 7 hours.[3] Unchanged dolasetron undergoes less than 1% excretion in the urine.[16] Polanosetron is longer acting than the first-generation 5-HT3 receptor antagonists and has an elimination half-life of about 40 hours.[19][3] Polanosetron undergoes about 80% renal excretion, with 40% of the drug being excreted unchanged.

Administration

5-HT3 receptor antagonists come in various formulations, offering multiple administration routes.[20] These include oral tablets, orally disintegrating tablets, oral soluble film, oral solution, intramuscular (IM) injection, intravenous (IV) injection, subcutaneous (SubQ) injection, and transdermal patch.[21][22] Palonosetron comes in an IV formulation. Ondansetron is available as oral tablets, orally disintegrating tablets, an oral solution, and IV and IM formulations. Dolasetron comes in an oral tablet and IV solution. Granisetron is available as an oral tablet, oral solution, transdermal patch, an IV formulation, and extended-release SubQ injection. The extended-release subcutaneous formulation of granisetron is long-acting and provides a therapeutic drug concentration for up to 5 days post-injection and is effective for delayed CINV, in addition to acute CINV.[10]

Common dosing and administration regimens for adults include, but are not limited to:

Ondansetron:
- For nausea and vomiting prophylaxis, chemotherapy-related:
  - IV: (moderately to highly emetogenic chemo): 0.15 mg/kg/dose (maximum 16 mg/dose) every 4 hours for 3 doses.[23] Treatment should be initiated 30 minutes before chemotherapy.
  - PO: (highly emetogenic chemo): 24 mg once 30 minutes before chemotherapy; ODT dose forms should not be chewed or crushed.
  - PO: (moderately emetogenic chemo): 8 mg every 8 hours for 2 doses, then 8 mg every 12 hours until 1 or 2 days after chemotherapy completion. Chemotherapy should be started 30 minutes before. Again, ODT dosage forms should not be cut, crushed, or chewed.
- Nausea and vomiting prophylaxis, post-operative: 4 mg intramuscularly (IM) or intravenously (IV) for 1 dose.[24]
- Nausea and vomiting prophylaxis, radiotherapy-related (total body): 8 mg PO for 1 dose, given 1 to 2 hours before each therapy fraction; ODT dosage forms should not be cut, crushed, or chewed.[25]
Granisetron:
- Nausea and vomiting prophylaxis, chemotherapy-related: 10 μg/kg IV 30 minutes before chemotherapy; oral dose within 1 hour before chemo. Alternately, 2 mg PO once or 1 mg PO every 12 hours for 2 doses.[15] Granisetron should only be administered on the days of chemotherapy
- Nausea and vomiting prophylaxis, radiotherapy-related: 2 mg orally for a single dose; treatment should be started within 1 hour of radiotherapy.[26]
- Nausea and vomiting prophylaxis, post-operative: 5-20 μg/kg IV as a single dose administered at the end of surgery.[27]
Palonosetron:
- Nausea and vomiting prevention, chemotherapy-related: 0.25 mg IV for 1 dose, started 30 minutes before chemotherapy.[28]
- Nausea and vomiting prophylaxis, post-operative: 0.075 mg IV for a single dose, started immediately before anesthesia induction.[29]

The American Society of Clinical Oncology (ASCO) guidelines suggest administering granisetron extended-release subcutaneous injection or granisetron transdermal patch to patients undergoing a multiday chemotherapy cycle instead of administering a 5-HT3 receptor antagonist each day of the multiday cycle.[30]

Special Patient Populations

Hepatic impairment: Ondansetron requires dosage adjustment in patients with severe hepatic impairment.[14] Palonosetron, dolasetron, and granisetron do not require a hepatic dosage adjustment

Renal adjustment: Ondansetron, palonosetron, and dolasetron do not require renal dosage adjustment. Granisetron requires renal dosage adjustment and is contraindicated in patients with a creatinine clearance of less than 30 mL/min.

Pregnancy considerations: Ondansetron for nausea and vomiting: 4 mg PO every 8 hours in pregnant women who are not dehydrated or 8 mg IV every 12 hours to be infused over 15 minutes.[31]

Older patients: Ondansetron does not require dosage adjustment in older adults.[14]

Adverse Effects

The serotonin 5-HT3 receptor antagonists share a similar safety and tolerability profile.[32]

Most Common Adverse Reactions [1][33]

Headache (9% to 27%)
Fatigue (9% to 13%)
Malaise (9% to 13%)
Constipation (6% to 11%)

One Percent to 10%

Drowsiness, sedation, dizziness, agitation, anxiety, paresthesia, the sensation of cold, pruritus, skin rash, diarrhea, gynecologic disease, urinary retention, transient increase (greater than 2-fold) of serum aminotransferases, injection site reaction, hypoxia, fever.[34]

5-HT3 receptor antagonists carry a risk of dose-dependent QT prolongation.[35] The Food and Drug Administration (FDA) issued a warning about the risk of QT prolongation associated with a single dose of 32 mg intravenous (IV) ondansetron.[35] Most published literature shows that the risk of QT prolongation with 5-HT3 antagonists is clinically insignificant in healthy patients. A review of several studies conducted on healthy patients concludes that dolasetron carries the highest risk of QT prolongation, followed by ondansetron and then granisetron.[36] Further studies are needed to determine the cardiovascular safety of 5-HT3 antagonists in patients with cancer, polypharmacy, and other cardiotoxic medications.[36] Experts recommend using the antiemetic agent with the least known QT prolongation, such as polanosetron, in patients at risk of QT prolongation.[3]

Pregnancy

5-HT3 receptor antagonists are FDA pregnancy category B. Available human studies examining early pregnancy conclude there is not a high risk of congenital malformations. There is a small increased risk of septal defects and cleft palate. Animal studies show no increased risk during early pregnancy. The presence or absence of 5-HT3 receptor antagonists in breast milk has not been established. The American Academy of Obstetrics and Gynecology (ACOG) guidelines provide a treatment algorithm for nausea and vomiting in pregnancy. Ondansetron can be added for patients who remain symptomatic despite the use of a pyridoxine/doxylamine combination along with adjunct therapy.[37] In patients without dehydration, the ACOG guideline recommends oral ondansetron. In patients with dehydration receiving IV fluid replacement, the ACOG guideline recommends IV ondansetron.

Drug-Drug Interactions

The 5-HT3 receptor antagonists are metabolized by different isoenzymes of the cytochrome P450 (CYP450) system.[38][39][40] Therefore, these drugs will likely interact with many prescription or over-the-counter medications and supplements. The clinical significance of the 5-HT3 drug-drug interactions is uncertain because studies are limited.[18] An in-vitro study showed that ketoconazole inhibits the metabolism of granisetron.[18] Granisetron does not inhibit CYP450 enzymes. Ondansetron is metabolized by CYP3A4, CYP2D6, and CYP1A2 enzymes. Therefore, medications that induce or inhibit these CYP450 isoenzymes alter the metabolism of ondansetron. However, ondansetron dosage adjustment is not recommended. Dolasetron is a prodrug activated by CYP450 enzymes in the liver.[18] Drug interactions with commonly used chemotherapy drugs are not clinically significant. The manufacturer of dolasetron does not recommend dosage adjustments. The World Health Organization (WHO), the Food and Drug Administration (FDA), and Health Canada (HC) requested that manufacturers of 5-HT3 receptor antagonists include the risk of serotonin syndrome in drug labeling.[41] However, there is insufficient evidence that administering 5-HT3 receptor antagonists with other serotonergic drugs contributes to the development of serotonin syndrome. The first-generation 5-HT3 receptor antagonists, dolasetron, ondansetron, granisetron, and tropisetron, may cause QT prolongation.[42] Palonosetron does not cause a clinically significant QT prolongation.

Contraindications

The major relative contraindications include the following:

Hypersensitivity to 5-HT3 receptor antagonists or any formulation components due to cross-reactivity concerns.
Concomitant use with apomorphine due to concern for a decreased level of consciousness and hypotension.[43]

Box Warnings

The 5-HT3 receptor antagonist labeling includes a warning about the risk of serotonin syndrome in combination with other serotonergic drugs. However, the evidence is limited.[41] The 5-HT3 receptor antagonists are associated with a varying level of QT prolongation based on the agent.[2] Ondansetron ODT contains a small amount of phenylalanine. Patients with phenylketonuria cannot metabolize phenylalanine.[44]

Monitoring

Baseline ECG for at-risk patient populations should be obtained, and sodium, potassium, calcium, and magnesium serum levels should be monitored.[45]

Arrhythmia

5-HT3 receptor antagonists have been associated with cardiac arrhythmia.[46] The risk of arrhythmia with 5-HT3 receptor antagonists increases with the concomitant use of other QT-prolonging agents, intravenous route of administration, and patients with a significant medical history.[47] Healthcare professionals should use 5-HT3 receptor antagonists with caution in patients with a history of congenital long QT syndrome, ventricular arrhythmias, cardiac disease, electrolyte abnormalities, or concomitant cardiotoxic chemotherapy.

Serotonin Syndrome

Evidence is insufficient to conclude that 5-HT3 receptor antagonists contribute to the development of serotonin syndrome.[41] However, the World Health Organization (WHO), the US Food and Drug Administration (FDA), and Health Canada suggest a risk of serotonin syndrome by using 5-HT3 receptor antagonists in combination with other serotonergic drugs. The package inserts for the 5-HT3 receptor antagonist require healthcare professionals to monitor patients for signs of serotonin syndrome.[41] Signs and symptoms include mental status changes, autonomic instability, tachycardia, labile blood pressure, diaphoresis, flushing, neuromuscular changes, GI symptoms, and seizures.[48] If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonists and initiate supportive management.

Constipation

Constipation is a commonly reported adverse effect with all formulations of 5-HT3 receptor antagonists.[49] Therefore, healthcare professionals should closely monitor patients at risk of intestinal obstruction.[46]

Toxicity

Overdose is rare, and there is no fatal dose yet established. 5-HT3 receptor antagonists have a broad therapeutic index with mild side effects that occur infrequently. There is no antidote for 5-HT3 receptor antagonists.[50] Therefore, the healthcare team treats patients with supportive therapy, such as IV fluid resuscitation and norepinephrine infusions. In a case report of intentional granisetron overdose, the patient presented with significant hemodynamic instability, characterized by hypotension and ECG changes.[50]

Enhancing Healthcare Team Outcomes

Nausea and vomiting can negatively impact a patient's health and quality of life, especially when induced by cancer treatment. CINV is associated with increased healthcare costs.[51] An interdisciplinary team can ensure that antiemetic guidelines are appropriately followed. Physicians, physician assistants, and nurse practitioners can identify patient-specific factors that increase the risk of CINV, such as female gender, age less than 50 years, and anxiety.[52] Nurses can assess patient history to anticipate nausea and vomiting and advocate to premedicate patients. Pharmacists can identify the emetogenic risk of cancer medications, identify drug interactions and adverse effects, and recommend the appropriate monitoring parameters.[53] An interdisciplinary team can work together to ensure patients understand the antiemetic role of 5-HT3 receptor antagonists in preventing CINV. This will help increase adherence when the healthcare team prescribes additional doses of 5-HT3 receptor antagonists for the patient to take at home.[54]

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