VEMTIX INJECTION

Indications

• Prevention of nausea and vomiting induced by cytotoxic chemotherapy
• Prevention of nausea and vomiting associated with radiotherapy
• Prevention and treatment of postoperative nausea and vomiting

Dosage

Adults: Refer to BNF for specific dosing guidelines, which typically suggest an initial dose of 8 mg given orally or intravenously, with further doses administered based on clinical need and circumstances

Mechanism of action

Ondansetron selectively antagonizes the serotonin receptor subtype 5-HT3. It blocks the stimulation of these receptors located on vagal afferents, which are activated during the release of serotonin from enterochromaffin cells in the small intestine due to cytotoxic chemotherapy and radiotherapy. This action prevents the initiation of the vomiting reflex that would otherwise occur. Additionally, ondansetron may inhibit serotonin release from the chemoreceptor trigger zone in the area postrema of the central nervous system.

Pharmacodynamics

Ondansetron exhibits high specificity and selectivity for the 5-HT3 receptor, with minimal activity at other serotonin receptor subtypes and low affinity for dopamine receptors. By blocking 5-HT3 receptors both peripherally and centrally, ondansetron effectively reduces the emetic response caused by the release of serotonin during chemotherapy or surgery. Its pharmacodynamic profile suggests that it does not significantly alter other neurotransmitter systems, thereby limiting potential side effects related to dopamine.

Pharmacokinetics

Ondansetron is rapidly absorbed, with peak plasma concentrations occurring approximately 1 to 2 hours post-administration. The drug has a volume of distribution of about 1-2 L/kg and is primarily metabolized in the liver via cytochrome P450 enzymes, notably CYP3A4. It has an elimination half-life of approximately 3 to 6 hours, with renal excretion of metabolites being the primary route of elimination. The pharmacokinetics may vary based on the method of administration (oral, intravenous) and patient-specific factors such as age and hepatic function.

Contra-indications

• Hypersensitivity to ondansetron or any component of the formulation
• Concurrent use with apomorphine due to risk of profound hypotension and loss of consciousness

Adverse effects

• Headache
• Dizziness
• Constipation
• Diarrhea
• Fatigue
• Transaminase elevations
• QT interval prolongation

Interactions

• May enhance the effects of serotonergic drugs, increasing the risk of serotonin syndrome
• Caution with drugs that prolong the QT interval, as ondansetron itself may cause QT prolongation
• Apomorphine: contraindicated due to hypotensive effects

Precautions

• Use with caution in patients with a history of cardiac arrhythmias or those with electrolyte imbalances
• Monitor patients for signs of serotonin syndrome when used with other serotonergic agents
• Caution in patients with hepatic impairment, as dosage adjustment may be necessary

Pregnancy

Limited data on the use of ondansetron during pregnancy. Use only if potential benefits justify potential risks to the fetus.

Breast-feeding

Ondansetron is excreted in breast milk; caution is advised when used during breastfeeding.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution
• Injection solution

Mechanism of action

Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established.

Pharmacodynamics

Ondansetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors,. The serotonin 5-HT₃ receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema,. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract,. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT₃ receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting,. Moreover, the effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33=QTcF) was observed from 15 min to 4 h after the start of the 15 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes. The 32 mg intravenous dose of ondansetron must not be administered. No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose. An ECG assessment study has not been performed for orally administered ondansetron. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0). The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations. In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations.