Dukoral Oral Suspension

Ondansetron is indicated for the prevention and treatment of post-operative nausea and vomiting, and for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Pharmacokinetics:

• Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects is approximately 56% and bioavailability is also slightly enhanced by the presence of food and at higher doses but unaffected by antacids.
• Ondansetron is distributed with volume of distribution of 1.9-2.6 L/Kg, indicating that much of the drug is taken up by body tissues. Circulating drug also distributes into erythrocytes. Plasma protein binding is 70% and crosses membranes readily.
• Biotransformation pathways involve the primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.
• Ondansetron is excreted in the urine (approximately 65%) and feces (35%) after extensive hepatic metabolism. The plasma half-life is 3.5 hours.

Pharmacodinetics: Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

Chemotherapy-induced Nausea and Vomiting-

Adults/Geriatric/Child of 12 years or over:

• Highly emetogenic cancer chemotherapy: 30 ml (24 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy.
• Moderate emetogenic cancer chemotherapy: 10 ml (8 mg) Ondansetron Oral Solution administered 30 minutes before start of emetogenic chemotherapy. A further 10 ml dose should be administered after 8 hours of the first dose. One 10 ml dose should be administered twice a day (every 12 hours) for 1-2 days after completion of chemotherapy.

Pediatric (4-11 years): 5 ml (4 mg) Ondansetron Oral Solution should be taken 30 minutes before the start of chemotherapy. The other 2 doses should be taken 4 and 8 hours after the first dose. Then 5 ml oral solution should be administered 3 times a day (every 8 hours) for 1-2 days after completion of chemotherapy.

Radiotherapy induced Nausea and Vomiting-

Adults/Geriatric/Child of 12 years or over:

• The recommended oral dosage: 10 ml (8 mg) Ondansetron Oral Solution 3 times daily.
• For total body irradiation: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.
• For single high-dose fraction radiotherapy to the abdomen: one 10 ml Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.
• For daily fractionated radiotherapy to the abdomen: 10 ml (8-mg) Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.

Postoperative Nausea and Vomiting-

• Adults/Geriatric/Child of 12 years or over: 20 ml (16 mg) Ondansetron Oral Solution 1 hour before induction of anesthesia

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because Ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of Ondansetron. On the basis of available data, no dosage adjustment of Ondasetron is recommended for patients on these drugs.

Ondansetron oral solution is contraindicated for patients known to have hypersensitivity to the drug.

Frequently reported adverse events were headache, constipation and diarrhea, but the majority have been mild or moderate in nature. In chemotherapy-induced nausea and vomiting, rash has occurred in approximately 1% of patients receiving Ondansetron. There also have been reports to a sensation of flushing or warmth, hiccups and liver enzyme abnormalities. Rare cases of anaphylaxis, brochospasm, tachycardia, angina (chest pain), hypokalemia, shortness of breath have also been reported, except for bronchospasm and anaphylaxis, the relationship to Ondansetron is unclear. There have been no evidence to extrapyramidal reactions, in rare case oculogyric crisis appearing alone, as well as with other dystonic reactions without definitive clinical evidence. In case of PONV, with the exception of headache, rates of these events were not significantly different in the Ondansetron and placebo groups.

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral Ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of Ondansetron up to 15 mg/kg per day did not affect fertility or general reproduction performance of male and female rats.

Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg per day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Ondansetron is excreted in the breast milk of rats. So caution should be exercised when Ondansetron is administered to a nursing women.

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.

There is no specific antidote for Ondansetron overdose. In addition to the adverse events, hypotension (and faintness) occurred in a patient that took 60 ml of Ondansetron oral solution. In all instances, the events resolved completely.

Anti-emetic drugs.

Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population.

Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment, a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.

Little information is available about dosage in pediatric patients 4 years of age or younger.

Dosage adjustment is not needed in patients over the age of 65.

Store in a cool and dry place below 30ºC. Protect from light. keep out of reach of children.