4.1 Therapeutic indications
Mundell is indicated to prevent and to treat nausea and vomiting in general

Instructions for use
You must remove the Mundell tablet from packaging with your hands dried and place it immediately on the tip of the tongue in order to dissolve it in saliva in seconds, for further swallowing. It is not necessary to take it with liquids.
Dosage
Prevention of nausea and vomiting in general:
Adult use: 4 tablets of Mundell 4 mg (16 mg of ondansetron)
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Pediatric use: Patients older than 11 years, it is recommended 4 – 8 mg of ondansetron (1 to 2 tablets of Mundell 4 mg).
For children 2 to 11 years: it is recommended 4 mg of ondansetron (1 tablet of Mundell 4 mg).
Table 1. Dosing Table:
POSOLOGY
WEIGHT
AGE
MUNDELL 4 MG
15-30 Kg
2-11 years old
1 tablet
More than 30 Kg
More than 11 years old
2 tablets
Postoperative nausea and vomiting prevention:
Use the same dose recommended for all ages. Administer it 1 hour before anesthesia induction.
Prevention of nausea and vomiting associated with chemotherapy:
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Mundell should be flexible within the therapeutic range and selected as shown below, or the doctor’s discretion.
- Highly emetogenic chemotherapy:
Adults: Single dose of 24 mg of ondansetron (6 tablets of Mundell 4 mg) administered 30 minutes before the start of chemotherapy day.
- Moderately emetogenic chemotherapy:
Adults: 8 mg of ondansetron (2 tablets of Mundell 4 mg), twice a day. The first dose should be administered 30 minutes before starting emetogenic chemotherapy, with subsequent dose 8 hours after the first one. It is recommended to administer 8 mg of ondansetron, twice a day (every 12 hours) for 1 to 2 days after the end of chemotherapy.
Pediatric Use: for patients aged 11 years or more, it is recommended the same dose proposed for adults. For children 2 to 11 years old, it is recommended to administer 4 mg of ondansetron (1 tablet of Mundell 4mg), 3 times a day (every 8 hours) until 1 to 2 days after the end of chemotherapy.
Prevention of nausea and vomiting associated with radiotherapy, in total body irradiation, single high dose fraction or daily fractions to the abdomen:
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Adult: 8 mg of ondansetron (2 tablets of Mundell 4 mg), 3 times a day.
Pediatric use: For children 2 to 11 years old, it is recommended that the dose of 4 mg of ondansetron (1 tablet of Mundell 4 mg), 3 times a day. The first dose should be administered 1 to 2 hours before the start of the radiotherapy treatment, with subsequent doses at every 8 hours after the first dose. It is recommended to administer 4 mg of ondansetron (1 tablet of Mundell 4 mg), 3 times per day (every 8 hours) for 1 to 2 days after the end of radiotherapy treatment.
For patients aged 11 years or more: it is recommended the same dose proposed for adults.
In cases of total body irradiation: 8 mg of ondansetron (2 tablets of Mundell 4 mg), 1 to 2 hours before each daily fractionate dose of radiotherapy.
In cases of abdomen radiotherapy in single high dose: 8 mg ondansetron (2 tablets of Mundell 4 mg), 1 to 2 hours before the radiotherapy, with subsequent doses every 8 hours after the first dose, until 1 to 2 days after the radiotherapy end.
In cases of abdomen radiotherapy in daily fractionated doses: 8 mg ondansetron (2 tablets of Mundell 4 mg) 1 to 2 hours before the radiotherapy, with subsequent doses at every 8 hours after the first dose, during all the radiotherapy treatment.
Patients with renal impairment: It is not necessary to adjust the dose, it is recommended the same dose for population in general.
Patients with hepatic impairment: clearance of ondansetron is significantly reduced and the apparent volume of distribution is increased, resulting in increased plasma half-life in patients with severe hepatic impairment. In these patients, the total daily dose should not exceed 8 mg of ondansetron.
Elderly: It is recommended the same dose for adults.
Route of administration
Oral administration.

Generals - Ondansetron does not stimulate gastric and intestinal peristalsis. It should not be used to replace nasogastric aspiration. The use of ondansetron in patients undergoing abdominal surgery or in patients with nausea and vomiting induced by chemotherapy may mask gastric distention or ileus.
Ondansetron prolongs the QT interval in a dose-dependent manner. Post marketing cases of Torades de Pointes have been reported in patients using ondansetron. The use of ondansetron should be avoid in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop QTc prolongation. These conditions include patients with electrolyte disturbances, patients with congenital long QT syndrome, or patients taking other medications that lead to QT interval prolongation or electrolyte disturbances. Cardiac monitoring is recommended in patients with electrolyte abnormalities (such as hypokalemia or hypomagnesemia), congestive heart failure bradyarrhythmias or patients who are taking other medication at a long QT interval.
This drug should be administered only by recommended to avoid unnecessary risks pathway.
Phenylketonurics: orally disintegrating tablets contain small amount of phenylalanine, a component of aspartame, so they should be administered with caution in these patients. Phenylketonurics: contains phenylalanine.
Warning: This product contains pigments that may possibly cause allergic reactions.
Women of childbearing age should consider using effective contraceptive measures;
Based on epidemiological studies performed in humans, ondansetron is suspected to cause orofacial malformation when administered during the first trimester of pregnancy. For this reason, it is recommended not to use ondansetron during the first trimester of pregnancy.
In a retrospective cohort study that evaluated 1.8 million pregnancies, ondansetron use in the first trimester was associated with an increased risk of oral clefts (three additional cases per 10,000 women treated; adjusted relative risk 1.24, 95% CI: 1.03-1.48);
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Until the moment, animal studies do not indicate direct or indirect harmful effects in relation to reproductive toxicity.
Pediatrics - It is recommended the administration of Mundell in children above 2 years old.
Geriatrics (Elderly) – It is not necessary dosage adjustment in elderly patients, although it should be noted a reduction in clearance and increase in its half-life time in patients above 75 years of age. In clinical studies with cancer patients, safety and efficacy have been proved even in patients older than 65 years.
Liver/kidney impairment - In patients with mild to moderate hepatic impairment, clearance is reduced by twice and the mean half-life is increased for individuals normal. In patients with severe hepatic impairment, clearance is reduced by two to three times the apparent volume of distribution is increased with a consequent increase in half-life to 20 hours.
In patients with severe hepatic impairment is not recommended to exceed daily dose of 8 mg of ondansetron.
Due to the small contribution (5%) of renal clearance in total body clearance is not considered that the renal failure significantly influence the total clearance of ondansetron. Therefore, it is not dose adjustment is required in these patients.

Ondansetron is metabolized in the liver by cytochrome P450 system, and therefore, inhibitors or inducers of these enzymes may alter its clearance and, consequently, the plasma half-life. According to available data, there is no need for dose adjustment of these medicines when administered together.
Caution is required when ondansetron is co-administered with drugs that prolong the QT interval and/or cause electrolyte disturbances.

Pregnancy: Category B. Mundell should not be used by pregnant women without medical or dental surgeon advice.
Breast-feeding: Tests have shown that ondansetron is excreted in the milk of breast-feeding rats. Therefore, caution is advised in the use of ondansetron for women who are breast-feeding.

In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron.

Very common reaction (> 1/10): headache, constipation.
Common reaction (> 1/100 and <1/10): fatigue, diarrhea, skin rash.
Rare reaction (> 1/10,000 and <1 / 1,000): bronchospasm and anaphylaxis.
Unknown frequency: QT interval prolongation (including Torsades de Pointes).
Among the various reactions documented, there are not evidences, in all cases, of reactions with the ondansetron use. In patients submitted to high or moderately emetogenic chemotherapy, symptoms of headache, fatigue and constipation were more frequent relative to the placebo and there were not dependent dose. Other reactions such as diarrhea, dizziness, and extrapyramidal reactions did not shown significantly different regarding the placebo. The significant increase in plasmatic concentration of liver enzymes was showed in 1 to 2% of patients who received ondansetron associated to cyclophosphamide, although these increases were transient and without relation with the dose or duration of therapy. It was noted the presence of cutaneous rash in 1% of patients who received ondansetron during the chemotherapy. The rare cases reported of anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusions and seizures have not demonstrated, except for bronchospasm and anaphylaxis, proven relation with the ondansetron. In patients with nausea and vomiting submitted to radiotherapy, the effects reported possibly associated to the use of ondansetron were similar to patients submitted to chemotherapy. The use of ondansetron in post-operative patients showed an increase in the frequency of headache (9%, compared to 5% for placebo). Rare and isolated cases, not associated to clinical research, were reported as secondary to the administration of injectable drugs, among which are cited: flushing, hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, angioedema, bronchospasm, hypotension, hypopnea, laryngeal edema and stridor). Cases of laryngospasm, cardiac arrest and shock during the administration of injectable drug were also reported.

Symptoms: Short and sudden blindness 2-3 minutes long, severe constipation, hypotension (weakness), vasovagal episode with heart block 2nd degree transition. In all cases, the events were completely solved.
Single intravenous doses up to 150 mg and total daily intravenous doses up to 252 mg administered inadvertently failed to demonstrate the occurrence of adverse events. These doses are more than 10 times the recommended daily dose.
Treatment: There is no specific antidote for ondansetron overdose. Patients should be monitored with appropriate therapeutic support.

ATC code: A04AA01
Mechanism of action: Ondansetron is a selective antagonist of serotonin receptor subtype 3 (5-HT3). While its mechanism of action has not been fully characterized, ondansetron is not a dopamine- receptor antagonist. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both receptors. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. The released serotonin may stimulate the vagal afferent nerves through the 5-HT3 receptors and start the vomiting reflex.
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +9661-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340
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o Website: www.sfda.gov.sa/npc
Please contact the relevant competent authority.
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Pharmacodynamic effects:
In normal volunteers, single intravenous doses of 0.15 mg/kg ondansetron did not affect the motility of the gastrointestinal tract or the pressure of the lower esophageal sphincter. Regular administration was shown to decrease colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.
Ondansetron does not affect the respiratory depressant action induced by alfentanil or the intensity of neuromuscular blockade produced by atracurium. Ondansetron is extensively metabolized in humans, and that only 5% of the active substance is recovered in the urine. The primary metabolic pathway is hydroxylation, followed by conjugation with glucuronide or sulfate. Although some non-conjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.
Clinical efficacy and safety
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by other, no significant effects on the degree of elimination of the drug. Moreover, the elimination of ondansetron can be compromised by inducing cytochrome P-450 system.
Bioavailability is slightly increased in the presence of food, but unaffected by concomitant administration of antacids.
The extent and rate of ondansetron's absorption is greater in women than in men, although it does not identify as a significant clinical difference.
Observed a reduction in clearance and increase in elimination half-life in patients above 75 years of age are not recommended, however, dose adjustment.
In patients with mild to moderate hepatic impairment, clearance is reduced by twice and the mean half-life increased to 11.6 hours compared to 5.7 hours in normal subjects. In patients with severe hepatic impairment, clearance is reduced by two to three times and the apparent volume of distribution is increased with a consequent increase in half-life to 20 hours. In patients with severe hepatic insufficiency, the total daily dose should not exceed 8 mg.
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Due to the small share (5%) of renal excretion in the total clearance of the drug, it is not considered that the renal failure significantly influence the total clearance of ondansetron. Therefore, it is not necessary dose adjustment in patients with renal insufficiency.
In the plasma concentration range between 10 and 500 ng/ml, 70 to 76% of ondansetron is connected to proteins.

Ondansetron is well absorbed from the gastrointestinal tract where it undergoes first-pass metabolism. Mean bioavailability in healthy subjects, following oral administration of 8 mg, is approximately 56%, not observed proportionality to the ingested dose, which may reflect some reduction in the first-pass metabolism. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids.
The extent and rate of ondansetron's absorption are greater in women than men. In patients with mild to moderate hepatic impairment, clearance is reduced by twice and the mean half-life increased to 11.6 hours compared to 5.7 hours in normal subjects. In patients with severe hepatic impairment, clearance is reduced by two to three times and the apparent volume of distribution is increased with a consequent increase in half-life to 20 hours. In patients with severe hepatic insufficiency, the total daily dose should not exceed 8 mg.

Not applicable

Excipients for all ondansetron hydrochloride dihydrate tablets:
Aspartame
Mannitol
Microcrystalline cellulose
Crospovidone
Magnesium stearate
Colloidal silicon dioxide
Stramberry aroma
Iron oxide red dye

Not applicable.

Keep Mundell at room temperature (15 to 30ºC). Protect from light. Store in dry condition.

Blister packs of 10 tablets comprising aluminum blister.

No special requirements.