Ondansetron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONDANSETRON (ONDANSETRON)

Composition:

Active substance: ondansetron;

1 tablet contains 4 mg or 8 mg of ondansetron hydrochloride dihydrate (calculated as ondansetron);

Excipients: pregelatinized starch, lactose monohydrate, microcrystalline cellulose, magnesium stearate;

Film-coating: hypromellose, copovidone, polyethylene glycol, medium-chain triglycerides, polydextrose, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, yellow to brownish-yellow in color.

Pharmacotherapeutic group.
Antiemetic agents and drugs for relief of nausea. Serotonin 5-HT3 receptor antagonists. ATC code A04AA01.

Pharmacological Properties

Pharmacodynamics

Ondansetron is a potent, highly selective antagonist of 5-HT₃ (serotonin) receptors. The drug prevents or relieves nausea and vomiting induced by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron has not been fully elucidated. It is likely that the drug blocks the initiation of the vomiting reflex by exerting antagonistic effects on 5-HT₃ receptors located in neurons of both the peripheral and central nervous systems. The drug does not reduce psychomotor activity and does not produce sedative effects.

Pharmacokinetics

After oral administration, ondansetron is completely absorbed via passive absorption from the gastrointestinal tract and undergoes first-pass metabolism. Plasma concentrations reach peak levels approximately 1.5 hours after administration. Doses exceeding 8 mg increase systemic exposure to ondansetron to a greater extent than proportionally, which may indicate reduced first-pass metabolism at higher oral doses.

Ondansetron is eliminated from systemic circulation through extensive enzymatic metabolism, primarily in the liver. Less than 5% of the drug is excreted unchanged in urine. The distribution of ondansetron is similar after oral, intramuscular, or intravenous administration: elimination half-life is approximately 3 hours (5 hours in elderly patients), and the volume of distribution at steady state is nearly 140 L. Plasma protein binding ranges from 70% to 76%. In patients with moderate renal impairment (creatinine clearance 15–60 mL/min), both systemic clearance and volume of distribution of ondansetron are reduced, resulting in a clinically insignificant prolongation of elimination half-life. Pharmacokinetics of ondansetron are practically unchanged in patients with severe renal impairment undergoing chronic hemodialysis (studies were conducted between hemodialysis sessions). In patients with severe chronic hepatic impairment, systemic clearance of ondansetron is markedly reduced, with a prolonged elimination half-life (15–32 hours). The absence of CYP2D6 enzyme does not affect ondansetron pharmacokinetics. Pharmacokinetic properties of ondansetron do not change with repeated administration. Oral bioavailability and elimination half-life of ondansetron are slightly increased in elderly patients, although the changes are clinically insignificant.

In women, absorption of the oral dose occurred more rapidly and to a greater extent, while systemic clearance and volume of distribution were lower.

The bioavailability of the drug is slightly higher when administered with food, but antacids do not affect its bioavailability.

Clinical characteristics.

Indications.

Prevention and treatment of nausea and vomiting caused by cytotoxic chemotherapy or radiotherapy. Prevention of nausea and vomiting in the postoperative period.

Contraindications.

• Hypersensitivity to the components of the drug and to other selective 5HT3 serotonin receptor antagonists;
• concomitant use with apomorphine;
• severe hepatic impairment;
• abdominal surgery.

Interaction with other medicinal products and other forms of interaction.

Ondansetron does not accelerate or inhibit the metabolism of other drugs when administered concomitantly. Specific studies have shown that ondansetron does not interact with ethanol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol.

Ondansetron is metabolized by the hepatic cytochrome P450 enzyme system: CYP3A4, CYP2D6, and CYP1A2. Due to the diversity of enzymes involved in ondansetron metabolism, inhibition or reduced activity of one of them (e.g., genetic deficiency of CYP2D6) is normally compensated by other enzymes and will not affect the overall clearance of ondansetron, or the effect will be negligible.

Caution should be exercised when ondansetron is used concomitantly with drugs that cause disturbances in electrolyte balance.

Drugs that prolong the QT interval: possible additive QT prolongation.

Serotonergic agents (e.g., SSRIs and SNRIs). Serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) has been reported following concomitant use of ondansetron and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (see section "Special precautions").

Apomorphine: concomitant use is contraindicated, as cases of severe arterial hypotension and loss of consciousness have been observed.

Cardiotoxic drugs (anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (e.g., erythromycin), antifungals (e.g., ketoconazole), antiarrhythmics (amiodarone), and beta-blockers (atenolol or timolol): increased risk of developing arrhythmias.

Phenytoin, carbamazepine, and rifampicin: during treatment with potential CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), ondansetron clearance is increased and its blood concentration is reduced.

Tramadol: according to some clinical studies, ondansetron may reduce the analgesic effect.

Special precautions for use.

Ondansetron is not effective in preventing nausea and vomiting due to motion sickness.

Cases of cross-sensitivity to various 5-HT3 receptor antagonists have been reported. Therefore, in patients with hypersensitivity to one of the 5-HT3 receptor antagonists, a similar reaction to other antagonists may be more pronounced due to cross-reactions. If even a mild hypersensitivity reaction occurs to any of the 5-HT3 receptor antagonist drugs, switching to another 5-HT3 antagonist is not recommended due to the potential for an enhanced hypersensitivity reaction.

Respiratory-related adverse reactions should be treated symptomatically. Healthcare providers should pay special attention to these reactions, as they may be signs of drug hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner. Cases of ventricular fibrillation/torsade de pointes have been reported with ondansetron use. Ondansetron should be avoided in patients with congenital long QT syndrome. Ondansetron should be used with caution in patients who have or may develop QT interval prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, and patients receiving other medicinal products that may cause QT prolongation or electrolyte imbalances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly following intravenous administration, symptoms occurred immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischemia.

Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic drugs (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant treatment with ondansetron and other serotonergic drugs is clinically justified, appropriate patient monitoring is recommended.

Since ondansetron reduces gastrointestinal motility, careful monitoring is required in patients showing signs of subacute intestinal obstruction during treatment.

In patients undergoing adenoidectomy or tonsillectomy, the use of ondansetron for the prevention of nausea and vomiting may mask the occurrence of postoperative bleeding. Therefore, such patients require careful monitoring after ondansetron administration.

Ondansetron does not affect the cytochrome P450 enzyme system; however, the use of other drugs that may influence the activity of these enzymes can lead to changes in ondansetron clearance and elimination half-life.

In children receiving ondansetron concomitantly with hepatotoxic chemotherapeutic agents, careful monitoring for possible liver function abnormalities is required.

Nausea and vomiting following chemotherapy: when dosing based on body weight and administering three doses at 4-hour intervals, the total daily dose will be higher than when administering a single dose of 5 mg/m² followed by oral administration. The comparative efficacy of these two different dosing regimens has not been studied in clinical trials. Cross-trial comparisons suggest similar efficacy for both regimens.

Patients with carbohydrate intolerance, including rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption, should not take this medicinal product due to the presence of carbohydrates, including lactose, in the tablet formulation.

Use during pregnancy or breastfeeding.

If a woman of childbearing potential uses ondansetron, contraception should be considered.

Epidemiological studies indicate that ondansetron may cause craniofacial malformations when used during the first trimester of pregnancy. In one cohort study involving 1.8 million pregnancies, ondansetron use during the first trimester was associated with an increased risk of orofacial clefts (3 additional cases per 10,000 women exposed to ondansetron; adjusted relative risk 1.24, 95% confidence interval: 1.03–1.48). Available epidemiological data on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects on reproductive performance. Ondansetron should not be used during the first trimester of pregnancy.

Breastfeeding should be discontinued during treatment with this medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Given the potential for nervous system-related adverse reactions, patients should be advised to refrain from driving or operating machinery while being treated with this medicinal product.

Administration and Dosage

The medicinal product should be administered orally.

When administering cytostatic therapy, the dosage regimen should be determined individually, depending on the severity of the vomiting reaction.

Moderate emetogenic chemotherapy and radiation therapy

Adults: orally, initially 8 mg 1–2 hours before the start of anticancer therapy, followed by another 8 mg dose 12 hours later.

To prevent delayed or prolonged nausea and vomiting after the first 24 hours, continue the treatment with 8 mg every 12 hours for 5 days.

For partial high-dose abdominal irradiation, administer 8 mg every 8 hours. The drug should be taken throughout the entire course of chemotherapy and radiation therapy, as well as for 1–2 days (if necessary, 3–5 days) after completion of therapy.

Highly emetogenic chemotherapy

Adults: orally, administer 24 mg of ondansetron (concomitantly with dexamethasone phosphate) 1–2 hours before the start of chemotherapy. To prevent delayed vomiting in the following days, administer 8 mg twice daily throughout the entire chemotherapy course and for 5 days after its completion.

Children. This medicinal form should not be used in children under 4 years of age. Pediatric doses should be calculated based on body surface area or body weight. If a 2 mg dose of ondansetron is required, a formulation with appropriate dosage strength or another pharmaceutical form should be used.

Dosage calculation based on body surface area. Immediately before chemotherapy, administer ondansetron (injection solution) as a single intravenous injection at a dose of 5 mg/m²; the intravenous dose must not exceed 8 mg. Oral administration should be initiated 12 hours after the intravenous dose and continued for up to 5 days. The total daily dose of ondansetron must not exceed 32 mg.

Dosage calculation based on body weight. Immediately before chemotherapy, administer ondansetron (injection solution) as a single intravenous injection at a dose of 0.15 mg/kg body weight; the intravenous dose must not exceed 8 mg. Subsequently, two additional intravenous injections may be administered at 4-hour intervals. The total daily dose of ondansetron must not exceed 32 mg. Oral administration should be initiated 12 hours after the intravenous dose and continued for up to 5 days.

Postoperative nausea and vomiting

Adults: administer 16 mg one hour before the start of anesthesia.

The maximum daily dose of ondansetron is 32 mg; for patients with hepatic impairment – 8 mg.

Children: for this indication, ondansetron is recommended in the form of an injection solution.

All types of therapy

Elderly patients.

There is no need to adjust the dosage for patients aged 65 years and older.

Patients with renal impairment.

There is no need to adjust the dosage regimen or route of administration in patients with impaired renal function.

Patients with moderate hepatic impairment.

In patients with moderate hepatic impairment, ondansetron clearance is significantly reduced and the serum elimination half-life is prolonged. In such patients, the maximum daily dose of the drug should not exceed 8 mg.

Patients with defective sparteine/debrisoquine metabolism. The elimination half-life of ondansetron in patients with defective sparteine and debrisoquine metabolism is not altered. After repeated administration, drug concentrations in these patients are similar to those in patients with normal metabolism. Therefore, dosage adjustment is not required in this patient group.

Children.

This medicinal product is not recommended for children under 4 years of age.

Overdose.

Currently, experience with ondansetron overdose is limited. In most cases, symptoms are similar to those observed in patients receiving recommended doses.

Symptoms: visual disturbances, constipation, arterial hypotension, vasovagal disturbances with transient atrioventricular block. Ondansetron prolongs the QT interval in a dose-dependent manner. In case of overdose, ECG monitoring is recommended.

Children: serotonin syndrome has been reported in infants and children aged 12 months to 2 years following accidental overdose of the oral formulation (doses exceeding the recommended level of 4 mg/kg).

Treatment: discontinue the drug, provide symptomatic and supportive therapy. Ipecacuanha is not recommended due to the antiemetic effect of the drug itself. There is no specific antidote.

Adverse Reactions

Immune system: Immediate-type allergic reactions, sometimes severe, including anaphylactic reactions, angioedema, anaphylactic shock, bronchospasm, vascular edema, pruritus, skin rashes, urticaria.

Nervous system: Headache, myoclonus, seizures, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences), gait disturbances, chorea, restlessness, burning sensation, tongue protrusion, diplopia, central nervous system depression, paresthesia; dizziness, mainly during rapid intravenous administration of the drug.

Eye organs: Transient visual disturbances (blurred vision), transient blindness, mainly during intravenous administration. In most cases, blindness resolves within 20 minutes.

Cardiovascular system: Chest pain and discomfort, cardiac area pain (with or without ST segment depression), arrhythmias, extrasystoles, tachycardia, including ventricular and supraventricular tachycardia, atrial fibrillation, palpitations, bradycardia, myocardial ischemia (see section "Special Instructions"), arterial hypotension, arterial hypertension, QT interval prolongation (including ventricular flutter/fibrillation ("torsade de pointes")), sensation of warmth, flushing, syncope, ECG changes.

Respiratory system: Hiccups, cough.

Gastrointestinal tract: Constipation, diarrhea, dry mouth.

Hepatobiliary system: Asymptomatic elevation of liver function parameters, liver function impairment.

General disorders: Weakness, loss of consciousness.

These cases occur mainly in patients undergoing chemotherapy with cisplatin-containing agents.

Metabolism: In approximately 5% of patients, there was a transient increase of more than two times the upper limit of normal in aspartate aminotransferase and alanine aminotransferase levels. It is unknown whether this increase is related to dose or duration of therapy.

Cases of liver failure and fatal outcomes have been reported in cancer patients receiving multiple drugs, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of liver failure in these cases remains unclear. Rare reports of hypokalemia have also been documented.

Other: Increased body temperature.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Packaging. 10 tablets in a blister, 1 blister per pack.

Prescription category. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical-Pharmaceutical Plant".

Manufacturer's address and place of business.
Ukraine, 03134, Kyiv, Miru Street, 17.