Ondansetron

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

Composition:

Active ingredient: ondansetron;

1 ml of the preparation contains 2 mg of ondansetron hydrochloride dihydrate (calculated as ondansetron);

Excipients: citric acid monohydrate, sodium citrate, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

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

Pharmacological properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective antagonist of 5-HT3 (serotonin) receptors. The medicinal product prevents or eliminates nausea and vomiting caused by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron is not fully understood. It is likely that the drug blocks the vomiting reflex by antagonizing 5-HT3 receptors located on neurons of both the peripheral and central nervous systems. The drug does not reduce psychomotor activity and does not produce sedative effects.

Pharmacokinetics.

After intramuscular administration, peak plasma concentration is reached within 10 minutes. The volume of distribution following parenteral administration in adults is 140 L. The majority of the administered dose undergoes hepatic metabolism. Less than 5% of the drug is excreted unchanged in urine. The elimination half-life is approximately 3 hours (in elderly patients – 5 hours). 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 slight and clinically insignificant prolongation of the drug's elimination half-life. The pharmacokinetics of ondansetron is practically unchanged in patients with severe renal impairment undergoing regular hemodialysis (studies were conducted between hemodialysis sessions). In patients with severe chronic hepatic impairment, systemic clearance of ondansetron is markedly reduced, leading to an increased elimination half-life (15–32 hours).

Clinical characteristics.

Indications.

Nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.

Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

• Hypersensitivity to any component of the medicinal product;
• Concomitant use with apomorphine hydrochloride.

Interaction with other medicinal products and other forms of interaction.

The preparation should not be mixed in the same syringe or infusion set with other medicinal products, except as specified in the section "Instructions for use and dosage".

Ondansetron does not accelerate or inhibit the metabolism of other drugs when used concomitantly. Ondansetron does not interact with alfentanil, tramadol, morphine, lidocaine, ethanol, temazepam, furosemide, 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 significantly affect the overall clearance of the drug.

Caution is advised when using ondansetron concomitantly with drugs that prolong the QT interval and/or cause electrolyte imbalances (see section "Special precautions").

Use of ondansetron with drugs that prolong the QT interval may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g., anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (erythromycin), antifungal agents (ketoconazole), antiarrhythmic drugs (amiodarone) and beta-blockers (atenolol or timolol) may increase the risk of developing arrhythmias.

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

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe arterial hypotension and loss of consciousness have been observed.

Caution should be exercised when using concomitantly:

• with inducers of CYP2D6 and CYP3A4 enzymes (barbiturates, carbamazepine, carisoprodol, glutethimide, griseofulvin, nitrous oxide, papaverine, phenylbutazone, phenytoin, rifampicin, tolbutamide) — ondansetron clearance increases and its blood concentration decreases;
• with inhibitors of CYP2D6 and CYP3A4 enzymes (allopurinol, macrolide antibiotics, antidepressants (MAO inhibitors), chloramphenicol, cimetidine, estrogen-containing oral contraceptives, diltiazem, disulfiram, fluconazole, fluoroquinolones, isoniazid, ketoconazole, lovastatin, metronidazole, omeprazole, propranolol, quinidine, quinine, verapamil).

Ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use.

In patients with hypersensitivity to other selective 5HT3 receptor antagonists, hypersensitivity reactions have been observed.

In patients with moderate to severe hepatic impairment, the daily dose should not exceed 8 mg. The antiemetic efficacy in cases of severe chemotherapy-induced nausea and vomiting may be enhanced by the administration of glucocorticoids (e.g., 20 mg dexamethasone) intravenously prior to chemotherapy.

Respiratory adverse reactions should be treated symptomatically. Medical personnel should pay special attention to such reactions, as they may be signs of hypersensitivity to the drug.

Ondansetron prolongs the QT interval in a dose-dependent manner. Cases of ventricular arrhythmias (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 prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medicinal products that may lead to QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy.

Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly after 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 agents (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, appropriate patient monitoring is recommended.

In patients undergoing surgery in the adenotonsillar region, ondansetron use for the prevention of nausea and vomiting may mask the occurrence of postoperative bleeding.

Since ondansetron reduces gastrointestinal motility, patients with signs of subacute intestinal obstruction should be closely monitored during treatment.

Liver function should be carefully monitored in children receiving ondansetron together with hepatotoxic chemotherapeutic agents.

Each 1 ml of the solution contains 0.039 mmol sodium in the form of sodium citrate and sodium chloride (3.6 mg). Caution should be exercised when administering the product to patients on a sodium-controlled diet.

Dosing regimens

When dosing according to body weight and administering three doses at 4-hour intervals, the total daily dose will be higher than with a single dose of 5 mg/m² and one oral dose. The comparative efficacy of these two dosing regimens has not been evaluated in clinical trials. However, comparison of results from different studies suggests similar efficacy between the two regimens.

The ondansetron infusion solution should be prepared immediately before administration. If necessary, it may be stored for up to 24 hours at 2–8 °C prior to complete use. During infusion, the medicinal product does not require protection from light under normal lighting conditions.

If prolonged storage is required, reconstitution should be performed under appropriate aseptic conditions.

Sterilization of ampoules in an autoclave is prohibited.

Use during pregnancy or breastfeeding.

If a woman of childbearing age is treated with ondansetron, contraception should be considered.

Epidemiological studies suggest that ondansetron may cause orofacial 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 oral clefts (3 additional cases per 10,000 women treated with 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 with respect to reproductive toxicity. Ondansetron should not be used during the first trimester of pregnancy.

Experimental studies have shown that ondansetron penetrates into the milk of animals. If treatment with ondansetron is necessary, breastfeeding should be discontinued.

Ability to influence the speed of reactions while driving or operating machinery.

Psychomotor tests have shown that ondansetron does not affect the ability to operate machinery and does not produce sedative effects. However, the adverse effect profile of the drug should be taken into account when deciding whether patients may drive or operate machinery.

Administration and Dosage

The medicinal product should be administered intramuscularly or intravenously as a single slow injection or by infusion. To prepare the ondansetron infusion solution, 0.9% sodium chloride solution, 5% glucose solution, or Ringer's solution may be used. The ondansetron infusion solution should be prepared immediately before administration; however, if necessary, it may be stored for up to 24 hours at 2–8 °C until fully used. During infusion, the medicinal product does not require protection from light under normal lighting conditions.

Nausea and vomiting induced by chemotherapy and radiotherapy.

The emetogenic potential of cancer therapy varies depending on the dose and combination of chemotherapy and radiotherapy regimens. The choice of dosage regimen depends on the severity of the emetogenic effect.

Emetogenic chemotherapy and radiotherapy

Adults.

Administer 8 mg solution intramuscularly or intravenously slowly over at least 30 seconds, immediately before chemotherapy.

To prevent delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the drug is recommended.

Highly emetogenic chemotherapy:

• Single dose of 8 mg administered intramuscularly or intravenously slowly immediately before chemotherapy; when administering doses exceeding 8 mg, ondansetron must be dissolved in 50–100 mL of 0.9% sodium chloride solution or another compatible intravenous solution and infused over no less than 15 minutes. A single dose exceeding 16 mg must not be administered (see section "Special precautions for use");
• Doses of 8 mg or less do not need to be diluted and may be administered by slow intravenous or intramuscular injection (at least 30 seconds) immediately before the start of chemotherapy, followed by two additional doses of 8 mg administered intramuscularly or intravenously slowly at 2–4 hour intervals, or by continuous intravenous infusion at 1 mg/hour for 24 hours.

The choice of dosage regimen is determined individually by the physician, depending on the intensity of the emetogenic effect.

The efficacy of the drug in highly emetogenic chemotherapy may be enhanced by additional single-dose administration of sodium dexamethasone phosphate at 20 mg before chemotherapy. For prevention of delayed or prolonged vomiting after the first 24 hours, oral administration of the drug for 5 days is recommended.

Children and adolescents (aged 6 months to 17 years).

In pediatric practice, ondansetron should be administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another appropriate solvent over at least 15 minutes. The drug dose may be calculated based on body surface area or body weight of the child.

Dosage calculation according to the child's body surface area

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at 5 mg/m²; the intravenous dose must not exceed 8 mg. Oral administration of the drug may be initiated 12 hours later and may continue for another 5 days. Adult dose must not be exceeded.

Dosage calculation according to the child's body weight

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at 0.15 mg/kg. The intravenous dose must not exceed 8 mg. Two additional intravenous doses may be administered on the first day with a 4-hour interval. Oral administration of the drug may be initiated 12 hours later and may continue for another 5 days. Adult dose must not be exceeded.

Elderly patients

For patients aged 65 years and older, all doses for intravenous injections should be dissolved and administered over 15 minutes. When repeated administration is required, the interval between injections should be at least 4 hours.

For patients aged 65 to 74 years, the initial dose of ondansetron should be 8 mg or 16 mg, administered by intravenous infusion over 15 minutes, which may be followed by two additional doses of 8 mg infused over 15 minutes with an interval of at least 4 hours between infusions.

For patients aged 75 years and older, the initial intravenous injection of ondansetron must not exceed 8 mg, administered by infusion over at least 15 minutes. After the initial 8 mg dose, two additional doses of 8 mg may be administered by infusion over 15 minutes with an interval of at least 4 hours between infusions.

Postoperative nausea and vomiting

Adults. For prevention of postoperative nausea and vomiting, 4 mg may be administered as a slow intravenous injection or intramuscular injection during anesthesia induction. For treatment of postoperative nausea and vomiting, a single dose of 4 mg administered intramuscularly or slowly intravenously is recommended.

Children and adolescents (aged 1 month to 17 years). For prevention and treatment of postoperative nausea and vomiting, administer the drug at 0.1 mg/kg (maximum 4 mg) as a slow intravenous injection (at least 30 seconds) before, during, or after induction of anesthesia, or after surgery.

Elderly patients.

Experience with the use of ondansetron for prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, ondansetron is well tolerated by patients aged 65 years and older who are receiving chemotherapy.

For all types of therapy

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with impaired metabolism of sparteine/debrisoquine

The half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is not altered. In these patients, repeated administration results in drug concentrations similar to those in patients with normal metabolism. Therefore, no adjustment of dosage or frequency of administration is required.

Compatibility with other medicinal products.

The drug in the form of an infusion solution at ondansetron concentrations of 16–160 µg/mL (e.g., 8 mg/500 mL or 8 mg/50 mL, respectively) may be administered through a Y-type catheter with the following medicinal products:

• cisplatin at concentrations up to 0.48 mg/mL (e.g., 240 mg/500 mL) over 1–8 hours;
• 5-fluorouracil at concentrations up to 0.8 mg/mL (e.g., 2.4 g/3 L or 400 mg/500 mL) at a rate of at least 20 mL/hour (500 mL/24 hours). Precipitation of ondansetron may occur when 5-fluorouracil concentration exceeds 0.8 mg/mL. The 5-fluorouracil infusion solution may contain no more than 0.045% magnesium chloride in addition to other compatible excipients;
• carboplatin at concentrations of 0.18–9.9 mg/mL (e.g., 90 mg/500 mL or 990 mg/100 mL) administered over 10–60 minutes;
• etoposide at concentrations of 0.14–0.25 mg/mL (e.g., 70 mg/500 mL or 250 mg/1000 mL) administered over 30–60 minutes;
• ceftazidime at doses of 250 mg–2 g, reconstituted with water for injection according to manufacturer's recommendations, administered as an intravenous bolus injection (e.g., 250 mg/2.5 mL or 2 g/10 mL) over 5 minutes;
• cyclophosphamide at doses of 100 mg–1 g, reconstituted with water for injection according to manufacturer's recommendations, administered as an intravenous bolus injection (100 mg/5 mL) over 5 minutes;
• doxorubicin at doses of 10–100 mg, reconstituted with water for injection according to manufacturer's recommendations, administered as an intravenous bolus injection (10 mg/5 mL) over 5 minutes;
• dexamethasone – administration of 20 mg dexamethasone slowly over 2–5 minutes as an intravenous injection through a Y-type catheter, through which approximately 8–16 mg of ondansetron diluted in 50–100 mL of the primary infusion solution is administered over approximately 15 minutes, is possible.

Children.

The medicinal product may be used in children: during chemotherapy and radiotherapy – from 6 months of age; for prevention and treatment of postoperative nausea and vomiting – from 1 month of age.

Overdose.

Data on ondansetron overdose are limited. In most cases, symptoms are similar to those described in patients receiving recommended doses (see section "Adverse reactions").

Ondansetron prolongs the QT interval in a dose-dependent manner. In case of overdose, ECG monitoring is recommended.

Symptoms: visual disturbances, severe constipation, arterial hypotension, vasovagal disturbances with transient second-degree atrioventricular block. In all cases, these effects were completely reversible.

Children: serotonin syndrome has been reported in infants and children aged 12 months to 2 years after 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 hypersensitivity reactions, sometimes severe, including anaphylactic reactions, angioneurotic edema, anaphylactic shock, urticaria, bronchospasm, pruritus, skin rashes.

Nervous system: headache, convulsions, movement disorders (including gait disturbances, extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia)1, chorea, myoclonus, restlessness, tongue protrusion, diplopia; dizziness during rapid intravenous administration of the drug; central nervous system depression, paresthesia.

Eye organs: transient visual disturbances (blurred vision), mainly during rapid intravenous administration of the drug, transient blindness2.

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

Respiratory system and thoracic organs: hiccups, cough.

Gastrointestinal tract: constipation, diarrhea, dry mouth.

Hepatobiliary system: asymptomatic elevation of liver function parameters3, hepatic dysfunction. Cases of liver failure have been reported in cancer patients receiving concomitant therapy, including potentially hepatocytotoxic chemotherapy and antibiotics.

Skin and subcutaneous tissue: toxic rashes, including toxic epidermal necrolysis.

General disorders and administration site reactions: local reactions at the site of intravenous administration (pain, redness, and burning at the injection site), increased body temperature, weakness, loss of consciousness.

Other: hypokalemia.

1. Observed without definitive evidence of persistent clinical consequences.
2. In most cases, blindness resolves within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient blindness of cortical origin have been reported.
3. These cases occur primarily in patients treated with chemotherapy agents containing cisplatin.

Reporting of suspected adverse reactions

It is very important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products in the same syringe or infusion container, except as specified in the section "Dosage and method of administration".

Packaging.

2 ml or 4 ml in ampoules; 5 ampoules in a blister; 1 blister per carton.

Prescription category. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.