Ondansetron

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

Composition:

Active substance: ondansetron;

1 ml of solution contains ondansetron hydrochloride dihydrate, calculated as ondansetron – 2 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

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

Pharmacological properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective antagonist of 5-HT3 (serotonin) receptors. The drug 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 has not been fully elucidated. It is possible that the drug suppresses 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.

The volume of distribution after 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 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, 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.

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

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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

Ondansetron is metabolized by various hepatic cytochrome P450 enzymes: 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 overall clearance or will have only a minor effect. Ondansetron should be used with caution in combination with medicinal products that prolong the QT interval and/or cause electrolyte imbalances (see section "Special precautions for use").

Concomitant use of ondansetron with other medicinal products that prolong the QT interval may result in additional QT prolongation. Concurrent use of ondansetron with cardiotoxic medicinal products (e.g., anthracyclines such as doxorubicin, daunorubicin, or trastuzumab), antibiotics (erythromycin), antifungal agents (ketoconazole), antiarrhythmic drugs (amiodarone), and beta-blockers (atenolol or timolol) increases the risk of developing arrhythmias (see section "Special precautions for use").

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

Apomorphine.

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

Phenytoin, carbamazepine, and rifampicin.

In patients receiving potential inducers of CYP3A4 (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron is increased and its blood concentration is decreased.

Tramadol.

According to data from some clinical studies, 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.

Respiratory-related reactions should be treated symptomatically. Healthcare professionals 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 (see section "Pharmacological properties"). Additionally, post-marketing surveillance data have reported cases of ventricular fibrillation (torsade de pointes) associated 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, bradyarrhythmia, and patients taking other medicinal products that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy. Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant treatment with ondansetron and other serotonergic medicinal products is clinically justified, appropriate patient monitoring is recommended. Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly after intravenous administration, symptoms appeared immediately after administration. Patients should be informed about the signs and symptoms of myocardial ischemia.

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

In patients undergoing adenotonsillar surgery, the use of ondansetron for the prevention of nausea and vomiting may mask the onset of bleeding. Therefore, such patients require careful monitoring after administration of the drug.

Children.

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

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 dose of the drug administered orally. The comparative efficacy of these two dosing regimens has not been evaluated in clinical trials. Comparison of results from different studies indicates similar efficacy for both dosing regimens.

Important information on excipients.

The medicinal product ondansetron contains less than 1 mmol (23 mg/dose) of sodium, i.e. essentially sodium-free.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential who are using ondansetron should consider using contraception.

Pregnant women.

Based on available epidemiological studies, ondansetron is suspected to cause craniofacial malformations when used during the first trimester of pregnancy. In one cohort study involving 1.8 million pregnancies, first-trimester use of ondansetron was associated with an increased risk of oral clefts (3 additional cases per 10,000 women exposed to ondansetron; adjusted relative risk 1.24, 95% CI 1.03–1.48). Available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with regard to reproductive toxicity. Ondansetron should not be used during the first trimester of pregnancy.

Experimental studies have shown that ondansetron passes into animal milk. If use of the drug is necessary, breastfeeding should be discontinued.

There is no information available on the effect of ondansetron on human fertility.

Ability to affect reaction speed when 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 on the ability to drive or operate machinery.

Method of Administration and Dosage.

Nausea and vomiting induced by chemotherapy and radiotherapy.

Adults.

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

Emetogenic chemotherapy and radiotherapy.

The recommended intravenous or intramuscular dose of ondansetron is 8 mg administered as a slow intravenous injection over at least 30 seconds, or by intramuscular injection immediately before treatment.

To prevent delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the drug is recommended for up to 5 days following completion of the treatment course.

Highly emetogenic chemotherapy (e.g., high-dose cisplatin).

Ondansetron may be administered as a single 8 mg intravenous or intramuscular dose immediately before chemotherapy.

For highly emetogenic chemotherapy, 8 mg of ondansetron or a lower dose does not need to be diluted and can be administered via slow intravenous or intramuscular injection (over at least 30 seconds) immediately before chemotherapy, followed by two additional intravenous or intramuscular doses of 8 mg given 2 and 4 hours later, or by continuous infusion of 1 mg/hour for 24 hours.

Doses exceeding 8 mg (up to 16 mg) should only be administered as an intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable diluent (see below, "Administration of injection solution"); the infusion should last no less than 15 minutes. Single doses exceeding 16 mg are not recommended, as higher doses increase the risk of QT interval prolongation (see section "Special precautions"). The choice of dosage regimen depends on the severity of emetogenic effect.

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate before chemotherapy.

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

Children 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 suitable diluent (see below, "Administration of injection solution") over no less than 15 minutes. The drug dose can be calculated based on body surface area or body weight of the child.

Dose calculation based on child's body surface area.

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at a dose of 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. The adult dose must not be exceeded.

Ondansetron should be diluted with 5% dextrose solution, 0.9% sodium chloride solution, or another suitable infusion solution and administered by intravenous infusion over no less than 15 minutes.

There are no data from controlled clinical trials regarding the use of ondansetron for prevention of delayed or prolonged chemotherapy-induced nausea and vomiting (CINV). There are no data from controlled clinical trials regarding the use of ondansetron for treatment of nausea and vomiting induced by radiotherapy in children.

Dose calculation based on child's body weight.

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at a dose of 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. The adult dose must not be exceeded.

Elderly patients.

For patients aged 65 years and older, all intravenous doses should be diluted 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 is 8 mg or 16 mg, administered by intravenous infusion over 15 minutes, which may be followed by two additional 8 mg doses infused over 15 minutes with an interval of at least 4 hours between infusions.

For patients aged 75 years and older, the initial intravenous dose of ondansetron must not exceed 8 mg, administered by infusion over no less than 15 minutes. After the initial 8 mg dose, two additional 8 mg doses may be administered by infusion over 15 minutes with an interval of at least 4 hours between infusions.

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 hepatic impairment.

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

Patients with impaired sparteine/debrisoquine metabolism.

The elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with normal metabolism. Therefore, no dosage adjustment or change in frequency of administration is required.

Postoperative nausea and vomiting.

Adults.

For prevention of postoperative nausea and vomiting, the recommended dose of ondansetron is 4 mg administered as a single intramuscular or slow intravenous injection during induction of anesthesia.

For treatment of postoperative nausea and vomiting, the recommended single dose of ondansetron is 4 mg administered as an intramuscular or slow intravenous injection.

Children aged 1 month to 17 years.

For prevention and treatment of postoperative nausea and vomiting in children undergoing general anesthesia, ondansetron may be administered at a dose of 0.1 mg/kg body weight (maximum up to 4 mg) as a slow intravenous injection (over no less than 30 seconds) before, during, or after induction of anesthesia or after surgery.

Elderly patients.

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

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 hepatic impairment.

In patients with moderate to severe hepatic impairment, ondansetron clearance is significantly reduced and serum half-life is prolonged. For such patients, the maximum daily dose of the drug must not exceed 8 mg. Patients with impaired sparteine/debrisoquine metabolism.

The elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with intact metabolism. Therefore, no dosage adjustment or change in frequency of administration is required.

Administration of injection solution.

The drug contains no preservatives; the solution should be used immediately after opening the ampoule; any unused solution must be discarded.

Ampoules containing the drug must not be autoclaved.

Compatibility with other intravenous solutions.

Intravenous infusion solutions should be prepared immediately before infusion. However, it has been established that ondansetron solution remains stable for 7 days at room temperature (up to 25°C) under daylight or in the refrigerator when diluted in the following media: 0.9% sodium chloride solution, 5% glucose solution, 10% mannitol solution, Ringer's solution, 0.3% potassium chloride and 0.9% sodium chloride solution, 0.3% potassium chloride and 5% glucose solution.

Ondansetron has been shown to remain stable when using polyethylene and glass bottles. It has been demonstrated that ondansetron diluted in 0.9% sodium chloride or 5% glucose remains stable in polypropylene syringes. Stability in polypropylene syringes has also been confirmed when ondansetron is diluted with other recommended diluents.

If prolonged storage of the drug is required, dilution should be performed under appropriate aseptic conditions.

Compatibility with other medicinal products.

Ondansetron may be administered as an intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, ondansetron at concentrations from 16 µg/mL to 160 µg/mL (i.e., 8 mg/500 mL or 8 mg/50 mL, respectively) may be co-administered with:

• cisplatin at concentrations up to 0.48 mg/mL for 1–8 hours;
• 5-fluorouracil at concentrations up to 0.8 mg/mL (e.g., 2.4 g in 3 L or 400 mg in 500 mL) at a rate not exceeding 20 mL/hour. Higher concentrations of 5-fluorouracil may cause ondansetron precipitation. The 5-fluorouracil infusion solution may contain up to 0.045% magnesium chloride in addition to other compatible excipients;
• carboplatin at concentrations from 0.18 mg/mL to 9.9 mg/mL (e.g., from 90 mg in 500 mL to 990 mg in 100 mL) for 10–60 minutes;
• etoposide at concentrations from 0.14 mg/mL to 0.25 mg/mL (e.g., from 72 mg in 500 mL to 250 mg in 1 L) for 30–60 minutes;
• ceftazidime at doses from 250 mg to 2 g, diluted in water for injection (e.g., 2.5 mL per 250 mg or 10 mL per 2 g ceftazidime), administered as an intravenous bolus injection over 5 minutes;
• cyclophosphamide at doses from 100 mg to 1 g, diluted in water for injection (5 mL per 100 mg cyclophosphamide), administered as an intravenous bolus injection over 5 minutes;
• doxorubicin at doses from 10 mg to 100 mg, diluted in water for injection (5 mL per 10 mg doxorubicin), administered as an intravenous bolus injection over 5 minutes;
• dexamethasone at a dose of 20 mg, administered as a slow intravenous injection over 2–5 minutes (concomitantly with 8 mg or 16 mg ondansetron diluted in 50–100 mL of injection solution) over approximately 15 minutes. Since these drugs are compatible, they may be administered through the same infusion line, with dexamethasone phosphate (as sodium salt) concentrations ranging from 32 µg to 2.5 mg per 1 mL and ondansetron concentrations from 8 µg to 1 mg per 1 mL.

Children.

Administered to children aged 6 months (during chemotherapy) and aged 1 month (for prevention and treatment of postoperative nausea and vomiting).

Overdose.

Data on ondansetron overdose are limited.

Symptoms. 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 cases of overdose, ECG monitoring is recommended. Manifestations reported include visual disturbances, severe constipation, arterial hypotension, vasovagal reactions with transient second-degree atrioventricular block. In all cases, these effects were fully reversible. Cases of serotonin syndrome in young children after oral overdose have been reported.

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. There is no specific antidote; therefore, symptomatic and supportive therapy should be administered in cases of overdose. Further management should be based on clinical indications or, if possible, in accordance with recommendations from the national poison center. The use of ipecac for treatment of ondansetron overdose is not recommended, as its effect may be counteracted by the antiemetic action of ondansetron.

Adverse Reactions

The adverse reactions listed below are classified by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Immune system disorders:

Rare: Immediate-type hypersensitivity reactions, occasionally severe, up to anaphylaxis.

Nervous system disorders:

Very common: Headache;

Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences);
Rare: Dizziness, mainly during rapid intravenous administration.

Eye disorders:

Rare: Transient visual disturbances (blurred vision), mainly during intravenous administration;
Very rare: Transient blindness, mainly during intravenous administration. In most cases, blindness resolves within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient blindness have been reported as cortical in origin.

Cardiac disorders:

Uncommon: Arrhythmia, chest pain (with or without ST-segment depression), bradycardia;
Rare: QT interval prolongation (including ventricular fibrillation/tachycardia (torsade de pointes));
Frequency not known: Myocardial ischemia (see section "Special precautions for use").

Vascular disorders:

Common: Sensation of warmth or flushing;
Uncommon: Arterial hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Hiccups.

Gastrointestinal disorders:

Common: Constipation.

Hepatobiliary disorders:

Uncommon: Asymptomatic elevation of liver function tests. These cases occur mainly in patients receiving chemotherapy regimens containing cisplatin.

Skin and subcutaneous tissue disorders:

Very rare: Toxic skin eruptions, including toxic epidermal necrolysis.

General disorders and administration site conditions:

Common: Local reactions at the site of intravenous administration.

The following adverse reactions have been reported during post-marketing surveillance:

Cardiovascular system disorders:

Chest pain and discomfort, extrasystoles, tachycardia (including ventricular and supraventricular tachycardia), atrial fibrillation, palpitations, syncope, ECG changes.

Hypersensitivity reactions:

Anaphylactic reactions, angioneurotic edema, bronchospasm, anaphylactic shock, pruritus, skin rash, urticaria.

Nervous system disorders:

Gait disturbance, chorea, myoclonus, restlessness, burning sensation, tongue protrusion, diplopia, paresthesia.

General disorders and administration site reactions:

Increased body temperature, pain, redness, burning at the injection site.

Other:

Hypokalemia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua

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.

Ondansetron must not be used in the same syringe or infusion solution with other medicinal products. Ondansetron for injection may only be combined with recommended infusion solutions (see section "Dosage and administration").

Packaging.

2 ml in ampoules, 5 ampoules in a blister pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Subsidiary enterprise "Farmatreyd".

Manufacturer's address and location of business activity.

85 Sambirska Street, Drohobych, Lviv Oblast, 82100, Ukraine.