Ondansetron-baxter
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONDANSETRON-BAXTER (ONDANSETRON-BAXTER)
Composition:
Active substance: ondansetron;
1 ml of injection solution contains ondansetron hydrochloride dihydrate 2.49 mg, equivalent to 2 mg of ondansetron;
Excipients: sodium chloride; citric acid, monohydrate; sodium citrate; water for injections.
Pharmaceutical form. Injection solution.
Main physicochemical properties: clear, colorless solution, almost free from visible particles.
Pharmacotherapeutic group. Antiemetic agents and drugs eliminating nausea. 5HT3 (serotonin) receptor antagonists.
ATC code A04AA01.
Pharmacological Properties
Pharmacodynamics
Ondansetron is a potent, highly selective antagonist of serotonin receptors (5HT3). The drug prevents or relieves 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 likely that the drug inhibits the initiation of the vomiting reflex by antagonizing 5HT3 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 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, 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 the active substance or to any of the excipients of the medicinal product.
Concomitant use with apomorphine hydrochloride, as severe arterial hypotension and loss of consciousness have been observed during combined administration.
Interaction with other medicinal products and other forms of interaction.
There are no data indicating that ondansetron accelerates or inhibits the metabolism of other drugs 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 ondansetron-metabolizing enzymes, inhibition or reduced activity of one of them (e.g., genetic deficiency of CYP2D6) is normally compensated by other enzymes and will not affect overall creatinine clearance or will have only a negligible 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").
The use of ondansetron with other medicinal products that prolong the QT interval may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic medicinal products (e.g., anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (e.g., erythromycin), antifungals (e.g., ketoconazole), antiarrhythmics (e.g., amiodarone), and beta-blockers (e.g., atenolol or timolol) may increase the risk of arrhythmias (see section "Special precautions for use").
Serotonergic medicinal products (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs))
Cases of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular disturbances) have been reported following concomitant use of ondansetron and other serotonergic agents, including SSRIs and SNRIs (see section "Special precautions for use").
Apomorphine
The 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 potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron is increased and its blood concentration is decreased.
Tramadol
According to limited clinical studies, ondansetron may reduce the analgesic effect of tramadol.
Special precautions for use
In patients with hypersensitivity to other selective 5HT3 receptor antagonists, cross-reactivity has been observed.
Respiratory reactions should be treated symptomatically. Healthcare professionals should pay particular attention to such reactions, as they may be harbingers of hypersensitivity reactions to the medicinal product.
Ondansetron prolongs the QT interval in a dose-dependent manner (see section "Pharmacological properties"). Additionally, post-marketing surveillance data have reported cases of ventricular tachycardia (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, bradyarrhythmias, or those receiving other medicinal products that may lead to QT prolongation or electrolyte disturbances.
Cases of myocardial ischaemia have been reported during ondansetron treatment. In some patients, particularly following intravenous administration, symptoms occurred immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischaemia.
Hypokalaemia and hypomagnesaemia 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 agents is clinically warranted, appropriate patient monitoring is recommended.
Since ondansetron prolongs colonic transit time, careful monitoring is required in patients with signs of subacute intestinal obstruction during treatment.
In patients undergoing adenotonsillar surgery, the use of ondansetron for the prevention of nausea and vomiting may mask the onset of postoperative bleeding. Therefore, such patients require careful monitoring after ondansetron administration.
Children
In children receiving ondansetron concomitantly with hepatotoxic chemotherapeutic agents, careful monitoring for possible hepatic function impairment is required.
Dosing regimens
When dosing according to body weight (mg/kg) and administering three doses at 4-hour intervals, the total daily dose will be higher than when using 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 for both regimens.
Excipients with known effect
This medicinal product in a dose of 2–6 ml contains less than 1 mmol (23 mg) of sodium, i.e., “essentially sodium-free”. If the dose exceeds 6 ml, the medicinal product cannot be considered “essentially sodium-free”, which should be taken into account when treating patients on a sodium-controlled diet. The maximum daily dose (16 ml) of this medicinal product contains 56 mg of sodium. This is equivalent to approximately 2.3% of the recommended daily intake of sodium for adults.
Use during pregnancy or breastfeeding.
Women of childbearing potential
Women of childbearing potential should use contraception.
Pregnancy
Based on human experience and epidemiological studies, there is a concern regarding the development of craniofacial defects following ondansetron use 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; adjusted relative risk 1.24 (95% CI 1.03–1.48)).
Epidemiological studies on congenital heart defects have yielded conflicting results. Animal studies have not indicated direct or indirect harmful effects with respect to reproductive toxicity.
Ondansetron should not be used during the first trimester of pregnancy.
Breastfeeding
Experimental studies have shown that ondansetron passes into the milk of animals. If treatment with the medicinal product is necessary, breastfeeding should be discontinued.
Fertility
There is no information available on the effect of ondansetron on human fertility.
Ability to affect performance when driving or operating machinery.
Psychomotor tests have shown that ondansetron does not impair the ability to drive or operate machinery and has no sedative effect. However, the adverse effect profile of the medicinal product should be considered when assessing a patient’s ability to drive or operate machinery.
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 dosing regimen depends on the severity of emetogenic effect. The dose of Ondansetron-Baxter (range from 8 to 32 mg per day) and route of administration are determined by the physician according to the information below.
Emetogenic chemotherapy and radiotherapy
The recommended intravenous dose of the drug is 8 mg administered as a slow intravenous injection over at least 30 seconds or as an intramuscular injection immediately before treatment.
For prevention of delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of ondansetron is recommended for up to 5 days after completion of the treatment course.
Highly emetogenic chemotherapy (e.g., high-dose cisplatin)
Ondansetron-Baxter may be administered as a single 8 mg intravenous or intramuscular dose immediately before chemotherapy.
For highly emetogenic chemotherapy, 8 mg of Ondansetron-Baxter or a lower dose does not need to be diluted and can be administered by 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 at 2 and 4 hours, or by continuous infusion of 1 mg/hour for 24 hours.
Doses exceeding 8 mg (up to 16 mg) may only be administered as intravenous infusion in 50–100 mL of 0.9 % sodium chloride solution or another suitable diluent (see below "Use of injection solution"); the infusion should last at least 15 minutes.
Single doses exceeding 16 mg must not be used, as higher doses increase the risk of QT interval prolongation (see section "Special precautions").
The choice of dosing regimen depends on the severity of emetogenic effect. The efficacy of the drug 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
The drug dose can be calculated based on body surface area or body weight of the child.
In pediatric practice, the drug should be administered by intravenous infusion after dilution in 25–50 mL of 0.9 % sodium chloride solution or another suitable diluent over at least 15 minutes.
Dosage calculation based on body surface area
The drug should be administered immediately before chemotherapy as a single intravenous injection at a dose of 5 mg/m². A single intravenous dose must not exceed 8 mg.
Oral administration may be initiated 12 hours later and may continue for up to 5 days. The total daily dose of ondansetron must not exceed the adult dose.
Ondansetron-Baxter should be diluted with 5 % dextrose solution, 0.9 % sodium chloride solution, or another suitable infusion solution and administered by intravenous infusion over at least 15 minutes.
There are no data from controlled clinical trials regarding the use of the drug for prevention of delayed or prolonged vomiting and nausea induced by chemotherapy. There are no data from controlled clinical trials regarding the use of the drug for treatment of nausea and vomiting induced by radiotherapy in children.
Dosage calculation based on body weight
The drug should be administered immediately before chemotherapy as a single intravenous injection at a dose of 0.15 mg/kg. A single intravenous dose must not exceed 8 mg. On the first day, two intravenous injections may be given with a 4-hour interval. Oral administration may be initiated 12 hours later and may continue for up to 5 days. The total daily dose of ondansetron must not exceed the adult dose.
Elderly patients
For patients aged 65 years and older, all intravenous injection 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 each, with an interval of at least 4 hours between infusions.
After an initial 8 mg dose, two additional 8 mg doses may be administered by infusion over 15 minutes each, with an interval of at least 4 hours between administrations.
Patients with renal impairment
There is no need to adjust the dosing 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 metabolism of sparteine/debrisoquine
The 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 dose 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
Children aged 1 month to 17 years
For prevention of postoperative nausea and vomiting in children undergoing general anesthesia, the drug may be administered at a dose of 0.1 mg/kg body weight (maximum 4 mg) by slow intravenous injection (over at least 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 was well tolerated in patients aged 65 years and older who received chemotherapy.
Patients with renal impairment
There is no need to adjust the dosing 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 metabolism of sparteine/debrisoquine
The half-life of ondansetron in subjects with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations are similar to those in patients with intact metabolism. Therefore, no dose adjustment or change in frequency of administration is required.
Instructions for use
Ondansetron-Baxter for injection must not be autoclaved.
Ondansetron-Baxter, injection solution, when diluted in compatible infusion solutions, is stable under normal room lighting or daylight for at least 24 hours; light protection during infusion is not required.
Compatibility with other intravenous fluids
Ondansetron-Baxter for injection may be mixed only with the following recommended intravenous infusion solutions: 0.9 % sodium chloride solution; 5 % glucose solution; 10 % mannitol solution; Ringer’s solution; 0.3 % potassium chloride solution in 0.9 % sodium chloride solution; 0.3 % potassium chloride solution in 5 % glucose solution.
Infusion solutions should be prepared immediately before infusion or stored in a refrigerator at 2–8 °C for no more than 24 hours prior to use.
Compatibility studies were conducted using polyvinyl chloride infusion bags and polyvinyl chloride infusion systems. Adequate stability is also expected when using polyethylene infusion bags or Type 1 glass vials. Ondansetron diluted in 0.9 % sodium chloride or 5 % glucose solution has been shown to be stable in polypropylene syringes. Stability in polypropylene syringes is also expected when ondansetron is diluted with other recommended solutions.
Compatibility with other medicinal products
Ondansetron-Baxter may be administered as an intravenous infusion at a rate of 1 mg/hour, for example from an infusion bag or syringe pump. The drug, as an infusion solution with ondansetron concentration of 16–160 µg/mL (e.g., 8 mg/500 mL or 8 mg/50 mL, respectively), may be administered via a Y-connector with the following drugs:
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 in 3 L or 400 mg in 500 mL) at a rate not exceeding 20 mL/hour (500 mL over 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. 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) over 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) over 30–60 minutes;
ceftazidime at doses from 250 mg to 2000 mg, 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 via a Y-connector over 2–5 minutes (simultaneously with 8 mg or 16 mg ondansetron diluted in 50–100 mL of compatible injection solution over approximately 15 minutes). Since sodium dexamethasone phosphate and ondansetron are compatible, they may be administered through the same infusion line, with concentrations in solution ranging from 32 µg to 2.5 mg/mL for sodium dexamethasone phosphate and from 8 µg to 1 mg/mL for ondansetron.
Children
For use in children aged 6 months (during chemotherapy) and aged 1 month (for prevention and treatment of postoperative nausea and vomiting).
Overdose
Symptoms and signs
Data on ondansetron overdose are limited. In most cases, symptoms are similar to those observed in patients receiving recommended doses (see section "Adverse reactions"). Overdose manifestations reported include visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree atrioventricular block. In all cases, these effects were completely reversible.
Ondansetron prolongs the QT interval in a dose-dependent manner. In case of overdose, ECG monitoring is recommended.
Children
Cases of serotonin syndrome in young children after oral overdose have been reported.
Serotonin syndrome has been reported in infants and children aged 12 months to 2 years after accidental oral overdose (doses exceeding the recommended level of 4 mg/kg).
Treatment
There is no specific antidote for ondansetron; therefore, symptomatic and supportive therapy should be administered in all cases of overdose.
Further management of patients should be based on clinical indications or, if possible, in accordance with recommendations from the national poison control center.
The use of ipecacuanha for treatment of ondansetron overdose is not recommended, as its effect may be counteracted by the antiemetic action of the drug.
Adverse Reactions.
The adverse reactions listed below are classified by organ systems and frequency of occurrence. The frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).
Immune system disorders:
Rare: Immediate-type hypersensitivity reactions, sometimes severe, including 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), primarily 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: Arrhythmias, chest pain (with or without ST segment depression), bradycardia;
Rare: QT interval prolongation (including ventricular fibrillation/torsade de pointes).
Cases of myocardial ischemia have been reported (frequency unknown) (see section "Special precautions").
Vascular disorders:
Common: Sensation of warmth or flushing;
Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disorders:
Uncommon: Hiccups.
Gastrointestinal disorders:
Common: Constipation.
Hepatobiliary disorders:
Uncommon: Asymptomatic elevation of liver function parameters.
These cases occur primarily in patients receiving chemotherapy 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 observed 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 eruptions, urticaria.
Nervous system disorders: Gait disturbances, 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 continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store in a place inaccessible to children, at a temperature not exceeding 25 ºC. Protect from light.
Incompatibilities.
Ondansetron-Baxter medicinal product must not be used in the same syringe or infusion solution with other medicinal products. The injectable formulation may be mixed only with recommended infusion solutions (see section "Dosage and administration").
Packaging.
4 ml in a vial, 5 vials in a tray, 1, 2 or 5 trays in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
BAXTER PHARMACEUTICALS INDIA PRIVATE LIMITED.
Manufacturer's address and location of operations.
CHACHARVADI-VASANA, AHMEDABAD, 382213, INDIA.