Emeton

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

Composition:

Active substance: ondansetron;

1 ml of solution contains 2 mg of ondansetron (as hydrochloride dihydrate);

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly colored liquid.

Pharmacotherapeutic group. Antiemetic and antinausea agents. Serotonin receptor antagonists (5HT3). ATC code A04AA01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Ondansetron is a potent, highly selective antagonist of serotonin receptors (5-HT3). The exact mechanism of action of ondansetron in nausea and vomiting is not fully understood. During radiotherapy and administration of cytotoxic drugs, serotonin (5-HT) is released in the small intestine, leading to stimulation of afferent endings of the vagus nerve via activation of 5-HT3 receptors, thereby triggering the peripheral mechanism of the vomiting reflex. Ondansetron blocks the initiation of this reflex. Activation of vagal afferent endings may, in turn, cause release of 5-HT in the posterior region of the floor of the fourth ventricle (area postrema), which may initiate the central mechanism of the vomiting reflex. Thus, the inhibition by ondansetron of chemotherapy- and radiotherapy-induced nausea and vomiting is likely mediated through antagonism at 5-HT3 receptors located both peripherally and in the central nervous system.

The mechanism of action of ondansetron in postoperative nausea and vomiting is not fully understood, but is likely similar to that in cytotoxic-induced nausea and vomiting. Ondansetron does not affect plasma prolactin concentrations.

The role of ondansetron in opioid-induced vomiting has not been fully elucidated.

Clinical safety and efficacy

The role of ondansetron in vomiting induced by opioids has not been established.

QT interval prolongation

The effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin) crossover study involving adult men and women. Ondansetron doses included 8 mg and 32 mg administered intravenously over 15 minutes. No significant changes in PR or QRS intervals on electrocardiogram were observed.

Children

Nausea and vomiting induced by chemotherapy and radiotherapy

The efficacy of ondansetron in controlling chemotherapy-induced nausea and vomiting was evaluated in a double-blind, randomized study involving patients aged 1 to 18 years (S3AB3006). On days of chemotherapy administration, patients received either 5 mg/m² of ondansetron intravenously plus 4 mg orally every 8–12 hours, or 0.45 mg/kg of ondansetron intravenously plus oral placebo every 8–12 hours. After completion of chemotherapy, both groups received ondansetron syrup 4 mg twice daily for 3 days. On the worst day of chemotherapy, vomiting occurred in 49% (5 mg/m² intravenous ondansetron plus 4 mg oral) and 41% (0.45 mg/kg intravenous ondansetron plus oral placebo). There was no difference in the overall frequency or nature of adverse reactions between the two groups.

A double-blind, randomized, placebo-controlled study (S3AB4003) involving patients aged 1 to 17 years demonstrated complete control of vomiting. On the worst day of chemotherapy, complete control of vomiting was achieved in:

• 73% of patients when ondansetron was administered intravenously at 5 mg/m² together with 2–4 mg of oral dexamethasone;
• 71% of patients when ondansetron syrup was administered at 8 mg together with 2–4 mg of oral dexamethasone on days of chemotherapy.

After chemotherapy, both groups received ondansetron syrup 4 mg twice daily for 2 days. There was no difference in the overall frequency or nature of adverse reactions between the two groups.

The efficacy of ondansetron in children aged 6 to 48 months was evaluated in an open-label, non-comparative, single-group study (S3A40320). All children received three intravenous doses of ondansetron 0.15 mg/kg, administered 30 minutes before the start of chemotherapy, and then at 4 and 8 hours after the first dose. Complete control of vomiting was achieved in 56% of patients.

Another open-label, non-comparative, single-group study (S3A239) evaluated the efficacy of a single intravenous dose of 0.15 mg/kg ondansetron followed by two oral doses of 4 mg ondansetron for children <12 years of age and 8 mg for children ≥12 years of age. Complete control of vomiting was achieved in 42% of patients.

Postoperative nausea and vomiting

The efficacy of a single dose of ondansetron in preventing postoperative nausea and vomiting was evaluated in a randomized, double-blind, placebo-controlled study in children aged 1 to 24 months (≥44 weeks post-conception with body weight ≥3 kg). The children included in the study were scheduled for elective surgery under general anesthesia and had an ASA status ≤ III. A single dose of 0.1 mg/kg ondansetron was administered over five minutes after induction of anesthesia. The number of children experiencing at least one episode of vomiting during the 24-hour assessment period (ITT population) was higher in the placebo group than in the ondansetron group (28% vs. 11%, p <0.0001).

Four double-blind, placebo-controlled studies were conducted in children aged 2 to 12 years undergoing general anesthesia. Patients were randomized to receive a single intravenous dose of ondansetron (0.1 mg/kg for children weighing ≤40 kg and 4 mg for children weighing >40 kg) or placebo. The study drug was administered over at least 30 seconds immediately before or after induction of anesthesia. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting (see Table 1).

Table 1

Prevention and treatment of postoperative nausea and vomiting in children

Study	Endpoint	Ondansetron %	Placebo %	p-value
S3A380	CR	68	39	≤0.001
S3GT09	CR	61	35	≤0.001
S3A381	CR	53	17	≤0.001
S3GT11	no nausea	64	51	0.004
S3GT11	no vomiting	60	47	0.004

CR – absence of vomiting, rescue, or discontinuation.

Pharmacokinetics.

Absorption

The distribution of ondansetron after oral, intramuscular, and intravenous administration is similar, with a terminal half-life of approximately 3 hours and a steady-state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of ondansetron.

After intravenous administration of 4 mg of ondansetron, maximum plasma concentration is reached within 5 minutes, and after intramuscular administration, within 10 minutes following injection.

Distribution, metabolism, and elimination

Ondansetron has a moderate degree of plasma protein binding (70–76%). Ondansetron is eliminated from systemic circulation primarily via hepatic metabolism involving multiple enzyme systems. Less than 5% of the drug is excreted unchanged in urine. The absence of the CYP2D6 isoenzyme (sparteine/debrisoquine polymorphism type) does not affect the pharmacokinetics of ondansetron. The pharmacokinetic parameters of ondansetron remain unchanged upon repeated administration.

Special patient groups

Gender

Gender differences in the distribution of ondansetron have been observed, with women showing higher rate and extent of absorption after oral administration, as well as reduced systemic clearance and volume of distribution (adjusted for body weight), compared to men.

Children aged 1 month to 17 years

In children aged 1 to 4 months who underwent surgery, body weight-normalized clearance was approximately 30% slower than in children aged 5 to 24 months, but comparable to clearance in children aged 3 to 12 years. The elimination half-life in children aged 1 to 4 months averaged 6.7 hours, compared to 2.9 hours in children aged 5 to 24 months and 3 to 12 years. Differences in pharmacokinetic parameters in children aged 1 to 4 months can be partially explained by the higher percentage of total body water in neonates and infants, and the higher volume of distribution of water-soluble drugs such as ondansetron.

In children aged 3 to 12 years undergoing elective surgery under general anesthesia, absolute values of both clearance and volume of distribution of ondansetron were lower compared to adult patients. Both parameters increased linearly with body weight, and by age 12, values approached those of young adults. When clearance and volume of distribution were normalized by body weight, these parameters were similar across different age groups. Dosing based on body weight compensates for age-related changes and is effective in normalizing systemic exposure in children.

A population pharmacokinetic analysis was conducted in individuals (cancer patients, surgical patients, and healthy volunteers) aged 1 month to 44 years after intravenous administration of ondansetron. Results showed that the area under the concentration-time curve (AUC) after oral and intravenous administration in children and adolescents was similar to that in adults, except in infants aged 1 to 4 months. The volume of distribution was age-dependent and lower in adults compared to children. Creatinine clearance depended on patient body weight but not on age (except in children aged 1 to 4 months). It is difficult to draw a definitive conclusion whether there was an additional reduction in ondansetron clearance in children aged 1 to 4 months or whether the observed reduction reflected natural variability due to the small number of patients studied in this age group.

Since children under 6 months of age receive only a single dose of the drug for postoperative nausea and vomiting, the reduced clearance is unlikely to be of clinical significance.

Elderly patients

Based on recent data on ondansetron plasma concentrations and modeling of the exposure-response relationship, a more pronounced effect on the QTcF interval is expected in patients aged 75 years and older compared to younger patients. Dosage information for intravenous administration in patients aged 65 years and over 75 years (see section "Dosage and administration").

Patients with renal impairment

In patients with impaired renal function (creatinine clearance 15–60 mL/min), systemic clearance and volume of distribution are reduced after intravenous administration of ondansetron, resulting in a slight but clinically insignificant prolongation of the elimination half-life (5.4 hours). Studies in patients with severe renal impairment requiring regular hemodialysis (evaluated between dialysis sessions) showed that the pharmacokinetics of ondansetron are practically unchanged after intravenous administration.

Patients with hepatic impairment

After oral, intravenous, or intramuscular administration in patients with severe hepatic impairment, systemic clearance of ondansetron is markedly reduced, with prolongation of the elimination half-life to 15–32 hours, and oral bioavailability approaching 100% due to reduced presystemic metabolism.

Clinical characteristics.

Indications.

Adults

Nausea and vomiting caused by cytotoxic chemotherapy and radiation therapy.

Prevention and treatment of postoperative nausea and vomiting.

Children

Nausea and vomiting caused by cytotoxic chemotherapy in children from 6 months of age. Prevention and treatment of postoperative nausea and vomiting in children from 1 month of age.

Contraindications.

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe arterial hypotension and loss of consciousness have been observed during their 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 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 have no effect or only a negligible effect on overall creatinine clearance.

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 administration of Emeton with cardiotoxic medicinal products (e.g., anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (e.g., erythromycin), antifungal agents (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").

Apomorphine

The concomitant use of ondansetron with apomorphine hydrochloride is contraindicated due to reported cases of severe hypotension and loss of consciousness 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 reduced.

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 medicinal products, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (see section "Special precautions for use").

Tramadol

Based on a limited number of 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 reactions should be treated symptomatically. Healthcare professionals should pay special attention to these reactions, as they may be signs of hypersensitivity to the medicinal product.

Ondansetron dose-dependently prolongs the QT interval (see section "Pharmacological properties"). Additionally, post-marketing surveillance data have reported cases of ventricular tachycardia (Torsade de Pointes) following administration of ondansetron. 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 cause QT prolongation or electrolyte disturbances.

Cases of myocardial ischaemia have been reported in patients receiving ondansetron. In some patients, particularly after intravenous administration, symptoms appeared 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 described 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 justified, appropriate patient monitoring is recommended.

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

Children

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

Dosing regimens

When calculating the dose based on body weight and administering three doses at four-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. Comparison of results from different studies suggests similar efficacy for both dosing regimens.

Excipients with known effect

Emeton at a dose of 2–6 ml contains less than 1 mmol (23 mg) of sodium, i.e., "practically sodium-free". If the dose exceeds 6 ml, the medicinal product cannot be considered "practically sodium-free", which should be taken into account when administering to patients on a sodium-controlled diet. The maximum daily dose (16 ml) of this medicinal product contains 56 mg of sodium, equivalent to approximately 2.3% of the recommended daily sodium intake for adults.

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

Pregnancy

Epidemiological studies suggest that ondansetron may cause craniofacial malformations when used during the first trimester of pregnancy. In one cohort study including 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 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.

Breastfeeding

Experimental studies have shown that ondansetron passes into breast milk in animals. If treatment is necessary, breastfeeding should be discontinued.

Fertility

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

Ability to drive and use machines.

Ondansetron does not affect the ability to drive or operate machinery and has no sedative effect; however, the adverse effect profile of the drug should be considered when driving or operating machinery.

Administration and Dosage

Nausea and vomiting caused by chemotherapy and radiation therapy

Adults

The emetogenic potential of cancer therapy varies depending on the dose and combination regimens of chemotherapy and radiation therapy. The route of administration and dosage of Emeton depend on the severity of emetogenic impact, ranging from 8 to 32 mg per day, and are selected according to the indications specified below.

Emetogenic chemotherapy and radiation therapy

The recommended intravenous or intramuscular dose of Emeton is 8 mg, administered as a slow intravenous injection over at least 30 seconds or by intramuscular injection immediately before the start of therapy, followed by oral administration of 8 mg of the drug every 12 hours.

To prevent delayed or prolonged vomiting after the first 24 hours, oral 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)

Emeton has been shown to be equally effective with the following dosage regimens during the first 24 hours after chemotherapy:

• A single dose of 8 mg administered as a slow intravenous injection (over at least 30 seconds) or intramuscular injection immediately before the start of chemotherapy;
• 8 mg of the drug administered as a slow intravenous (over at least 30 seconds) or intramuscular injection immediately before the start of chemotherapy, followed by two intravenous (over at least 30 seconds) or intramuscular injections of 8 mg each at 4-hour intervals, or by continuous infusion at a rate of 1 mg/hour for 24 hours;
• A maximum single intravenous dose of 16 mg, diluted in 50–100 mL of 0.9% sodium chloride solution or another suitable diluent (see section "Administration and Dosage"), administered as an infusion over at least 15 minutes immediately before chemotherapy, followed by two intravenous (over at least 30 seconds) or intramuscular injections of 8 mg each at 4-hour intervals.

Single doses exceeding 16 mg are not recommended, as higher doses increase the risk of QT interval prolongation (see sections "Pharmacodynamics", "Special Warnings and Precautions for Use", and "Adverse Reactions"). The choice of dosage regimen depends on the severity of emetogenic impact.

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

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

Children aged 6 months to 17 years

In pediatric clinical studies, ondansetron was administered by intravenous infusion after dilution in 25–50 mL of 0.9% sodium chloride solution or another suitable diluent (see section "Administration and Dosage") over at least 15 minutes. The drug dosage can be calculated based on body surface area or body weight.

Dosage calculation based on body weight results in higher daily doses compared to calculation based on body surface area (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

Emeton should be diluted in 0.9% sodium chloride or another compatible infusion fluid (see section "Administration and Dosage") and administered intravenously over at least 15 minutes.

There are no data from controlled clinical trials regarding the use of Emeton for the prevention of delayed or prolonged nausea and vomiting caused by chemotherapy and radiation therapy. There are no data from controlled clinical trials on the use of the drug for the treatment of nausea and vomiting induced by radiation therapy in children.

Dose calculation according to body surface area in children

Emeton should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m². The single intravenous dose must not exceed 8 mg.

Oral administration of the drug may be initiated 12 hours later and continued for up to 5 days (see Table 2). The total daily dose (within 24 hours) of the drug (as divided doses) must not exceed the adult dose of 32 mg.

Table 2

Child's body surface area	Day 1 (a,b)	Days 2–6 (b)
< 0.6 m2	5 mg/m2 intravenously plus 2 mg syrup every 12 hours	2 mg syrup every 12 hours
≥ 0.6 m2 - ≤ 1.2 m2	5 mg/m2 intravenously plus 4 mg syrup or tablets every 12 hours	4 mg syrup or tablets every 12 hours
> 1.2 m2	5 mg/m2 or 8 mg intravenously plus 8 mg syrup or tablets every 12 hours	8 mg syrup or tablets every 12 hours

a – the intravenous dose must not exceed 8 mg;

b – the daily dose (within 24 hours) of the drug (in the form of individual doses) must not exceed the adult dose of 32 mg.

Dose calculation based on child's body weight

Dose calculation based on the child's body weight results in higher daily doses compared to dose calculation based on the child's body surface area (see sections "Pharmacodynamics" and "Dosage and Administration").

Emeton should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The single intravenous dose must not exceed 8 mg.

Oral administration of the drug may be initiated 12 hours after and continued for up to 5 days (see Table 3). The daily dose (within 24 hours) of the drug (in the form of individual doses) must not exceed the adult dose of 32 mg.

Table 3

Child's body weight	Day 1 (a,b)	Days 2–6 (b)
≤10 kg	up to 3 doses of 0.15 mg/kg intravenously every 4 hours	2 mg syrup every 12 hours
≥ 10 kg	up to 3 doses of 0.15 mg/kg intravenously every 4 hours	4 mg syrup or tablets every 12 hours

a – the intravenous dose should not exceed 8 mg;

b – the daily dose (within 24 hours) of the drug (as separate doses) should not exceed the adult dose of 32 mg.

Elderly patients

Patients aged 65 to 74 years may follow the adult dosing regimen when using the drug. All intravenous doses should be diluted in 50–100 mL of 0.9% sodium chloride solution or another suitable diluent (see section "Administration and dosage") and administered as an infusion over at least 15 minutes immediately before chemotherapy.

The initial dose of 8 mg may be supplemented by two subsequent intravenous doses of 8 mg each, administered over 15 minutes with an interval of at least 4 hours (see section "Pharmacokinetics").

Patients with renal impairment

There is no need to adjust the daily dosage, dosing regimen, or route of administration.

Patients with hepatic impairment

In patients with moderate or severe hepatic impairment, the clearance of Emeton is significantly reduced, and the serum elimination half-life is considerably prolonged. For such patients, the total daily dose should not exceed 8 mg; therefore, parenteral or oral administration is recommended.

Patients with sparteine/debrisoquine metabolism deficiency

The elimination half-life of ondansetron in patients with sparteine and debrisoquine metabolism deficiency is not altered. Therefore, repeated administration of the drug results in the same ondansetron concentration as in the general population. There is no need to adjust the dosage or frequency of administration.

Postoperative nausea and vomiting

Adults

For the prevention of postoperative nausea and vomiting, ondansetron may be administered orally or via intravenous or intramuscular injection. The recommended dose of Emeton is 4 mg, administered as an intramuscular or slow intravenous injection during anesthesia.

For the treatment of postoperative nausea and vomiting, the recommended single dose of Emeton is 4 mg, administered intramuscularly or slowly intravenously.

Children aged 1 month to 17 years

For the prevention of postoperative nausea and vomiting in children undergoing surgery under general anesthesia, a single dose of Emeton may be administered before, during, or after anesthesia via slow intravenous injection (over at least 30 seconds) at a dose of 0.1 mg/kg up to a maximum dose of 4 mg.

For the treatment of postoperative nausea and vomiting in children who have undergone surgery under general anesthesia, a single dose of Emeton may be administered via slow intravenous injection (over at least 30 seconds) at a dose of 0.1 mg/kg up to a maximum dose of 4 mg.

There are no data on the use of Emeton for the treatment of postoperative nausea and vomiting in children under 2 years of age.

Elderly patients

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

Patients with renal impairment

There is no need to adjust the daily dosage, dosing regimen, or route of administration.

Patients with hepatic impairment

In patients with moderate or severe hepatic impairment, the clearance of Emeton is significantly reduced, and the serum elimination half-life is considerably prolonged. For such patients, the total daily dose should not exceed 8 mg; therefore, parenteral or oral administration is recommended.

Patients with sparteine/debrisoquine metabolism deficiency

The elimination half-life of ondansetron in patients with sparteine and debrisoquine metabolism deficiency is not altered. Therefore, repeated administration of the drug results in the same ondansetron concentration as in the general population. There is no need to adjust the dosage or frequency of administration.

Administration of injection solution

Emeton vials do not contain preservatives and should be used immediately after opening; any remaining solution must be discarded. Emeton vials must not be autoclaved.

After dilution

After dilution in compatible intravenous infusion solutions, the drug is stable under normal room lighting or daylight conditions for at least 24 hours; therefore, protection from light during infusion is not required.

Compatibility with other intravenous solutions

Emeton should only be mixed with the recommended solutions, namely:

• 0.9% sodium chloride solution;
• 5% glucose solution;
• 10% mannitol solution;
• Ringer's solution;
• 0.3% potassium chloride solution and 0.9% sodium chloride solution;
• 0.3% potassium chloride solution and 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. If prolonged storage of the drug is required, dilution should be performed under appropriate aseptic conditions.

It has been established that ondansetron maintains stability when using polyethylene and glass bottles. It is known that ondansetron diluted in 0.9% sodium chloride or 5% glucose maintains stability in polypropylene syringes. Stability in polypropylene syringes has also been demonstrated when ondansetron is diluted with other recommended solutions.

Compatibility with other drugs

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

• cisplatin at concentrations up to 0.48 mg/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; 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 2 g, diluted in water for injection (e.g., 2.5 mL per 250 mg or 10 mL per 2 g of 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 (when administered simultaneously 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 mcg to 2.5 mg per 1 mL and ondansetron concentrations from 8 mcg to 1 mg per 1 mL.

Children

The drug is indicated for children aged 6 months and older undergoing chemotherapy and for children aged 1 month and older for the 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 described in patients receiving recommended doses (see section "Adverse reactions").

Manifestations of overdose have included visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree AV block. In all cases, these effects were fully reversible.

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

There is no specific antidote; therefore, symptomatic and supportive therapy should be administered in cases of overdose.

Further management of patients should be based on clinical indications or, if possible, in accordance with recommendations from the national poison center.

The use of ipecacuanha for the treatment of ondansetron overdose is not recommended, as its effect may not manifest due to the antiemetic action of ondansetron.

Adverse Reactions

The adverse reactions listed below are classified by organ system and frequency of occurrence. The frequency categories are defined as follows: 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), and not known (frequency cannot be estimated from available data).

Immune system:

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

Nervous system:

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

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 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.

Post-marketing surveillance has revealed the following adverse reactions:

Cardiovascular system: 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 rashes, urticaria.

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

General disorders and administration site reactions: Increased body temperature, pain, redness, burning sensation at the injection site.

Other: Hypokalemia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 2.5 years.

Unused contents of the ampoule should be discarded and must not be stored for future use.

Storage conditions:

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

Keep out of reach and sight of children.

Incompatibilities:

Emeton should not be mixed in the same syringe or infusion solution with other medicinal products, except for the recommended diluents (see section "Instructions for use and dosage").

Packaging: 2 ml or 4 ml in a polyethylene ampoule. Packs of 5 or 50 ampoules in a cardboard carton.

Prescription status: Prescription only.

Manufacturer:

PHARMASELL LLC

Manufacturer's address and place of business:

3 Prorizna Street, Village Kvitneve, Brovary District, Kyiv Oblast, 07408, Ukraine.