Emesetron-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EMESETRON-ZDOROVIYA (EMESETRON-ZDOROVIYA)

Composition:

Active substance: ondansetron;

1 ml of solution contains ondansetron 2 mg;

Excipients: citric acid monohydrate; sodium citrate; disodium edetate; sorbitol (E 420); sodium hydroxide; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colourless or slightly yellowish solution.

Pharmacotherapeutic group.

Antiemetics and drugs used to counteract nausea. Serotonin receptor antagonists (5HT3). 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 likely that the drug inhibits the initiation of 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 performance 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 is 70–76%.

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. Pharmacokinetics of ondansetron are practically unchanged in patients with severe renal impairment undergoing chronic hemodialysis (studies were conducted between hemodialysis sessions). In patients with severe chronic hepatic impairment, systemic clearance of ondansetron is markedly reduced, with a consequent increase in 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 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 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").

Apomorphine.

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe 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.

Serotonergic agents (e.g., SSRIs and SNRIs).

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

Tramadol.

According to some clinical studies, ondansetron may reduce the analgesic effect of tramadol.

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

Special precautions for use

In patients with known 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 such reactions, as they may be signs of drug hypersensitivity.

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, bradyarrhythmias, or those receiving other medicinal products that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly following intravenous administration, symptoms occurred immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischem 1.

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.

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 should be closely monitored after ondansetron administration.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

This medicinal product contains the excipient sorbitol (E 420). If the patient has been diagnosed with an intolerance to certain sugars, consult a physician before taking this medicinal product.

Children

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

Dosing regimens

When dosing is calculated according to body weight and three doses are administered at 4-hour intervals, the total daily dose will be higher than with a single 5 mg/m² dose followed by 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 indicates similar efficacy for both dosing regimens.

Use during pregnancy or breastfeeding

Women of childbearing potential. If ondansetron is administered to women of childbearing potential, consideration should be given to using contraception.

Pregnancy. Epidemiological data suggest that ondansetron may cause craniofacial malformations when used during the first trimester of pregnancy. In one cohort study involving 1.8 million pregnancies, ondansetron use during the first trimester was associated with an increased risk of oral clefts (3 additional cases per 10,000 women treated with 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 reproductive toxicity. Ondansetron should not be used during the first trimester of pregnancy.

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

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

Ability to affect performance of skills such as driving or operating machinery.

Psychomotor tests have shown that ondansetron does not affect the ability to operate machinery and has no sedative effect. However, the adverse reaction profile of the medicinal product should be taken into account when deciding whether patients may drive or operate machinery.

Method of Administration and Dosage

Nausea and vomiting caused by chemotherapy and radiation therapy

The emetogenic potential of cancer therapy varies depending on the dose and combination regimens of chemotherapy and radiation therapy. The choice of dosing regimen depends on the severity of emetogenic impact. The route of administration and doses should be flexible within 8–32 mg per day.

Adults

Emetogenic chemotherapy and radiation therapy

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

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 after the treatment course.

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

The drug may be administered as a single 8 mg dose intravenously or intramuscularly immediately before chemotherapy.

Doses exceeding 8 mg (up to 16 mg) may only be administered as an intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable solvent (see below "Use of the injection solution"); the infusion should last at least 15 minutes and be given immediately before chemotherapy.

The initial dose may be followed by two additional intravenous or intramuscular administrations of 8 mg (over no less than 30 seconds) at 4-hour intervals. Single doses exceeding 16 mg should not be used due to increased risk of QT interval prolongation (see section "Special precautions").

For highly emetogenic chemotherapy, a single dose of 8 mg or a lower dose does not need to be diluted and may be administered as a 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.

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.

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 after the treatment course.

Children aged 6 months to 17 years

In pediatric practice, the medicinal product should be administered by intravenous infusion, diluted in 25–50 mL of 0.9% sodium chloride solution, 5% glucose solution, or another suitable solvent (see below "Use of the injection solution") over at least 15 minutes. The drug dose can be calculated based on body surface area or body weight. Dose calculation based on body weight results in higher total daily doses compared to calculation based on body surface area (see section "Special precautions").

There are no data from controlled clinical trials on the use of ondansetron for the prevention of nausea and vomiting caused by radiation therapy in children.

Dose calculation based on body surface area in children

The drug should be administered immediately before chemotherapy as a single intravenous injection at a dose of 5 mg/m²; the intravenous dose should not exceed 8 mg. Oral administration may be initiated 12 hours later and may continue for up to 5 additional days. The adult maximum daily dose of 32 mg should not be exceeded.

Dose calculation for chemotherapy based on body surface area in children aged 6 months to 17 years:

Body surface area	Day 1 (A, B)	Day 2–6 (B)
< 0.6 m²	5 mg/m² intravenously, then 2 mg orally (use dosage forms with appropriate strength) after 12 hours.	2 mg orally (use dosage forms with appropriate strength) every 12 hours.
≥ 0.6 m² to ≤ 1.2 m²	5 mg/m² intravenously, then 4 mg orally (use dosage forms with appropriate strength) after 12 hours.	4 mg orally (use dosage forms with appropriate strength) every 12 hours.
> 1.2 m²	5 mg/m² or 8 mg intravenously, then 8 mg orally (use dosage forms with appropriate strength) after 12 hours.	8 mg orally (use dosage forms with appropriate strength) every 12 hours.

A. The intravenous dose should not exceed 8 mg.
B. The total daily dose should not exceed the adult dose (32 mg).

Dose calculation based on child's body weight

The drug should be administered intravenously as a single bolus injection at a dose of 0.15 mg/kg, immediately before chemotherapy. The intravenous dose must not exceed 8 mg. On the first day, two additional intravenous doses may be given at 4-hour intervals. Oral administration may be initiated 12 hours after the initial dose and may continue for up to 5 additional days. The adult dose (32 mg) must not be exceeded.

Dose calculation for chemotherapy based on body weight in children aged 6 months to 17 years:

Weight	Day 1 (A, B)	Day 2–6 (B)
≤ 10 kg	Up to 3 doses of 0.15 mg/kg intravenously every 4 hours.	2 mg orally (use dosage forms with appropriate strength) every 12 hours.
> 10 kg	Up to 3 doses of 0.15 mg/kg intravenously every 4 hours.	4 mg orally (use dosage forms with appropriate strength) every 12 hours.

A. The intravenous dose must not exceed 8 mg.
B. The total daily dose must not exceed the adult dose (32 mg).

Geriatric Patients

For patients aged 65 years and older, all doses for intravenous injection should be diluted and administered over 15 minutes; with repeated administration, the interval between injections must 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 doses of 8 mg each, given by infusion 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 at least 15 minutes. After the initial 8 mg dose, two further doses of 8 mg 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 dosing regimen or route of administration in patients with impaired renal function.

Patients with Hepatic Impairment

In patients with moderate to severe hepatic impairment, drug 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; therefore, parenteral or oral administration is recommended.

Patients with Impaired Metabolism of Sparteine/Debrisoquine

The elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. In these patients, repeated administration results in drug concentrations similar to those in patients with normal metabolism. Therefore, dose adjustment or change in frequency of administration is not required.

Postoperative Nausea and Vomiting

Adults

The recommended dose for prevention of postoperative nausea and vomiting 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 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, the drug may be administered at a dose of 0.1 mg/kg body weight (maximum up to 4 mg) by slow intravenous injection (over no less than 30 seconds) before, during, or after induction of anesthesia or following surgery.

Geriatric Patients

Experience with the use of the drug for prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, the drug is well tolerated in patients aged 65 years and older receiving 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, drug clearance is significantly reduced and serum half-life is prolonged. For such patients, the maximum daily dose must not exceed 8 mg; therefore, parenteral or oral administration is recommended.

Patients with Impaired Metabolism of Sparteine/Debrisoquine

The elimination half-life of ondansetron in subjects with impaired sparteine and debrisoquine metabolism is unchanged. Repeated administration in these patients results in drug concentrations similar to those in patients with normal metabolism. Therefore, dose adjustment or change in frequency of administration is not required.

Administration of Injection Solution

The medicinal product contains no preservatives and must be used immediately after opening the ampoule; any unused solution must be discarded. Ampoules must not be autoclaved.

Compatibility with Other Intravenous Solutions

Intravenous 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 a 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.

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

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

Compatibility with Other Medicinal Products

The drug may be administered by intravenous infusion at a rate of 1 mg/hour.

Via a Y-injector, the following drugs may be co-administered with ondansetron at concentrations of 16 to 160 mcg/mL (i.e., 8 mg/500 mL or 8 mg/50 mL, respectively):

• 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., 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., 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 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 (concurrently with 8 mg or 16 mg ondansetron diluted in 50–100 mL of infusion 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.

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. 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.

Manifestations reported in overdose include visual disturbances, severe constipation, 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.

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 official poisoning management guidelines.

The use of ipecacuanha for treatment of ondansetron overdose is not recommended, as its emetic effect may be counteracted by the antiemetic action of ondansetron.

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).

Adverse reactions.

Immune system disorders: immediate-type hypersensitivity reactions, sometimes severe, up to anaphylaxis; anaphylactic reactions, angioedema, bronchospasm, anaphylactic shock, pruritus, skin rashes, urticaria.

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

Eye disorders: transient visual disturbances (blurred vision), 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 were reported as cortical in origin.

Cardiac disorders: arrhythmias, chest pain (with or without ST segment depression), bradycardia, QT interval prolongation (including ventricular fibrillation/torsade de pointes), chest pain and discomfort, extrasystoles, tachycardia including ventricular and supraventricular tachycardia, atrial fibrillation, palpitations, syncope, ECG changes, myocardial ischemia.

Vascular disorders: sensation of warmth or flushing, hypotension.

Respiratory, thoracic and mediastinal disorders: hiccups.

Gastrointestinal disorders: constipation.

Hepatobiliary disorders: asymptomatic elevation of liver function parameters.

These cases occur mainly in patients treated with chemotherapeutic agents containing cisplatin.

Skin and subcutaneous tissue disorders: toxic skin eruptions, including toxic epidermal necrolysis.

General disorders and administration site conditions: local reactions at the site of intravenous administration, increased body temperature, pain, redness, burning sensation at the injection site.

Other: hypokalemia.

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 in the same syringe or infusion solution with other medicinal products. The injectable form of the medicinal product may be combined only with the recommended infusion solutions (see section "Dosage and administration").

Packaging.

2 ml or 4 ml in vials, pack of 5 in a box; pack of 5, pack of 5×2 in blisters in a box. |tablets|

Prescription category. Prescription only.

Manufacturer.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's location and address of the place of business.

22, Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.