ZETRON

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZETRON (ZETRON®)

Composition:

Active substance: ondansetron;

1 ml of syrup contains: ondansetron hydrochloride dihydrate – 1 mg, equivalent to ondansetron – 0.8 mg;

5 ml of syrup contains: ondansetron 4 mg (as hydrochloride dihydrate);

Excipients: citric acid; sodium citrate, dihydrate; sodium benzoate (E 211); sorbitol solution 70% (E 420); strawberry flavor; purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Antiemetic agents and drugs for relief of 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 induced by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron in nausea and vomiting is not fully understood. During radiotherapy and administration of cytostatic agents, serotonin (5-HT) is released in the small intestine, leading to stimulation of afferent vagal nerve endings via activation of 5-HT3 receptors, thereby triggering the peripheral mechanism of the vomiting reflex. Ondansetron blocks initiation of this reflex. Activation of afferent vagal nerve endings, in turn, may induce release of 5-HT in the posterior region of the floor of the fourth ventricle (area postrema), which may contribute to development of the vomiting reflex via a central mechanism. Thus, suppression of chemotherapy- and radiotherapy-induced nausea and vomiting by ondansetron is likely mediated by antagonism at 5-HT3 receptors located both peripherally and within the central nervous system (CNS). Ondansetron does not affect plasma prolactin concentrations. The drug does not reduce psychomotor performance and has no sedative effect. The role of ondansetron in opioid-induced vomiting has not yet been established.

Pharmacokinetics.

The pharmacokinetic parameters of ondansetron do not change with repeated administration.

Absorption.

Ondansetron is completely absorbed from the gastrointestinal tract after oral administration and undergoes hepatic first-pass metabolism. Maximum plasma concentration is reached approximately 1.5 hours after intake. When the drug Zetron is administered orally in doses exceeding 8 mg, ondansetron plasma levels increase disproportionately, likely due to reduced first-pass metabolism in the liver. The mean bioavailability in healthy male volunteers after a single 8 mg tablet dose is approximately 55–60%. Bioavailability slightly increases when the drug is taken with food, but remains unchanged when taken with antacids.

Distribution.

Ondansetron exhibits moderate plasma protein binding (70–76%). The distribution of ondansetron is similar following oral, intramuscular, and intravenous administration in adults, as reflected by the volume of distribution at steady state.

Metabolism.

Ondansetron is primarily metabolized in the liver involving several enzymatic systems. The absence of the CYP2D6 isoenzyme (sparteine/debrisoquine polymorphism type) does not affect the pharmacokinetics of ondansetron.

Elimination.

Ondansetron is eliminated from systemic circulation primarily via hepatic metabolism. Less than 5% of the absorbed dose is excreted unchanged by the kidneys. The elimination half-life of ondansetron is similar following oral, intramuscular, or intravenous administration and is approximately 3 hours.

Special patient groups

Gender.

The pharmacokinetics of ondansetron are influenced by patient gender. Women exhibit higher rates and extent of absorption, as well as lower systemic clearance and volume of distribution (adjusted for body weight), compared to men.

Children.

Differences in pharmacokinetic parameters are partially explained by the higher percentage of body water in neonates and infants, and by the higher volume of distribution in children aged 1 to 4 months.

In children aged 3 to 12 years, absolute values of clearance and volume of distribution of ondansetron were lower compared to adults. Both parameters increased linearly with body weight, and in patients up to 12 years of age, these values approached those observed in adults.

When clearance and volume of distribution are normalized to body weight, these parameters are similar across different age groups. Dose adjustment based on body weight compensates for age-related changes and systemic exposure to ondansetron in children.

According to study results, the area under the plasma 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.

Elderly patients.

A more pronounced effect on the QTcF interval is expected in patients aged ≥ 75 years compared to younger patients.

Patients with renal impairment.

In patients with moderate renal impairment (creatinine clearance 15–60 mL/min), systemic clearance and volume of distribution are reduced after intravenous ondansetron administration, resulting in a slight, clinically insignificant prolongation of elimination half-life (5.4 hours). Studies in patients with severe renal impairment requiring regular hemodialysis showed no changes in ondansetron pharmacokinetics after intravenous administration.

Patients with hepatic impairment.

In patients with severe hepatic dysfunction, systemic clearance of ondansetron is markedly reduced, with elimination half-life prolonged to 15–32 hours, and oral bioavailability reaches 100% due to reduced presystemic metabolism.

Clinical characteristics.

Indications.

Adults

• Nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.
• Prevention of postoperative nausea and vomiting.

For the treatment of postoperative nausea and vomiting, ondansetron is recommended in the form of injection solution.

Children

• Nausea and vomiting induced by chemotherapy in children aged 6 months and older.

There are no study data on the use of oral ondansetron in children aged from 1 month for the prevention and treatment of postoperative nausea and vomiting; in this case, ondansetron in the form of injection solution is recommended.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Concomitant use with apomorphine (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Ondansetron does not accelerate or inhibit the metabolism of other drugs when used 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 liver 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 usually compensated by other enzymes, resulting in no or minimal changes in total ondansetron clearance, which do not require dose adjustment.

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 together with drugs that prolong the QT interval may lead to additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g., anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such as erythromycin), antifungal agents (such as ketoconazole), antiarrhythmic drugs (such as amiodarone), and β-blockers (such as atenolol or timolol) may increase 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 changes in mental status, autonomic instability, and neuromuscular disturbances) has 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 severe arterial hypotension and loss of consciousness have been observed during concomitant administration.

Phenytoin, carbamazepine, and rifampicin

In patients treated with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of orally administered ondansetron was increased and blood concentrations were decreased.

Tramadol

According to data from small clinical studies, ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use

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

Respiratory reactions should be treated symptomatically. Healthcare providers should pay special attention to such reactions, as they may be precursors of hypersensitivity reactions to the drug.

Ondansetron prolongs the QT interval in a dose-dependent manner. 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 cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy.

Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly following intravenous administration, symptoms appeared immediately after ondansetron 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 treatment with Zetron.

In patients undergoing adenoid and tonsil 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 ondansetron administration.

Serotonin syndrome, including changes in mental status, autonomic instability, and neuromuscular disturbances, has been reported in patients receiving ondansetron concomitantly with other serotonergic agents (SSRIs and SNRIs) (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.

The medicinal product Zetron contains sorbitol. The energy value of 1 g of sorbitol is 2.6 kcal. If a child has a known intolerance to certain sugars, consult a physician before administering this medicinal product. Patients with rare hereditary fructose intolerance should not take this product.

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 followed by oral administration of the drug. 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.

Use during pregnancy or breastfeeding

Women of reproductive potential

Women of reproductive potential should use contraception.

Pregnancy

Based on human experience and epidemiological data, there is suspicion of an increased risk of craniofacial defects with ondansetron use during the first trimester of pregnancy.

Studies on ondansetron use during the first trimester of pregnancy have been associated with an increased risk of cleft palate.

Studies on congenital heart defects have yielded 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 the milk of animals. Therefore, if use of 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 reaction speed when driving or operating machinery

Zetron has no effect or negligible effect on the ability to drive or operate machinery.

Psychomotor tests have shown that ondansetron does not impair performance and does not produce sedative effects. Given the pharmacological profile of ondansetron, no harmful effect on reaction speed during driving or operating machinery is expected.

Method of Administration and Dosage

Nausea and vomiting induced 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 choice of dosage regimen is determined by the emetogenicity of the antineoplastic therapy.

Emetogenic chemotherapy and radiation therapy

Ondansetron can be administered rectally (suppositories), orally (syrup or tablets), intramuscularly, or intravenously, depending on the pharmaceutical form.

The recommended oral dose is 8 mg of ondansetron 1–2 hours before the start of chemotherapy or radiation therapy, followed by 8 mg every 12 hours for up to 5 days to prevent delayed or prolonged vomiting.

Highly emetogenic chemotherapy

A single dose may be 24 mg of the medicinal product Zetron, administered concurrently with sodium phosphate dexamethasone at a dose of 12 mg, 1–2 hours before the start of chemotherapy. To prevent delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the medicinal product Zetron may be continued for up to 5 days after completion of the treatment course. The recommended oral dose is 8 mg twice daily.

Nausea and vomiting induced by chemotherapy in children aged 6 months to 17 years

The dose of the medicinal product Zetron can be calculated based on body surface area or body weight (see below). In pediatric clinical studies, ondansetron was administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable solvent over no less than 15 minutes.

The total daily dose calculated by body weight is higher than the total daily dose calculated by body surface area (see section "Special Instructions").

There are no data from controlled clinical studies on the use of ondansetron in children for the prevention of delayed or prolonged vomiting associated with chemotherapy, nor data on its use in children for the treatment of nausea and vomiting caused by radiation therapy.

Dose calculation based on body surface area

Zetron should be administered intravenously as a single dose of 5 mg/m² immediately before chemotherapy; the intravenous dose must not exceed 8 mg. Oral administration may be initiated 12 hours later and continued for up to 5 days (see Table 1). The total daily dose of ondansetron (divided into multiple doses) must not exceed the adult dose of 32 mg.

Dosage according to body surface area for nausea and vomiting induced by chemotherapy in children aged 6 months to 17 years.

Table 1

a The intravenous dose must not exceed 8 mg.

b The total daily dose (divided into several administrations) must not exceed the adult dose – 32 mg.

Dosing based on body weight

The total daily dose calculated by body weight is higher compared to the total daily dose calculated by body surface area (see section "Special instructions").

Zetron should be administered intravenously as a single dose immediately before chemotherapy at a dose of 0.15 mg/kg body weight; the intravenous dose must not exceed 8 mg. Subsequently, two additional intravenous doses may be administered at 4-hour intervals. 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 of ondansetron (divided into several administrations) must not exceed the adult dose – 32 mg.

Dosing according to body weight for nausea and vomiting induced by chemotherapy in children aged 6 months to 17 years

Table 2

a The intravenous dose should not exceed 8 mg.

b The total daily dose (divided into several administrations) should not exceed the adult dose – 32 mg.

Elderly patients

Elderly patients do not require adjustment of the oral dose or frequency of administration of the medicinal product Zetron.

Postoperative nausea and vomiting

Adults

For prevention of postoperative nausea and vomiting

Ondansetron may be administered orally, intramuscularly, or intravenously. For oral administration, a recommended dose of 16 mg of the medicinal product Zetron should be given 1 hour prior to anesthesia.

For treatment of postoperative nausea and vomiting

The injectable form of the medicinal product Zetron is recommended.

Children aged 1 month to 17 years

Oral form of ondansetron

There are no clinical data on the use of oral ondansetron in children for the prevention and treatment of postoperative nausea and vomiting; it is recommended to use ondansetron as an injection solution administered by slow intravenous injection (over no less than 30 seconds).

Injectable form of ondansetron

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

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

Elderly patients

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

For both indications

Patients with impaired renal function

There is no need to adjust the daily dose, frequency of administration, or route of administration of ondansetron in patients with impaired renal function.

Patients with impaired hepatic function

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

Patients with slow metabolism of sparteine/debrisoquine

In patients with slow metabolism of sparteine/debrisoquine, the half-life of ondansetron is not altered. Therefore, with repeated administration of ondansetron to such patients, its concentration does not differ from that in the general population. Hence, no adjustment of the daily dose or frequency of administration of the medicinal product is required in these cases.

Children

The medicinal product Zetron may be administered to children aged 6 months and older (in chemotherapy) (see sections "Indications" and "Dosage and administration").

Overdose

Symptoms

Data on ondansetron overdose are limited. In most cases, symptoms are similar to those observed 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 observed in overdose include visual disturbances, severe constipation, arterial hypotension, vasovagal reactions with transient second-degree AV block. In all cases, these effects were completely reversible.

Children

Cases indicating serotonin syndrome have been reported following accidental overdose of orally administered ondansetron (doses exceeding the recommended level of 4 mg/kg body weight) in children aged 12 months to 2 years.

Treatment

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

Further treatment should be guided by clinical indications.

The use of ipecacuanha for treatment of ondansetron overdose is not recommended, as its emetic effect may not occur due to the antiemetic action of the medicinal product Zetron.

Adverse Reactions

The adverse reactions listed below are classified by organ systems and frequency of occurrence. Frequencies are categorized 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).

Frequencies were estimated during administration of standard recommended therapeutic doses of ondansetron. The adverse reaction profile in children and adolescents is consistent with that in adults.

Immune system disorders:
Rare – immediate-type hypersensitivity reactions (urticaria, bronchospasm, laryngospasm, angioedema), in some cases severe, including anaphylaxis.

Nervous system disorders:
Very common – headache;
Uncommon – convulsions, movement disorders including extrapyramidal symptoms such as dystonia, oculogyric crisis (spasms of gaze), 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 resolved within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. In some cases, transient blindness was of cortical origin).

Cardiovascular system disorders:
Common – sensation of warmth or flushing;
Uncommon – arrhythmia, hypotension; chest pain, with or without ST-segment depression, bradycardia;
Rare – QT interval prolongation (including ventricular fibrillation/torsade de pointes);
Frequency not known – myocardial ischemia (see section "Special Warnings and Precautions for Use").

Respiratory system disorders:
Uncommon – hiccups.

Gastrointestinal disorders:
Common – constipation.

Hepatobiliary disorders:
Uncommon – asymptomatic elevation of liver enzymes (ALT and AST) (mainly observed in patients receiving cisplatin-based chemotherapy).

Skin and subcutaneous tissue disorders:
Very rare – toxic skin rash, including toxic epidermal necrolysis.

Reporting of suspected adverse reactions

"Reporting of suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical 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 at temperatures not exceeding 25 °C.

Do not freeze. Keep out of reach of children.

Packaging.

50 ml vials, 1 vial with a dosing spoon in a cardboard box.

Prescription status.

Prescription only.

Manufacturer(s).

RAFARM S.A., Greece / RAFARM S.A., Greece
BROS LTD, Greece / BROS LTD, Greece

Manufacturer's address and place of business.

Thesi Pousi-Xatzi Agiou Louka, Paiania (Attica), P.O. Box 37, ZIP 19002, Greece /
Thesi Pousi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, TO 37, Greece
15 Augis & Galinis Street, Nea Kifisia (Attica) 14564, Greece /
Augis & Galinis 15, Nea Kifisia (Attiki) 14564, Greece

Marketing Authorization Holder.

Pharmaceutical company «VOCATE S.A.», Greece /
Pharmaceutical company «VOCATE S.A.», Greece

Address of the Marketing Authorization Holder.

166 74 Glyfada, Gounari str., 150 Athens, Greece /
166 74 Glyfada, Gounari str., 150 Athens, Greece