Zetron

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

Composition:

Active substance: ondansetron;

1 ml of solution contains: ondansetron hydrochloride dihydrate – 2.49 mg, equivalent to ondansetron – 2 mg;

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

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antiemetic and anti-nausea agents. Serotonin (5HT3) receptor antagonists. ATC code A04AA01.

Pharmacological Properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective antagonist of 5-HT₃ (serotonin) receptors. The drug prevents or eliminates nausea and vomiting caused by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron in nausea and vomiting is not fully understood. 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.

After intramuscular administration, peak plasma concentration is reached within 10 minutes. The volume of distribution following 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 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 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 any component of the drug.

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

Interaction with other medicinal products and other forms of interactions.

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").

Concomitant use of ondansetron with drugs that prolong the QT interval may lead to additional QT prolongation. Concurrent 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 beta-blockers (such as atenolol or timolol) may increase the risk of developing arrhythmias (see section "Special precautions for use").

Apomorphine

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

Tramadol

According to a limited number of clinical studies, ondansetron may reduce the analgesic effect of tramadol.

The use of Zetron with other medicinal products that prolong the QT interval may result in additional QT prolongation. Concurrent use of Zetron with cardiotoxic medicinal products (e.g., anthracyclines) may increase the risk of arrhythmias (see section "Special precautions for use").

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 indicate hypersensitivity 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 fibrillation (torsade de pointes) 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 induce QT prolongation or electrolyte disturbances.

Hypokalaemia and hypomagnesaemia should be corrected prior to initiating treatment. Cases of myocardial ischaemia have been reported in patients receiving ondansetron. In some patients, particularly after intravenous administration, symptoms occurred immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischaemia.

Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic drugs (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant treatment with ondansetron and other serotonergic drugs is clinically justified, appropriate monitoring of the patient is recommended.

Since ondansetron reduces gastrointestinal motility, careful monitoring is required in patients showing signs of subacute intestinal obstruction during Zetron use.

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

One injection of Zetron contains less than 1 mmol of sodium (23 mg) per dose, i.e. it is practically sodium-free.

Children

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

Dosing regimens

When calculating the dose according to body weight and administering three doses with a 4-hour interval, the total daily dose will be higher than when using a single dose of 5 mg/m² and one oral dose of ondansetron. The efficacy of these two dosing regimens has not been studied. Results from various studies indicate similar efficacy for both dosing regimens.

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should use contraceptive methods.

Pregnancy

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

Studies on ondansetron use in the first trimester of pregnancy have been associated with an increased risk of orofacial clefts.

Studies on congenital heart defects have shown conflicting results. Animal studies have not indicated direct or indirect harmful effects related to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

Breastfeeding

Studies have shown that ondansetron passes into the breast 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 fertility in humans.

Ability to affect reaction speed when driving or operating machinery

Psychomotor tests have shown that ondansetron does not affect the ability to operate machinery and does not have sedative effects. However, the adverse effect profile of the drug should be taken into account when deciding on the ability to drive or operate machinery.

Method of Administration and Dosage

Nausea and vomiting induced by chemotherapy and radiotherapy

Adults

The emetogenic potential of cancer therapy varies depending on the dose and combination regimens of chemotherapy and radiotherapy. The choice of dosage regimen depends on the severity of emetogenicity. The dose of Zetron (range from 8 to 32 mg per day) and route of administration should be selected according to the information provided below.

Emetogenic chemotherapy and radiotherapy

The recommended intravenous or intramuscular dose of Zetron is 8 mg administered as a slow injection over at least 30 seconds 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 following completion of the treatment course.

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

Zetron may be administered as a single 8 mg dose intravenously or intramuscularly immediately before chemotherapy. Doses exceeding 8 mg (up to 16 mg) must be given only as an intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable solvent (see below "Instructions for Use"); the infusion should last no less than 15 minutes. A single dose exceeding 16 mg must not be administered, as higher doses increase the risk of QT interval prolongation (see section "Special precautions for use").

For highly emetogenic chemotherapy, 8 mg of Zetron or lower doses do not require dilution 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 choice of dosage regimen depends on the severity of emetogenicity. The efficacy of Zetron in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate before chemotherapy.

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

Children (aged 6 months to 17 years)

In pediatric practice, Zetron should be administered via intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable solvent (see below "Instructions for Use") over at least 15 minutes. The drug dose can be calculated based on body surface area or body weight.

Zetron should be diluted with 5% dextrose solution, 0.9% sodium chloride solution, or another appropriate infusion solution and administered by intravenous infusion over at least 15 minutes.

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

Dose calculation based on body surface area in children

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

Dose calculation based on body weight in children

Zetron should be administered immediately before chemotherapy as a single intravenous injection at a dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg. On the first day, two additional intravenous doses may be administered with a 4-hour interval. Oral administration of the drug may be initiated 12 hours later and may continue for up to 5 additional days. Adult dose must not be exceeded.

Elderly patients

For patients aged 65 years and older, all intravenous injections 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 doses of 8 mg each, infused over 15 minutes with an interval of at least 4 hours between infusions.

For patients aged 75 years and older, the initial intravenous dose of ondansetron must not exceed 8 mg, administered by infusion over at least 15 minutes. After the initial 8 mg dose, two additional 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 dosage regimen or route of administration in patients with impaired renal function.

Patients with hepatic impairment

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

Patients with impaired sparteine/debrisoquine metabolism

The half-life of ondansetron in patients 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, no adjustment of dosage or frequency of administration is required.

Postoperative nausea and vomiting

Adults

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

For treatment of postoperative nausea and vomiting, the recommended single dose of Zetron 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, Zetron may be administered at a dose of 0.1 mg/kg body weight (maximum dose up to 4 mg) as a slow intravenous injection (over at least 30 seconds) before, during, or after anesthesia induction or after surgery.

Elderly patients

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

Patients with renal impairment

There is no need to adjust the dosage regimen or route of administration in patients with impaired renal function.

Patients with hepatic impairment

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

Patients with impaired sparteine/debrisoquine metabolism

The 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 intact metabolism. Therefore, no adjustment of dosage or frequency of administration is required.

Instructions for Use

Zetron ampoules do not contain preservatives and must be used immediately after opening; any unused solution must be discarded.

Zetron 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) in daylight or in the refrigerator when diluted in the following media: 0.9% sodium chloride solution, 5% glucose solution, 10% mannitol solution, Ringer's solution, 0.3% potassium chloride and 0.9% sodium chloride solution, 0.3% potassium chloride and 5% glucose solution.

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

Compatibility with other drugs

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

• cisplatin at concentrations up to 0.48 mg/mL 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 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 co-administered 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 µg to 2.5 mg per mL and ondansetron concentrations from 8 µg to 1 mg per mL.

Children

For use in children aged 6 months (during chemotherapy) and 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 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 of overdose include visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree AV block. In all cases, these effects were fully reversible.

There have been reports of serotonin syndrome in young children following oral overdose.

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 or, if possible, according to recommendations from the national poison control center.

Ipecac syrup is not recommended for treatment of ondansetron overdose, as its 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 oral overdose of ondansetron (doses exceeding the recommended level of 4 mg/kg).

Adverse reactions.

The adverse reactions listed below are classified by system organ class and frequency of occurrence. 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, up to anaphylaxis.

Nervous system disorders:
Very common – headache;
Uncommon – convulsions, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences);
Rare – dizziness, mainly after 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 of these patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient blindness have been reported as cortical in origin.

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

Respiratory, thoracic and mediastinal disorders:
Uncommon – hiccups.

Gastrointestinal disorders:
Common – constipation.

Hepatobiliary disorders:
Uncommon – asymptomatic elevations in 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.

From post-marketing experience, the following adverse reactions have been reported:

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

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

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

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

Other:
Hypokalemia.

Reporting suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.

Incompatibilities.

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

Packaging.

4 ml in a vial; 5 vials 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 Kifissia (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.