Osetron®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OSERON® (OSETRON)

Composition:

active substance: ondansetron;

1 ml of solution contains ondansetron hydrochloride equivalent to 2 mg of ondansetron;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colourless solution, practically free from particles.

Pharmacotherapeutic group. Antiemetic and antinausea agents. 5HT3 serotonin receptor antagonists. ATC code A04AA01.

Pharmacological properties.

Pharmacodynamics. Ondansetron is an antiemetic agent belonging to the group of serotonin antagonists. Serotonin 5-HT3 receptors are located on vagal afferent fibers of the peripheral nervous system as well as in the chemoreceptor trigger zone (area postrema).

Chemotherapy and radiation therapy promote the release of 5-HT (serotonin) from enterochromaffin cells of the small intestine and provoke the vomiting reflex by stimulating 5-HT3 receptors on afferent fibers. Ondansetron blocks the development of these reflexes and may additionally affect 5-HT3 receptors in the central nervous system by acting on vagal areas of the area postrema. Thus, during cytotoxic chemotherapy and radiation therapy, the action of ondansetron is due to antagonism of 5-HT3 receptors in both peripheral and central nervous system neurons. The drug has anxiolytic activity and does not cause motor coordination disturbances or reduce activity and work capacity.

Pharmacokinetics. After intravenous administration, the drug rapidly distributes via the bloodstream throughout all organs and tissues of the body. Maximum plasma concentration of ondansetron is achieved within 5 minutes after intravenous infusion of 4 mg and within 10 minutes after intramuscular injection. Plasma protein binding is high (70–76%). Ondansetron is primarily eliminated from systemic circulation via hepatic metabolism; at least 5% of the dose is excreted unchanged in urine. The mean elimination half-life in adult patients is approximately 3 hours. In patients with impaired liver function, the half-life is prolonged to 15–20 hours. The drug is actively metabolized in the body, and metabolites are excreted in feces and urine.

Clinical characteristics.

Indications. Nausea and vomiting caused by cytotoxic chemotherapy and radiation therapy. Prevention and treatment of postoperative nausea and vomiting.

Contraindications. Hypersensitivity to ondansetron or to any of the excipients of the medicinal product. Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of pronounced arterial hypotension and loss of consciousness have been observed during simultaneous administration.

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, lignocaine, 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 total 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 administration of ondansetron with cardiotoxic drugs (e.g., anthracyclines such as doxorubicin, daunorubicin, or trastuzumab), antibiotics (e.g., erythromycin), antifungal agents (e.g., ketoconazole), antiarrhythmic drugs (e.g., amiodarone), and beta-blockers (e.g., atenolol or timolol) increases the risk of developing arrhythmias (see section "Special precautions for use").

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

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

Apomorphine

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of pronounced hypotension and loss of consciousness have been observed during combined administration.

Phenytoin, carbamazepine, and rifampicin

In patients receiving potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron is increased and its blood concentration is reduced.

Tramadol

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

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 hypersensitivity to the medicinal product.

Ondansetron dose-dependently prolongs the QT interval (see section "Pharmacological properties"). In addition, post-marketing surveillance has 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, and patients 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 after intravenous administration, symptoms appeared immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischemia.

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 patient monitoring is recommended.

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

In patients undergoing surgery in the adenotonsillar region, 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.

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

Children

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

Dosing regimens

When calculating the dose based on body weight and administering three doses at 4-hour intervals, the total daily dose will be higher than when using a single dose of 5 mg/m² and one oral dose of the drug. 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.

Use during pregnancy or breastfeeding.

Women of childbearing potential. If ondansetron is administered to women of childbearing potential, contraception should be considered.

Pregnancy. Based on human experience from epidemiological studies, there are concerns about the development of craniofacial defects following ondansetron use during the first trimester of pregnancy.

In one cohort study involving 1.8 million pregnancies, ondansetron use during the first trimester was associated with an increased risk of oral clefts [3 additional cases per 10,000 women treated with ondansetron; adjusted relative risk: 1.24 (95% confidence interval (CI) 1.03–1.48)]. Available epidemiological data on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects on reproductive performance.

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

Breastfeeding. Experimental studies have shown that ondansetron penetrates into the breast milk of 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 affect performance when driving or operating machinery. Psychomotor tests have shown that ondansetron does not affect the ability to drive or operate machinery and has no sedative effect. However, the adverse reaction profile of the medicinal product should be taken into account when deciding whether a patient can drive or operate machinery.

Administration and Dosage.

Nausea and vomiting induced by chemotherapy and radiotherapy.

Adults.

The emetogenic potential of cancer therapy varies depending on the dose and combination regimens of chemotherapy and radiotherapy. The choice of dosing regimen depends on the severity of emetogenic effect.

Emetogenic chemotherapy and radiotherapy.

The recommended intravenous or intramuscular dose of ondansetron is 8 mg administered as a slow intravenous injection over at least 30 seconds or as an intramuscular injection immediately before treatment.

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

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

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

For highly emetogenic chemotherapy, 8 mg of ondansetron or a lower dose does not need to be diluted and may be administered by slow intravenous or intramuscular injection (over at least 30 seconds) immediately before chemotherapy, followed by two additional intravenous or intramuscular doses of 8 mg given 2 and 4 hours later, or by continuous infusion of 1 mg/hour for 24 hours.

Doses exceeding 8 mg (up to 16 mg) may only be administered as intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable solvent (see below, "Use of injection solution"); the infusion should last no less than 15 minutes.

Single doses exceeding 16 mg must not be used (see section "Special Instructions").

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

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

Children aged 6 months to 17 years

The drug dosage can be calculated based on the child's body surface area or body weight.

Dosage calculation according to child's body surface area

Osetron® 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 may be initiated 12 hours after the initial dose and may continue for an additional 5 days. Adult dosage must not be exceeded.

Dosage calculation according to child's body weight

Osetron® 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 may be initiated 12 hours after the initial dose and may continue for an additional 5 days. Adult dosage must not be exceeded.

Elderly patients

For patients aged 65 years and older, all intravenous injection doses should be diluted and administered over 15 minutes. When repeated administration is required, the interval between injections should be at least 4 hours.

For patients aged 65 to 74 years, the initial dose of ondansetron is 8 mg or 16 mg, administered by intravenous infusion over 15 minutes, followed by two additional doses of 8 mg infused over 15 minutes each, with intervals between infusions of at least 4 hours.

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 each, with intervals between infusions of at least 4 hours.

Patients with renal impairment

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

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, ondansetron clearance is significantly reduced and 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 elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with normal metabolism. Therefore, dosage adjustment or change in frequency of administration is not required.

Postoperative nausea and vomiting.

Adults.

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

For treatment of postoperative nausea and vomiting, the recommended single dose of ondansetron is 4 mg administered as an intramuscular or slow intravenous injection.

Children aged 1 month to 17 years

For prevention and treatment of postoperative nausea and vomiting in children undergoing general anesthesia, ondansetron may be administered at a dose of 0.1 mg/kg body weight (maximum up to 4 mg) by slow intravenous injection (over at least 30 seconds) before, during, after induction of anesthesia, or after surgery.

Elderly patients

Experience with ondansetron for prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, ondansetron 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, ondansetron clearance 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 elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. Repeated administration results in similar drug concentrations as in patients with normal metabolism. Therefore, dosage adjustment or change in frequency of administration is not required.

Use of injection solution

The medicinal product contains no preservatives and the solution 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) 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 shown that ondansetron remains stable when using polyethylene and glass bottles. Ondansetron diluted in 0.9% sodium chloride or 5% glucose has been shown to be 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

Osetron® may be administered as intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, with ondansetron concentration ranging from 16 to 160 mcg/mL (i.e., 8 mg / 500 mL or 8 mg / 50 mL, respectively), the following drugs may be co-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 ondansetron precipitation. 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 in 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 intravenous bolus injection over 5 minutes;
• cyclophosphamide in doses from 100 mg to 1 g, diluted in water for injection (5 mL per 100 mg cyclophosphamide), administered as intravenous bolus injection over 5 minutes;
• doxorubicin in doses from 10 mg to 100 mg, diluted in water for injection (5 mL per 10 mg doxorubicin), administered as intravenous bolus injection over 5 minutes;
• dexamethasone 20 mg, administered as 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 mcg to 2.5 mg/mL and ondansetron concentrations from 8 mcg to 1 mg/mL.

Children. To be used in 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 observed in patients receiving recommended doses (see section "Adverse Reactions").

Reported manifestations of overdose include visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree atrioventricular block. In all cases, these effects resolved completely.

Ondansetron prolongs the QT interval in a dose-dependent manner. In case of overdose, ECG monitoring is recommended.

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

Ipecac syrup is not recommended for treatment of ondansetron overdose, as its effect may be ineffective due to the antiemetic action of the drug.

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

Adverse reactions are classified by organ systems and by frequency of occurrence. The frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Immune system

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 fibrillation/tachycardia (torsade de pointes).

Myocardial ischemia (frequency not known) (see section "Special precautions").

Vascular disorders

Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common: Constipation.

Hepatobiliary disorders

Uncommon: Asymptomatic elevation of liver function tests.

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: Reactions at the site of intravenous administration.

During post-marketing surveillance, the following adverse reactions have been reported:

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

Hypersensitivity reactions: Anaphylactic reactions, angioedema, bronchospasm, anaphylactic shock, pruritus, skin eruptions, urticaria.

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

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

Other: Hypokalemia.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children. Do not freeze.

Incompatibilities. Osetron® must not be used in the same syringe or infusion solution with other medicinal products. Osetron® for injection may only be mixed with the recommended infusion solutions (see section "Administration and dosage").

Packaging. 2 mL (4 mg) or 4 mL (8 mg) in a vial, 5 vials per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Limited

Manufacturer’s address and place of business.

Production site: VI, Village Khol, Nalagarh Road, Baddi, District Solan, Himachal Pradesh, 173205, India

To report adverse reactions or lack of efficacy with this medicinal product, please call:

+380 44 207 51 97 or +380 50 414 39 39; or email: [email protected] (24/7).