Ondanset

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONDANSET (ONDANSET)

Composition:

Active substance: ondansetron;

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

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

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 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. The drug possibly blocks the initiation of the vomiting reflex by exerting antagonistic effects on 5-HT3 receptors located on neurons of both the peripheral and central nervous systems. The drug does not impair psychomotor performance and has no sedative effect.

Pharmacokinetics.

The volume of distribution after parenteral administration in adults is approximately 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 ranges from 70% to 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. The pharmacokinetics of ondansetron is almost unchanged in patients with severe renal impairment undergoing chronic hemodialysis (the study was conducted between hemodialysis sessions). In patients with severe chronic hepatic impairment, systemic clearance of ondansetron is markedly reduced, leading to an increased elimination half-life (15–32 hours).

Clinical characteristics.

Indications.

Nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

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

Hypersensitivity to any component of the drug.

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 the effect will be negligible.

Ondansetron should be used with caution in combination with medicinal products that prolong the QT interval and/or cause electrolyte imbalance (see section "Special precautions").

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 CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron is increased and its blood concentration is decreased.

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 drugs, including SSRIs and SNRIs (see section "Special precautions").

Tramadol

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

Concomitant use of Onsetan with other medicinal products that prolong the QT interval may result in additional QT prolongation. Combined use of Onsetan with cardiotoxic drugs (e.g., anthracyclines) increases the risk of arrhythmias (see section "Special precautions").

Special precautions for use

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

Respiratory-related 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 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 lead to QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic medicinal agents (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 ondansetron therapy.

In patients undergoing surgery in the adenotonsillar region, administration of ondansetron for the prevention of nausea and vomiting may mask the occurrence of postoperative bleeding. Therefore, such patients should be closely monitored after ondansetron administration.

One injection of Ondanset contains less than 1 mmol of sodium (23 mg) per dose and is therefore essentially sodium-free.

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

Children

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

Dosing regimens

When dosing is based on 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. Comparison of results from different studies suggests similar efficacy for both dosing regimens.

Use during pregnancy or breastfeeding

The safety of Ondanset during pregnancy in humans has not been established. In animal studies, ondansetron did not impair embryonal or fetal development nor affect the course of pregnancy, or peri- and postnatal development. However, since animal studies are not always predictive for humans, ondansetron is not recommended during pregnancy.

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

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

Ability to influence the ability to drive and use machines

Psychomotor tests have shown that ondansetron does not impair the ability to drive or operate machinery and has no sedative effect. However, the drug's adverse effect profile should be taken into account when assessing a patient's ability to 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 effect.

Adults

Emetogenic chemotherapy and radiation therapy

The recommended intravenous or intramuscular dose of Ondanset 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 the drug is recommended.

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

Ondanset may be administered as a single 8 mg intravenous or intramuscular dose 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 "Administration of injection solution"); the infusion should last no less than 15 minutes. A single dose exceeding 16 mg must not be administered (see section "Special precautions").

For highly emetogenic chemotherapy, 8 mg of Ondanset or a lower dose does not require dilution 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 at 2 and 4 hours, or by continuous infusion of 1 mg/hour for 24 hours.

The efficacy of Ondanset in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of sodium dexamethasone phosphate at a dose of 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

In pediatric practice, Ondanset should be administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable solvent (see below "Administration of injection solution") over at least 15 minutes.

The drug dose can be calculated based on body surface area or body weight of the child.

Dose calculation according to child's body surface area

Ondanset 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 another 5 days. Adult dose must not be exceeded.

Dose calculation according to child's body weight

Ondanset 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. Two additional intravenous doses may be administered on the first day with a 4-hour interval. Oral administration of the drug may be initiated 12 hours later and may continue for another 5 days. Adult dose 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; in repeated administration, 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 8 mg doses infused over 15 minutes, with an interval between infusions of at least 4 hours.

In patients aged 75 years and older, the initial intravenous injection of ondansetron must not exceed 8 mg, administered by infusion over at least 15 minutes. After the initial 8 mg dose, two additional 8 mg doses may be administered by infusion over 15 minutes, with an interval between infusions of at least 4 hours.

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with sparteine/debrisoquine metabolism disorders

The half-life of ondansetron in patients with sparteine and debrisoquine metabolism disorders is unchanged. In such patients, plasma concentrations after repeated administration are 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 Ondanset 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 Ondanset 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, Ondanset 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, or after induction of anesthesia or after surgery.

Elderly patients

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

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with sparteine/debrisoquine metabolism disorders

The half-life of ondansetron in patients with sparteine and debrisoquine metabolism disorders is unchanged. In such patients, plasma concentrations after repeated administration are similar to those in patients with intact metabolism. Therefore, no adjustment of dosage or frequency of administration is required.

Administration of injection solution

Ondanset vials contain no preservatives, and the solution must be used immediately after opening; any unused solution must be discarded.

Ondanset vials must not be autoclaved.

Compatibility with other intravenous fluids

Intravenous infusion 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 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 maintains stability when using polyethylene and glass vials. It has been shown that ondansetron diluted in 0.9% sodium chloride or 5% glucose maintains stability in polypropylene syringes. Stability in polypropylene syringes has also been demonstrated when ondansetron is diluted with other recommended solvents.

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

Compatibility with other drugs

Ondanset may be administered by intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, Ondanset may be co-administered with the following drugs at ondansetron concentrations ranging from 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 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 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 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 injection solution) over approximately 15 minutes; since these drugs are compatible, they may be administered through the same infusion line, with dexamethasone phosphate (as sodium salt) concentrations ranging from 32 mcg to 2.5 mg per mL and ondansetron concentrations from 8 mcg to 1 mg per 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 Ondanset 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 of overdose include visual disturbances, severe constipation, arterial 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 accidental 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 recommendations from the national poison center.

The use of ipecac syrup for treatment of ondansetron overdose is not recommended, as its effect may be ineffective due to the antiemetic action of Ondanset.

Children: serotonin syndrome has been reported in infants and children aged 12 months to 2 years after accidental overdose of the oral formulation (doses exceeding the recommended level of 4 mg/kg).

Adverse Reactions

The adverse effects listed below are classified by system organ class and frequency of occurrence. Adverse effects are categorized by frequency 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, occasionally severe, up to anaphylaxis.

Nervous system disorders:

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).

Cardiac disorders:

Uncommon: Arrhythmia, chest pain (with or without ST-segment depression), bradycardia;

Rare: QT interval prolongation (including ventricular fibrillation/torsade de pointes);

Not known: Myocardial ischemia (see section "Special precautions for use").

Vascular disorders:

Common: Sensation of warmth or flushing;

Uncommon: Arterial hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Hiccups.

Gastrointestinal disorders:

Common: Constipation.

Hepatobiliary disorders:

Uncommon: Asymptomatic increase in liver function parameters.

These cases occur mainly in patients treated with chemotherapy regimens containing cisplatin.

Skin and subcutaneous tissue disorders:

Very rare: Toxic skin eruptions, including toxic epidermal necrolysis.

General disorders and administration site conditions:

Common: Local reactions at the site of intravenous administration.

Post-marketing surveillance has reported the following adverse reactions:

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

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

Nervous system disorders: 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 in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Incompatibilities.

Ondansetron must not be used in the same syringe or infusion solution with other medicinal products. Ondansetron may be combined only with recommended infusion solutions (see section "Method of administration and dosage").

Packaging.

2 ml (4 mg) or 4 ml (8 mg) of the medicinal product in an ampoule. 5 ampoules per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

HELP S.A.

HELP S.A.

Manufacturer's address.

Pedini, Ioannina, 45500, Greece

Pedini Ioanninon, Ioannina, 45500, Greece

Marketing Authorization Holder.

M.Biotech Ltd

M.Biotech Ltd

Address of Marketing Authorization Holder.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom