Yunorm

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

Composition:

Active substance: ondansetron;

1 ml of solution contains 2 mg of ondansetron hydrochloride dihydrate calculated as ondansetron;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Antiemetic agents and drugs eliminating nausea. Serotonin receptor antagonists (5HT3). ATC code A04AA01.

Pharmacological properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective 5-HT3 (serotonin) receptor antagonist. The drug prevents or eliminates nausea and vomiting caused by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron has not been fully elucidated. It is likely that the drug blocks the initiation of the vomiting reflex by exerting antagonistic effects on 5-HT3 receptors located in neurons of both the peripheral and central nervous systems. The drug does not reduce the patient's psychomotor activity and does not produce sedative effects.

Pharmacokinetics.

The volume of distribution after parenteral administration in adults is 140 L. The majority of the administered dose undergoes hepatic metabolism. Less than 5% of the drug is excreted unchanged in urine. The elimination half-life is approximately 3 hours (in elderly patients – 5 hours). Plasma protein binding is 70–76%.

In patients with moderate renal impairment (creatinine clearance 15–60 mL/min), both systemic clearance and volume of distribution of ondansetron are reduced, resulting in a slight and clinically insignificant prolongation of the drug's elimination half-life. The pharmacokinetics of ondansetron are almost 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 elimination half-life (15–32 hours).

Clinical characteristics.

Indications.

Nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.

Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

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

Ondansetron does not accelerate or inhibit the metabolism of other drugs when administered concomitantly. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol.

Ondansetron is metabolized by various hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6, and CYP1A2. Due to the diversity of ondansetron-metabolizing enzymes, inhibition or reduced activity of one of them (e.g., genetic deficiency of CYP2D6) is normally compensated by other enzymes and will not affect overall creatinine clearance or will have only a negligible effect.

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

The use of Yunormu® together with other medicinal products that prolong the QT interval may result in additional QT prolongation. Concomitant use of Yunormu® with cardiotoxic medicinal products (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) may increase the risk of 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 following 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 severe arterial 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.

Tramadol

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

Special precautions for use.

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

Respiratory reactions should be treated symptomatically. Healthcare professionals should pay special attention to such 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 induce QT prolongation or electrolyte disturbances. Myocardial ischemia has been reported in patients receiving ondansetron. In some patients, particularly after intravenous administration, symptoms appeared immediately after administration but resolved rapidly with prompt treatment. Therefore, caution should be exercised during and after ondansetron administration.

Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic 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 showing signs of subacute intestinal obstruction during treatment with the medicinal product Yunorm®.

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 require careful monitoring after ondansetron administration.

Children

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

Dosing regimen

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 followed by a single oral dose. 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 dosing regimens.

Excipients with known effect

The medicinal product Yunorm® (2 ml and 4 ml) contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is nearly sodium-free.

The medicinal product in the maximum daily dose (16 ml) contains 2.512 mmol (or 57.6 mg) of sodium. This corresponds to approximately 2.9% of the maximum recommended daily dietary sodium intake for an adult.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential should use contraception.

Pregnancy.

Based on human experience from epidemiological studies, there is a suspicion of an increased risk of craniofacial malformations 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 orofacial clefts (3 additional cases per 10,000 women treated; adjusted relative risk 1.24 (95% CI 1.03–1.48)).

Epidemiological 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 breast milk of animals. If treatment with the medicinal product is necessary, breastfeeding should be discontinued.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Psychomotor tests have shown that ondansetron does not impair the ability to operate machinery and has no sedative effect. However, the adverse effect profile of the drug should be taken into account when assessing a patient's 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 dosing regimen depends on the severity of emetogenic effect. The dose of Yunorm® (range from 8 to 32 mg per day) and route of administration should be selected as outlined below.

Emetogenic chemotherapy and radiotherapy

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

To prevent delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the drug is recommended for up to 5 days following completion of the treatment course.

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

Yunorm® may be administered as a single 8 mg intravenous or intramuscular dose immediately before chemotherapy.

For highly emetogenic chemotherapy, 8 mg of Yunorm® or a lower dose does not require dilution and can be administered via 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) must be administered only 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 are not recommended, as higher doses increase the risk of QT interval prolongation (see section "Special precautions").

The choice of dosing regimen depends on the severity of emetogenic effect. The efficacy of Yunorm® in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate before chemotherapy.

Oral or rectal administration of the drug is recommended for prevention of delayed or prolonged vomiting after the first 24 hours.

Children aged 6 months to 17 years

In pediatric practice, Yunorm® should be administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable solvent (see below "Use of injection solution") over no less than 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

Yunorm® 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 later and may continue for another 5 days. Adult dose must not be exceeded.

Yunorm® must be diluted with 5% glucose solution, 0.9% sodium chloride solution, or another suitable infusion solution and administered by intravenous infusion over no less than 15 minutes.

There are no data from controlled clinical trials regarding the use of ondansetron in children for prevention of delayed or prolonged vomiting during chemotherapy, or for treatment of nausea and vomiting caused by radiotherapy.

Dose calculation according to child's body weight

Yunorm® 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 at 4-hour intervals.

Oral administration 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 doses should be diluted and administered over 15 minutes. When repeated administration is required, the interval between injections should be no less than 4 hours.

In 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 each, with intervals between infusions of no less than 4 hours.

In patients aged 75 years and older, the initial intravenous dose of ondansetron must not exceed 8 mg, administered by infusion over no less than 15 minutes. After the initial 8 mg dose, two additional 8 mg doses may be administered by infusion over 15 minutes each, with intervals between infusions of no less than 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, Yunorm® clearance is significantly reduced and serum half-life is prolonged. In 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. After repeated administration, drug concentrations in these patients are similar to those in patients with normal metabolism. Therefore, dose adjustment or change in frequency of administration is not required.

Postoperative nausea and vomiting

Adults

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

Elderly patients

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

Patients with renal impairment

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

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, Yunorm® clearance is significantly reduced and serum half-life is prolonged. In 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 subjects with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations are similar to those in patients with intact metabolism. Therefore, dose adjustment or change in frequency of administration is not required.

Use of injection solution

Ampoules of Yunorm® contain no preservatives; therefore, the solution must be used immediately after opening. Any unused solution must be discarded.

Ampoules of Yunorm® 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 solutions: 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 vials. Ondansetron diluted in 0.9% sodium chloride solution or 5% glucose solution has been shown to remain stable in polypropylene syringes. Stability in polypropylene syringes has also been demonstrated when ondansetron is diluted with other recommended diluents.

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

Compatibility with other drugs

Yunorm® may be administered as intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, Yunorm® at ondansetron concentrations 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 for 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 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 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 intravenous bolus injection over 5 minutes;
• dexamethasone at a dose of 20 mg, administered as slow intravenous injection over 2–5 minutes (when co-administered with 8 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 µg to 2.5 mg/mL and ondansetron concentrations from 8 µg to 1 mg/mL.

Children

Indicated for children aged 6 months (during chemotherapy) and from 1 month of age (for prevention and treatment of postoperative nausea and vomiting).

Overdose

Data on overdose are limited. In most cases, symptoms are similar to those observed in patients receiving recommended doses (see section "Adverse reactions").

Manifestations of overdose reported include visual disturbances, severe constipation, arterial 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 have been reports of serotonin syndrome in young children after oral overdose.

No specific antidote exists; therefore, symptomatic and supportive therapy should be administered in cases of overdose.

Further management of patients should be based on clinical judgment or, if possible, in accordance with recommendations from a national poison center.

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

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 reactions listed below are classified by system organ class and frequency of occurrence. Frequencies are categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (frequency cannot be estimated from available data). Adverse reactions occurring very commonly, commonly, and uncommonly are generally based on clinical trial data, with placebo group incidence taken into account. Reactions occurring rarely, very rarely, and not known are generally derived from post-marketing data.

The following adverse reaction frequencies were assessed based on the use of standard recommended doses of ondansetron. Adverse reaction profiles in children and adolescents were comparable to those in adults.

Immune system disorders:

Rare: Immediate-type hypersensitivity reactions, sometimes severe, including anaphylaxis.

Nervous system disorders:

Very common: Headache;

Uncommon: Convulsions, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without lasting clinical consequences);

Rare: Dizziness, mainly during rapid intravenous administration.

Eye disorders:

Rare: Transient visual disturbances (blurred vision), primarily during intravenous administration;

Very rare: Transient blindness, mainly during intravenous administration; in most cases, vision returns 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: Arrhythmia, chest pain (with or without ST-segment depression), bradycardia;

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

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

Vascular disorders:

Common: Feeling of warmth or flushing;

Uncommon: Arterial hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Hiccups.

Gastrointestinal disorders:

Common: Constipation.

Hepatobiliary disorders:

Uncommon: Asymptomatic elevation of liver function tests.

These cases occur primarily 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.

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 rash, 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.

* Information on these adverse reactions is derived from post-marketing experience based on spontaneous reports and published literature. As these reports are voluntary and from an uncertain population size, it is not possible to reliably estimate their frequency.

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. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light. Do not freeze.

Incompatibilities.

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

Packaging.

2 ml or 4 ml in glass ampoules; 5 ampoules in a blister pack per carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of operations.

108, Kobzarska Street, Cherkasy, 18030, Ukraine. Tel. (044) 281-01-01.