Yunorm

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

Composition:

Active substance: ondansetron;

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

Excipients: anhydrous citric acid, sodium benzoate (E 211), sorbitol (E 420), sodium citrate, menthol, water for injections.

Pharmaceutical form. Syrup.

Main physicochemical characteristics: a clear, colorless or slightly yellowish liquid with a menthol odor.

Pharmacotherapeutic group. Antiemetic agents and drugs eliminating nausea. Serotonin (5-HT3) receptor antagonists. ATC code A04A A01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ondansetron is a potent, highly selective antagonist of 5-HT₃ (serotonin) receptors. The mechanism of action of ondansetron in nausea and vomiting is not fully understood. The use of chemotherapeutic agents and radiation therapy may cause the release of serotonin (5-HT) in the small intestine, triggering the vomiting reflex by activating afferent fibers of the vagus nerve via 5-HT₃ receptors. Ondansetron blocks the initiation of this reflex.

Activation of afferent vagal nerve endings, in turn, may lead to the release of 5-HT in the posterior region of the floor of the fourth ventricle (area postrema), which may also contribute to the development of the vomiting reflex via a central mechanism. Thus, the effect of ondansetron in the treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy is likely mediated by its antagonistic action on 5-HT₃ receptors located both in the peripheral and central nervous systems.

The mechanisms of action of the drug in preventing postoperative nausea and vomiting are not fully elucidated, but are likely similar to those involved in cytotoxic nausea and vomiting.

Ondansetron does not affect plasma prolactin concentrations.

The role of ondansetron in vomiting induced by opioids has not yet been studied.

Pharmacokinetics

Absorption

After oral administration, ondansetron is completely absorbed from the gastrointestinal tract and undergoes hepatic first-pass metabolism. Peak plasma concentration reaches approximately 30 ng/mL, achieved about 1.5 hours after an 8 mg dose. With doses exceeding 8 mg, plasma levels of ondansetron increase disproportionately, likely due to reduced first-pass metabolism at higher doses. The mean bioavailability in healthy male volunteers after a single 8 mg tablet is approximately 55–60%. Bioavailability is slightly increased when the drug is taken with food, but is unchanged when taken with antacids.

In adults, the distribution of ondansetron is similar following oral, intramuscular, and intravenous administration, with a comparable terminal half-life of approximately 3 hours and a steady-state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of ondansetron.

Intravenous infusion of ondansetron at a dose of 4 mg over 5 minutes results in peak plasma concentrations of approximately 65 ng/mL. After intramuscular injection, peak plasma concentrations are about 25 ng/mL, reached within 10 minutes after injection.

Following administration of the rectal formulation (suppositories), ondansetron plasma concentrations are detectable within 15–60 minutes after administration. Concentrations increase linearly until peak levels of 20–30 ng/mL are typically reached about 6 hours after administration. Plasma concentrations then decline more slowly than after oral administration due to prolonged absorption of ondansetron. Absolute bioavailability of ondansetron from the suppository is approximately 60% and is independent of gender. The elimination half-life after suppository administration is determined by the rate of absorption rather than systemic clearance and is approximately 6 hours. A slight, clinically insignificant increase in half-life is observed in females compared to males.

Distribution

Ondansetron exhibits moderate plasma protein binding (70–76%).

Biotransformation and elimination

From systemic circulation, ondansetron is primarily eliminated via hepatic metabolism involving multiple enzymatic pathways.

Less than 5% of the absorbed dose is excreted unchanged in urine. The absence of the CYP2D6 isoenzyme (debrisoquine polymorphism) does not affect the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are not altered upon repeated administration.

Special patient groups

Gender differences

The pharmacokinetics of ondansetron are gender-dependent. In females, after oral administration, a higher rate and extent of ondansetron absorption, as well as reduced systemic clearance and volume of distribution (corrected for body weight), have been observed.

Children aged 1 month to 17 years

In children aged 1 to 4 months (n=19) who underwent surgical procedures, clearance (adjusted for body weight) was approximately 30% slower than in patients aged 5 to 24 months (n=22), but comparable to that in patients aged 3 to 12 years. The mean elimination half-life in the 1- to 4-month age group was 6.7 hours, compared to 2.9 hours in the 5- to 24-month and 3- to 12-year age groups. These pharmacokinetic differences in infants aged 1 to 4 months are partially explained by the higher percentage of body water in neonates and infants, leading to a larger volume of distribution for water-soluble drugs such as ondansetron.

In children aged 3 to 12 years undergoing elective surgery under general anesthesia, absolute values of clearance and volume of distribution of ondansetron were lower than in adults. Both parameters increased linearly with body weight and approached values observed in young adults by age 12.

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

Based on study results, the area under the concentration-time curve (AUC) after oral and intravenous administration in children and adolescents was similar to that in adults, except in children aged 1 to 4 months. The volume of distribution was age-dependent and lower in adults compared to children. Clearance depended on body weight but not on age (except in children aged 1 to 4 months). It is difficult to conclude whether the observed reduction in clearance in infants aged 1 to 4 months is age-dependent or reflects natural variability due to the small number of patients studied in this age group. Since patients under 6 months of age will receive only a single dose of the drug for postoperative nausea and vomiting, the reduced clearance is unlikely to be clinically significant.

Elderly patients

Data indicate a slight age-related reduction in clearance and an increase in the elimination half-life of ondansetron in elderly patients. However, no overall differences in safety and efficacy have been observed between younger and older oncology patients.

Based on more recent data on ondansetron plasma concentrations and results from modeling the exposure-response relationship, a more pronounced effect on the QTcF interval is expected in patients aged 75 years and older compared to younger patients. Specific recommendations for intravenous dosing are provided for patients aged 65 years and older, particularly those over 75 years (see section "Dosage and administration").

Patients with renal impairment

In patients with renal impairment (creatinine clearance 15–60 mL/min), systemic clearance and volume of distribution are reduced after intravenous ondansetron administration, resulting in a small but clinically insignificant prolongation of the elimination half-life (5.4 hours). Studies involving patients with severe renal impairment requiring regular hemodialysis (evaluated between dialysis sessions) showed virtually no change in ondansetron pharmacokinetics after intravenous administration.

Patients with hepatic impairment

After oral, intravenous, or intramuscular administration in patients with severe hepatic impairment, systemic clearance of ondansetron is markedly reduced, with the elimination half-life prolonged to 15–32 hours. Oral bioavailability approaches 100% due to reduced presystemic metabolism.

The pharmacokinetics of ondansetron after suppository administration have not been evaluated in patients with hepatic impairment.

Clinical characteristics.

Indications.

Adults

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

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

Children

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

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with apomorphine (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

There are no data indicating that ondansetron may stimulate or inhibit the metabolism of other drugs when used concomitantly. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol.

Ondansetron is metabolized by various hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6, and CYP1A2. Due to the diversity of enzymes involved in ondansetron metabolism, inhibition or reduced activity of one of them (e.g., genetic deficiency of CYP2D6) is usually compensated by other enzymes, resulting in no or minimal changes in total ondansetron clearance, which generally does not require dose adjustment.

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

Concomitant use of ondansetron with other medicinal products that prolong the QT interval may lead to additional QT prolongation. Combined use of ondansetron with cardiotoxic medicinal products (e.g., anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (e.g., erythromycin), antifungal agents (e.g., ketoconazole), antiarrhythmics (e.g., amiodarone), and β-blockers (e.g., atenolol or timolol) may increase the risk of arrhythmias (see section "Special precautions for use").

Serotonergic agents (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs))

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

Apomorphine

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

Phenytoin, carbamazepine, and rifampicin

In patients treated with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron after oral administration was increased, and blood concentrations were reduced.

Tramadol

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

Special precautions for use.

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

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

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

Ondansetron prolongs the QT interval in a dose-dependent manner. Additionally, post-marketing surveillance data have reported cases of ventricular tachycardia (torsade de pointes) associated with ondansetron use. Ondansetron should be avoided in patients with congenital long QT syndrome. Ondansetron should be used with caution in patients who have or may develop QT interval prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medications that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy.

Serotonin syndrome, including changes in mental status, autonomic instability, and neuromuscular disturbances, has been described in patients receiving ondansetron concomitantly with other serotonergic agents (SSRIs and SNRIs) (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, appropriate patient monitoring is recommended.

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 adenotonsillar surgery, the use of ondansetron for the prevention of nausea and vomiting may mask the onset of postoperative bleeding. Therefore, such patients require careful observation following ondansetron administration.

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

Children

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

Nausea and vomiting induced by chemotherapy

When dosing according to 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 oral administration of the medicinal product. 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 between both dosing regimens.

Use during pregnancy or breastfeeding.

Women of reproductive age

Women of reproductive age should consider using contraceptive methods.

Pregnancy

Based on available epidemiological studies in humans, ondansetron may cause craniofacial malformations when used during the first trimester of pregnancy.

In one cohort study involving 1.8 million pregnancies, the use of ondansetron during the first trimester was associated with an increased risk of craniofacial clefts (3 additional cases per 10,000 women treated; adjusted relative risk 1.24 (95% CI 1.03–1.48)).

Available 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 period

Experimental studies have shown that ondansetron passes into the breast milk of animals. Therefore, if treatment 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.

Yunorm® has no effect or a negligible effect on the ability to drive or operate machinery.

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

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 of chemotherapy and radiotherapy regimens. The choice of dosing regimen is determined by the emetogenicity of the antineoplastic therapy.

Chemotherapy and radiotherapy with moderate emetogenic potential

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

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

Highly emetogenic chemotherapy

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

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

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

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

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

Dose calculation based on body surface area

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

Table 1

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

a The intravenous dose should not exceed 8 mg.

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

Dosing based on body weight

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

Jounorm® should be administered intravenously just before chemotherapy as a single dose of 0.15 mg/kg body weight; the intravenous dose should not exceed 8 mg. Subsequently, two additional intravenous doses may be given at 4-hour intervals. After 12 hours, oral administration of the drug may be initiated and continued for up to 5 days (see Table 2). The total daily dose of ondansetron (divided into several administrations) should not exceed the adult dose – 32 mg.

Table 2

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

a The intravenous dose should not exceed 8 mg.

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

Elderly patients

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

Postoperative nausea and vomiting

Adults

For prevention of postoperative nausea and vomiting

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

For treatment of postoperative nausea and vomiting

The injectable form of the medicinal product Yunorm® is recommended.

Children aged 1 month to 17 years

Oral form of ondansetron

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

Injectable form of ondansetron:

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

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

Elderly patients

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

For both indications

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with slow metabolism of sparteine/debrisoquine

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

Children

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

Overdose.

Symptoms

Data on ondansetron overdose are limited. In most cases, symptoms are similar to those described in patients receiving recommended doses (see section "Adverse reactions"). Manifestations of overdose have included visual disturbances, severe constipation, arterial hypotension, and vasovagal reactions with transient second-degree atrioventricular block.

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

Children

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

Treatment

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

Further management should be based on clinical indications.

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

Adverse reactions

The adverse reactions listed below are classified by system organ class and frequency of occurrence. The frequencies are categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known. Very common, common, and uncommon adverse reactions were primarily identified during clinical studies. The incidence in the placebo group was also taken into account. Rare and very rare adverse reactions are mainly derived from spontaneous reports received during the post-marketing period.

The frequency of these events was assessed during administration of standard recommended therapeutic doses of ondansetron. The adverse reaction profile in children and adolescents is consistent with that observed in adults.

Table 3

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Shelf life after first opening – 28 days.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Do not freeze. Keep out of reach and sight of children.

Packaging.

50 ml in a bottle; 1 bottle with a measuring device in a carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "Yuria-Farm".

Manufacturer's address and place of business.

108, Kozbirska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.