Yunorm syrup 4 mg/ 5 ml bottle of 50 ml

Instructions for use: Yunorm syrup 4 mg/5 ml bottle 50 ml

Composition

active ingredient: ondansetron;

5 ml of syrup contains ondansetron hydrochloride dihydrate (equivalent to ondansetron) 4 mg;

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

Dosage form

Syrup.

Main physicochemical properties: transparent, colorless or slightly yellowish liquid with a menthol odor.

Pharmacotherapeutic group

Antiemetics and antinausea drugs. Serotonin (5-HT3) receptor antagonists. ATC code A04A A01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Ondansetron is a potent, highly selective 5-HT3 (serotonin) receptor antagonist. The mechanism of action of ondansetron in nausea and vomiting is not fully understood. Chemotherapy and radiation therapy can cause the release of serotonin (5-HT) in the small intestine, which triggers the vomiting reflex by activating the vagus nerve afferent endings via 5-HT3 receptors. Ondansetron blocks the initiation of this reflex.

Activation of vagal afferent endings may in turn trigger 5-HT release in the area postrema and this may also contribute to the development of the vomiting reflex via a central mechanism. Thus, the action of ondansetron in the treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is likely to be mediated by an antagonistic effect on 5-HT3 receptors on neurons located both in the peripheral and central nervous systems.

The mechanisms of action of the drug in eliminating postoperative nausea and vomiting have not been elucidated; they are probably similar to those in cytotoxic nausea and vomiting.

Ondansetron does not affect the concentration of prolactin in blood plasma.

The role of ondansetron in opiate-induced vomiting has not yet been studied.

Pharmacokinetics.

Absorption

After oral administration, ondansetron is completely absorbed from the gastrointestinal tract and undergoes first-pass metabolism. Peak plasma concentrations of about 30 ng/ml are reached approximately 1.5 hours after an 8 mg dose. At doses exceeding 8 mg, the concentration of ondansetron in the blood increases disproportionately, since at high doses, a decrease in first-pass metabolism may occur. The average bioavailability in healthy male volunteers after taking a single 8 mg tablet was approximately 55–60%. Bioavailability is slightly increased when the drug is taken with food, but is not changed when taken with antacids.

In adults, the distribution of ondansetron is similar after oral, intramuscular and intravenous administration, with a terminal half-life of approximately 3 hours and a steady-state volume of distribution of approximately 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 administration of ondansetron, peak plasma concentrations are approximately 25 ng/ml and are achieved within 10 minutes after injection.

After rectal administration of ondansetron (suppositories), plasma concentrations of the drug are determined 15–60 minutes after administration. Concentrations increase linearly until peak concentrations of 20–30 ng/mL are reached, usually 6 hours after administration. Plasma concentrations then decline, but at a slower rate than after oral administration, due to the prolonged absorption of ondansetron. The 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 of ondansetron, not by systemic clearance, and is approximately 6 hours. A small, clinically insignificant increase in the elimination half-life is observed in women compared to men.

Distribution

Ondansetron has a moderate degree of binding to plasma proteins (70–76%).

Biotransformation and excretion

Ondansetron is eliminated from the systemic circulation primarily by hepatic metabolism involving multiple enzymatic pathways.

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

Special patient groups

Gender differences

The pharmacokinetics of ondansetron are gender-dependent. In women, a greater rate and extent of absorption of ondansetron and a reduced systemic clearance and volume of distribution (adjusted for weight) were observed after oral administration.

In children aged 1 to 4 months (n=19) undergoing surgery, 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 elimination half-life in the 1 to 4 month group averaged 6.7 hours compared to 2.9 hours in the 5 to 24 month and 3 to 12 year age groups. The differences in pharmacokinetic parameters in patients aged 1 to 4 months are partly explained by the higher percentage of body fluid in neonates and infants and the higher volume of distribution of water-soluble drugs such as ondansetron.

In children aged 3 to 12 years undergoing elective surgery under general anaesthesia, the absolute values of ondansetron clearance and volume of distribution were reduced compared to those in adults. Both parameters increased linearly with body weight and by 12 years these values approached those in young adults.

When adjusting clearance and volume of distribution for body weight, these parameters were approximated across age groups. Weight-based dose calculation compensates for age-related changes and is effective in normalizing systemic exposure to ondansetron in children.

In this study, the area under the pharmacokinetic curve (AUC) after oral and intravenous administration to 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 was lower in adults than in children. Clearance was weight-dependent but not age-dependent (except in children aged 1 to 4 months). It is difficult to conclude whether there was an additional age-dependent decrease in ondansetron clearance in children aged 1 to 4 months or whether the decrease was due to natural variability due to the small number of patients studied in this age group. Since patients under 6 months of age will receive only one dose of the drug in the event of postoperative nausea and vomiting, the decrease in clearance is unlikely to be clinically significant.

Elderly patients

There is evidence that elderly patients have a slight age-related decrease in clearance and an increase in the half-life of ondansetron. However, there are no overall differences in safety and efficacy between younger patients and older cancer patients.

Based on more recent data on ondansetron plasma concentrations and exposure-response modelling, a more pronounced effect on QTcF is expected in patients aged 75 years and older than in younger patients. Specific recommendations for intravenous dosing are provided for patients aged 65 years and older than 75 years (see section 4.2).

Patients with renal impairment

In patients with renal insufficiency (creatinine clearance 15-60 ml/min), systemic clearance and volume of distribution are reduced after intravenous administration of ondansetron, resulting in a small but clinically insignificant increase in half-life (5.4 hours). Studies in patients with severe renal insufficiency requiring regular hemodialysis (inter-hemodialysis studies) have shown virtually no change in the pharmacokinetics of ondansetron after intravenous administration.

Patients with liver dysfunction

After oral, intravenous, or intramuscular administration, systemic clearance of ondansetron is sharply reduced in patients with severe hepatic impairment, with a half-life of 15–32 hours, and oral bioavailability reaches 100% due to reduced first-pass metabolism.

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

Indication

Adults

Nausea and vomiting caused by cytotoxic chemotherapy and radiotherapy.

Prevention of postoperative nausea and vomiting.

For the treatment of postoperative nausea and vomiting, it is recommended to use ondansetron in the form of an injectable solution.

Children

Chemotherapy-induced nausea and vomiting in children aged 6 months and older.

There are no data from studies on the use of oral ondansetron in children aged 1 month and older for the prevention and treatment of postoperative nausea and vomiting; in this case, it is recommended to use ondansetron as a solution for injection.

Contraindication

Hypersensitivity to the active substance or any of the excipients of the medicinal product.

Concomitant use with apomorphine (see section “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

Ondansetron is metabolized by a variety of hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6, and CYP1A2. Due to the diversity of ondansetron metabolizing enzymes, inhibition or reduction in the activity of one of them (e.g., genetic deficiency of CYP2D6) is usually compensated by the other enzymes, resulting in no or minor changes in the overall clearance of ondansetron and no dose adjustment is required.

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

The use of ondansetron with other drugs that prolong the QT interval may lead to additional prolongation of this interval. The concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (e.g. erythromycin), antifungals (e.g. ketoconazole), antiarrhythmics (e.g. amiodarone) and β-blockers (e.g. atenolol or timolol) may increase the risk of arrhythmias (see section "Special instructions").

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

Serotonin syndrome (including mental status changes, autonomic instability and neuromuscular disorders) has been described following concomitant use of ondansetron and other serotonergic drugs, including SSRIs and SNRIs (see section 4.4).

Apomorphine

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

Phenytoin, carbamazepine, and rifampicin

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

Tramadol

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

Application features

Hypersensitivity reactions have been observed in patients with a history of hypersensitivity to other selective 5-HT3 receptor antagonists.

Respiratory reactions should be treated symptomatically. Healthcare professionals should pay special attention to them as they are precursors of drug hypersensitivity reactions.

Myocardial ischemia has been reported in patients receiving ondansetron. In some patients, symptoms have occurred immediately after administration of ondansetron, particularly following intravenous administration. Patients should be advised of the signs and symptoms of myocardial ischemia.

Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, post-marketing reports of ventricular fibrillation/flutter (torsade de pointes) have been reported with ondansetron. 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 prolongation, including patients with electrolyte imbalance, congestive heart failure, bradyarrhythmia, or patients receiving other drugs that may cause QT prolongation or electrolyte imbalance. Hypokalemia and hypomagnesemia should be corrected before initiating ondansetron.

Serotonin syndrome, including mental status changes, autonomic instability and neuromuscular disorders, has been reported in patients following concomitant use of ondansetron and other serotonergic drugs (SSRIs and SNRIs) (see Interactions). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate monitoring of the patient is recommended.

Since ondansetron weakens intestinal peristalsis, careful monitoring of patients with signs of subacute intestinal obstruction is required during the use of the drug Uninorm®.

In patients undergoing adenotonsillar surgery, the use of ondansetron for the prevention of nausea and vomiting may mask the occurrence of bleeding. Therefore, such patients should be carefully monitored after the use of ondansetron.

The drug Yunorm® contains sorbitol. The energy value of 1 g of sorbitol is 2.6 kcal. If your child has been diagnosed with an intolerance to some sugars, contact your doctor before taking this medicine. Patients with rare hereditary forms of fructose intolerance should not take this medicine.

Children

Children receiving ondansetron with hepatotoxic chemotherapeutic agents should be closely monitored for possible liver dysfunction.

When calculating the dose according to body weight and using three doses with an interval of 4 hours, the total daily dose will be higher than when using a single dose of 5 mg/m2 followed by oral administration of the drug. The comparative efficacy of these two dosing regimens has not been evaluated in clinical studies. Comparison of the results of different studies indicates similar efficacy of both dosing regimens.

Use during pregnancy or breastfeeding

Women of reproductive age

Women of reproductive age should consider using contraception.

Pregnancy

Based on epidemiological studies in humans, ondansetron may cause maxillofacial malformations when administered during the first trimester of pregnancy.

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

Available epidemiological studies of congenital heart defects show conflicting results.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

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

Breastfeeding period

Experimental studies have shown that ondansetron passes into breast milk in animals. Therefore, if necessary, use of the drug should be discontinued during breastfeeding.

Fertility

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Uninorm® has no or negligible influence on the ability to drive or use machines.

Psychomotor tests have shown that ondansetron does not impair performance and does not have a sedative effect. Due to the pharmacological properties of ondansetron, no harmful effects on the reaction rate when driving or using other mechanisms are predicted.

Method of administration and doses

Nausea and vomiting caused by chemotherapy and radiation therapy

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 anticancer therapy.

Emetogenic chemotherapy and radiation therapy

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

The recommended oral dose is 8 mg 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 emesis.

Highly emetogenic chemotherapy

A single dose may be 24 mg of Uninorm® simultaneously with dexamethasone sodium phosphate orally at a dose of 12 mg 1–2 hours before the start of chemotherapy. To prevent delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of Uninorm® may be continued for up to 5 days after the course of treatment. The recommended oral dose is 8 mg 2 times a day.

Chemotherapy-induced nausea and vomiting in children aged 6 months to 17 years

The dose of Uninorm® can be calculated based on body surface area or body weight (see below). In pediatric clinical trials, ondansetron was administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable diluent over at least 15 minutes.

The total daily dose calculated based on body weight is higher than the total daily dose calculated based on 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, as well as data on its use in children for the treatment of nausea and vomiting induced by radiotherapy.

Dose calculation by body surface area

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

Table 1

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

a Intravenous dose should not exceed 8 mg.

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

Dose calculation by body weight

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

Junorm® should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg body weight; the intravenous dose should not exceed 8 mg. Subsequently, two intravenous doses may be administered with an interval of 4 hours. After 12 hours, oral administration of the drug can be started and continued for up to 5 days (see Table 2). The total daily dose of ondansetron (divided into several doses) should not exceed the adult dose of 32 mg.

Table 2

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

a Intravenous dose should not exceed 8 mg.

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

Elderly patients

Elderly patients do not require adjustment of the oral dose or frequency of administration of the drug Junorm®.

Postoperative nausea and vomiting

Adults

For the prevention of postoperative nausea and vomiting

Ondansetron can be administered orally, intramuscularly or intravenously. For oral administration, 16 mg of Uninorm® is recommended 1 hour before anesthesia.

For the treatment of postoperative nausea and vomiting

It is recommended to use the injectable form of the drug Yunorm®.

Children aged 1 month to 17 years

Oral form of ondansetron

There are no data from studies 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 a solution for injection by slow intravenous injection (not less than 30 seconds).

Ondansetron injection form:

For the prevention of postoperative nausea and vomiting in children scheduled for surgery under general anesthesia, ondansetron is administered as a single slow intravenous injection (not 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 the treatment of postoperative nausea and vomiting in children scheduled for surgery under general anesthesia, ondansetron is administered as a single slow intravenous injection (over at least 30 seconds) at a dose of 0.1 mg/kg body weight (maximum 4 mg) after surgery.

There are no data from studies 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 ondansetron for the prevention and treatment of postoperative nausea and vomiting in elderly patients is limited, but the drug is well tolerated in patients aged 65 years and older receiving chemotherapy.

For both indications

Patients with renal impairment

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

Patients with liver dysfunction

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

Patients with poor metabolism of sparteine/debrisoquine

In patients with poor metabolism of sparteine/debrisoquine, the half-life of ondansetron is not altered. Therefore, when ondansetron is re-administered to such patients, its concentration will not differ from that in the general population. Therefore, correction of the daily dose or frequency of administration of the drug in this case is not required.

Children.

The drug Yunorm® is used in children from 6 months of age (during chemotherapy) (see sections “Indications” and “Method of administration and dosage”).

Overdose

Symptoms

There is limited information on overdose with ondansetron. In most cases, the symptoms are similar to those described in patients given the recommended doses (see section "Adverse Reactions"). Symptoms of overdose have been reported to include visual disturbances, severe constipation, hypotension, and vasovagal reactions with transient second-degree atrioventricular block.

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

Children

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

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

Further treatment should be carried out according to clinical indications.

The use of ipecacuanha for the treatment of ondansetron overdose is not recommended, as its effect may not be manifested due to the antiemetic effect of the drug Junorm®.

Side effects

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

The incidence of these events was assessed at standard recommended therapeutic doses of ondansetron. The adverse reaction profile in children and adolescents is similar to that in adults.

Table 3

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.

Expiration date

2 years.

Storage conditions

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

Do not freeze. Keep out of reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

LLC "Yuria-Pharm".

Location of the manufacturer and address of its place of business

Ukraine, 18030, Cherkasy region, Cherkasy city, Kobzarska st., 108. Tel.: (044) 281-01-01.