Susprin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUSRIN® (SUSPRIN®)

Composition:

active ingredient: ondansetron;

5 ml of solution contains 4 mg of ondansetron hydrochloride dihydrate calculated as ondansetron;

excipients: citric acid monohydrate; sodium benzoate (E 211); sodium citrate; sorbitol solution, non-crystallizing (E 420); strawberry flavoring; purified water.

Pharmaceutical form. Oral solution.

Basic physicochemical properties: clear liquid with a characteristic odor.

Pharmacotherapeutic group. Antiemetics and antinausea agents. Serotonin receptor antagonists (5HT3). ATC code A04AA01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ondansetron is a potent, highly selective antagonist of serotonin receptors (5-HT3). The mechanism of action of ondansetron in nausea and vomiting is not fully understood. Radiation therapy and chemotherapy may cause the release of serotonin (5-HT) in the small intestine, stimulating the afferent endings of the vagus nerve by activating 5-HT3 receptors, thereby triggering the peripheral mechanism of the vomiting reflex. Ondansetron blocks the initiation of this reflex. Activation of vagal afferent endings may also cause the release of 5-HT in the area postrema, thus initiating the central mechanism of the vomiting reflex. Therefore, ondansetron suppresses nausea and vomiting induced by chemotherapy and radiotherapy through its antagonistic effect on 5-HT3 receptors located in both the peripheral and central nervous systems.

The mechanism of action of ondansetron in postoperative nausea and vomiting has not been fully elucidated.

Ondansetron does not affect plasma prolactin concentrations.

The role of ondansetron in opioid-induced vomiting is not fully understood.

Pharmacokinetics

After oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes presystemic metabolism. Maximum plasma concentration (approximately 30 ng/mL) is reached about 1.5 hours after an 8 mg dose. When doses exceeding 8 mg are administered, ondansetron blood levels increase disproportionately, likely due to reduced presystemic metabolism. The mean bioavailability in healthy male volunteers after oral administration of a single 8 mg tablet is approximately 55–60%. Bioavailability is slightly increased when the drug is taken with food, but remains unchanged when taken with antacids. The distribution of ondansetron is similar following oral, intramuscular, and intravenous administration in adults, with a comparable terminal half-life of 3 hours and a steady-state volume of distribution of 140 L. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of ondansetron.

Ondansetron has a moderate degree of plasma protein binding (70–76%). It is eliminated from systemic circulation primarily via hepatic metabolism involving multiple enzyme systems. Less than 5% of the absorbed dose is excreted unchanged in urine. The absence of the CYP2D6 enzyme (sparteine/debrisoquine polymorphism) does not affect ondansetron pharmacokinetics. The pharmacokinetic parameters of ondansetron remain unchanged with repeated administration.

Special patient groups

Sex

Ondansetron pharmacokinetics are influenced by patient sex. Women exhibit a higher rate and extent of absorption and lower systemic clearance and volume of distribution (adjusted for body weight) compared to men.

Children

Differences in pharmacokinetic parameters are partly explained by the higher percentage of body water in neonates and infants and the higher volume of distribution in children aged 1 to 4 months.

In children aged 3 to 12 years, absolute values of ondansetron clearance and volume of distribution were reduced compared to those in adults. Both parameters increased linearly with body weight, approaching adult values in patients up to 12 years of age.

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

According to study results, the area under the plasma concentration-time curve (AUC) after oral and intravenous administration in children and adolescents was similar to that in adults, except in infants aged 1 to 4 months. The volume of distribution was age-dependent and lower in adults than in children.

Elderly patients

A more pronounced effect on the QTcF interval is expected in patients over 75 years of age compared to younger patients.

Patients with renal impairment

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

Patients with hepatic impairment

In patients with severe hepatic impairment, systemic clearance of ondansetron is significantly reduced, with the elimination half-life prolonged to 15–32 hours. Oral bioavailability reaches 100% due to reduced presystemic metabolism.

Clinical characteristics

Indications

Adults

Treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.

Prevention of postoperative nausea and vomiting.

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

Children

Treatment of nausea and vomiting induced by cytotoxic chemotherapy in children ≥ 6 months of age.

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

Contraindications

Concomitant use of ondansetron with apomorphine hydrochloride.

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other types of interactions

There is no evidence that ondansetron accelerates or inhibits the metabolism of other drugs when used concomitantly. It has been 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 the overall clearance of ondansetron or will have only a negligible effect.

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

Concomitant use of ondansetron with other medicinal products that prolong the QT interval may lead to additional QT prolongation.

Combining ondansetron with cardiotoxic medicinal products (e.g., anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (erythromycin), antifungal agents (ketoconazole), antiarrhythmics (amiodarone), and beta-blockers (atenolol or timolol) may increase the risk of arrhythmias (see section "Special precautions").

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

Cases of serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) have been reported in patients receiving concomitant ondansetron and other serotonergic medicinal agents, particularly SSRIs and SNRIs (see section "Special precautions").

Apomorphine

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

Phenytoin, carbamazepine, and rifampicin

In patients receiving treatment with potential inducers of CYP3A4 (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron (after oral administration) increases and blood concentration decreases.

Tramadol

Ondansetron may reduce the analgesic effect of tramadol.

Special Warnings and Precautions for Use

Hypersensitivity reactions have been reported in patients with a history of hypersensitivity to other selective 5HT3 receptor antagonists. Respiratory disorders should be treated symptomatically; physicians should pay special attention to these, as they may be precursors of hypersensitivity reactions.

Ondansetron dose-dependently prolongs the QT interval (see section "Pharmacological Properties"). Cases of Torsade de Pointes have been reported in patients receiving ondansetron. Ondansetron should be avoided in patients with congenital long QT syndrome. Caution is advised when administering ondansetron to 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.

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

Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment with this medicinal product.

There are reports of serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) in patients receiving ondansetron concomitantly with other serotonergic agents, including SSRIs and SNRIs (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). If concomitant treatment with ondansetron and other serotonergic drugs is clinically justified, appropriate patient monitoring is recommended.

Since ondansetron reduces gastrointestinal motility, careful monitoring is required in patients showing signs of intestinal obstruction following administration of the drug.

In patients undergoing adenotonsillar surgery, the use 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.

Continuous monitoring of liver function is necessary in children receiving ondansetron concomitantly with hepatotoxic chemotherapeutic agents.

The product contains sorbitol. The energy value of 1 g of sorbitol is 2.6 kcal. Sorbitol may have a mild laxative effect. If intolerance to certain sugars is diagnosed, consult a physician before taking this medicinal product.

Use During Pregnancy or Breastfeeding

Women of childbearing potential who are using ondansetron should consider using contraception.

Pregnancy

Epidemiological studies suggest that ondansetron may be associated with 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 oral clefts (3 additional cases per 10,000 women treated with ondansetron; adjusted relative risk 1.24 (95% CI 1.03–1.48)). Available epidemiological data on cardiac malformations show 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. If treatment with the drug is necessary, women should discontinue breastfeeding.

Fertility

There are no data on the effect of ondansetron on human fertility.

***Ability to Affect Reaction Rate When Driving or Operating Machinery ***

Psychomotor tests have shown that ondansetron does not affect the ability to drive or operate machinery and has no sedative effect. Based on the pharmacology of ondansetron, no adverse influence on such activities is expected.

Method of Administration and Dosage

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 radiation therapy regimens. The choice of dosage regimen depends on the severity of the emetogenic effect.

Emetogenic chemotherapy and radiation therapy

An 8 mg (10 mL) dose should be administered 1–2 hours before the start of chemotherapy or radiation therapy, followed by another 8 mg (10 mL) dose 12 hours later, and continued for up to 5 days.

Highly emetogenic chemotherapy

The drug should be administered as a single dose of up to 24 mg (30 mL) of ondansetron combined with 12 mg of sodium phosphate dexamethasone orally 1–2 hours before chemotherapy.

After the first 24 hours, oral administration of the drug is recommended for up to a maximum of 5 days following the treatment course.

The recommended oral dosage is 8 mg twice daily.

Children

Dose calculation for children aged 6 months to adolescents under 17 years

The drug dose can be calculated based on body surface area or body weight. If the dose is calculated according to body weight, the total daily dose is higher compared to dosing based on body surface area.

Dose calculation according to body surface area in children

Ondansetron 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 started 12 hours later and may continue for up to 5 days (see Table 1). The total daily dose (divided into administrations) must not exceed the adult dose of 32 mg.

Table 1

Dose calculation according to body surface area for children over 6 months of age and adolescents up to 17 years of age

a) The intravenous dose must not exceed 8 mg.

b) The total daily dose must not exceed the adult dose of 32 mg.

Dose calculation based on pediatric body weight

When the dose is calculated according to body weight, the total daily dose is higher compared to dosing based on body surface area.

Ondansetron should be administered intravenously as a single bolus injection of 0.15 mg/kg, immediately before chemotherapy. 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 after the last intravenous dose and continued for up to 5 additional days (see Table 2). The total daily dose (divided doses) must not exceed the adult dose of 32 mg.

Table 2

Dose calculation based on body weight for children over 6 months of age and adolescents under 17 years of age

a The intravenous dose should not exceed 8 mg.

b The total daily dose should not exceed the adult dose of 32 mg.

Geriatric patients

Ondansetron is well tolerated by patients over 65 years of age. Dose adjustment or frequency of administration is not required.

Postoperative nausea and vomiting

Adults

16 mg (20 mL) given 1 hour prior to anesthesia.

For the treatment of postoperative nausea and vomiting, ondansetron is administered as an injection solution.

Postoperative nausea and vomiting in children over 1 month of age and adolescents under 17 years of age

No studies have been conducted on the oral use of ondansetron for the prevention or treatment of postoperative nausea and vomiting; therefore, the recommended route is slow (over not less than 30 seconds) intravenous injection.

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

Geriatric patients

Experience with ondansetron for the prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, ondansetron is well tolerated by patients over 65 years of age receiving chemotherapy.

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with impaired metabolism of sparteine/debrisoquine

The half-life of ondansetron is not altered in patients with impaired sparteine and debrisoquine metabolism. After repeated administration, drug concentrations are similar to those in patients with normal metabolism. Therefore, dose adjustment or change in frequency of administration is not required.

Children

Ondansetron oral solution is indicated for use in children over 6 months of age for the treatment of nausea and vomiting induced by chemotherapy.

For the prevention or treatment of postoperative nausea and vomiting in children over 1 month of age, ondansetron injection solution is recommended.

Overdose

Symptoms

Data on ondansetron overdose are limited. In most cases, symptoms were similar to adverse reactions observed in patients receiving recommended doses (see section "Adverse Reactions"). Visual disturbances, severe constipation, arterial hypotension, and vasovagal reactions with transient second-degree atrioventricular block have been reported in cases of overdose. Serotonin syndrome has been reported in children aged 12 months to 2 years following overdose.

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

Treatment

There is no specific antidote for ondansetron. In case of overdose, symptomatic and supportive therapy should be administered.

Ipecacuanha is not recommended, as its clinical effect may be inhibited due to the antiemetic action of ondansetron.

Adverse Reactions

The adverse reactions listed below are classified by system organ class and frequency of occurrence. Frequencies are defined as follows: very common (≥1/10), common (≥1/1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Very common, common, and uncommon adverse reactions were generally identified in clinical studies. Rare and very rare adverse reactions were primarily reported during the post-marketing period.

The adverse reaction profile in children and adolescents was generally the same as in adults.

Immune system disorders:
Rare – immediate-type hypersensitivity reactions, sometimes 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)^1;
Rare – dizziness during rapid intravenous administration.

Eye disorders:
Rare – transient visual disturbances (blurred vision), mainly during intravenous administration;
Very rare – transient blindness, mainly during intravenous administration^2.

Cardiac disorders:
Uncommon – arrhythmia, chest pain (with or without ST segment depression), bradycardia;
Rare – QT interval prolongation, including ventricular fibrillation/tachycardia (torsade de pointes);
Frequency not known – myocardial ischemia (see section "Special Warnings and Precautions for Use").

Vascular disorders:
Common – sensation of warmth or flushing;
Uncommon – arterial hypotension.

Respiratory, thoracic and mediastinal disorders:
Uncommon – hiccup.

Gastrointestinal disorders:
Common – constipation;
Frequency not known – dry mouth.

Hepatobiliary disorders:
Uncommon – asymptomatic elevation of liver function parameters^3.

Skin and subcutaneous tissue disorders:
Very rare – toxic skin eruptions, including toxic epidermal necrolysis.

^1 No conclusive data on persistent clinical consequences are available.
^2 In most cases, transient blindness resolved within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient cortical blindness have been reported.

• These cases occurred primarily in patients receiving cisplatin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach and sight of children.

After first opening of the vial, the medicinal product should not be stored for longer than 28 days.

Packaging

50 ml in a vial. 1 vial with a dosing device in a cardboard pack.

Prescription status

Prescription only.

Manufacturer

LLC "KUSUM PHARM".

Manufacturer's address and location of operations

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

or

Manufacturer

LLC "GLEDPHARM LTD".

Manufacturer's address and location of operations

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.