Susprin

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

Composition:

Active substance: ondansetron (ondansetron);

each film-coated tablet contains ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron or ondansetron hydrochloride dihydrate equivalent to 8 mg of ondansetron.

Excipients: microcrystalline cellulose, anhydrous lactose, partially pregelatinized corn starch, magnesium stearate, Opadry 03B51322 green* coating;

*Opadry 03B51322 green: hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), polyethylene glycol, indigocarmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, green or light green in color, round, biconvex, smooth on both sides.

Pharmacotherapeutic group. Antiemetic agents and drugs for relief of nausea. Serotonin (5HT3) receptor antagonists. 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 vagus nerve 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 is not 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 administered in doses exceeding 8 mg, ondansetron blood levels increase disproportionately, as presystemic metabolism may be reduced in such cases. The mean bioavailability in healthy male volunteers after oral administration of a single 8 mg tablet is approximately 55–60%. Bioavailability slightly increases when the drug is taken with food, but remains unchanged when taken with antacids. The distribution of ondansetron is similar following intramuscular, intravenous, and oral 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 type) does not affect ondansetron pharmacokinetics. Pharmacokinetic parameters of ondansetron remain unchanged with repeated administration.

Special patient groups

Sex

Ondansetron pharmacokinetics are influenced by patient sex. In women, higher rates and extent of absorption and lower systemic clearance and volume of distribution (adjusted for body weight) are observed 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 lower than in adults. Both parameters increased linearly with body weight, and in patients up to 12 years of age, these values approached adult levels.

When clearance and volume of distribution were normalized to body weight, these parameters were similar across different age groups. Dose calculation based on body weight compensates for age-related changes and 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 infants aged 1 to 4 months. The volume of distribution was age-dependent and lower in adults compared to children.

Elderly patients

A more pronounced effect on the QTcF interval is expected in patients aged 75 years and older 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 changes in ondansetron pharmacokinetics after intravenous administration.

Patients with hepatic impairment

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

Clinical characteristics.

Indications.

Adults

Treatment of nausea and vomiting caused 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 an injection solution.

Children

Treatment of nausea and vomiting caused by cytotoxic chemotherapy in children aged ≥ 6 months.

There are no study data on the use of oral ondansetron in children aged from 1 month for prevention or treatment of postoperative nausea and vomiting; therefore, in this case, ondansetron in the form of an 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 such effect will be negligible.

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

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

Concomitant use of 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 for use").

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

There are reports of serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) in patients receiving concomitant ondansetron and other serotonergic medicinal products, including SSRIs and SNRIs (see section "Special precautions for use").

Apomorphine

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

Phenytoin, carbamazepine, and rifampicin

In patients receiving treatment with potential CYP3A4 inducers (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron (after oral administration) is increased and plasma concentrations are decreased.

Tramadol

Ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use

Cases of 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 such reactions, as they may be harbingers 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. The use of ondansetron should be avoided in patients with congenital long QT syndrome. Ondansetron should be used with caution in patients who have or may develop QT interval prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medicinal products that may lead to QT prolongation or electrolyte disturbances.

Cases of myocardial ischemia have been reported in patients receiving ondansetron. In some patients, particularly following intravenous administration, symptoms appeared 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.

There are reports of serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular abnormalities) in patients receiving ondansetron concomitantly with other serotonergic medicinal 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 with 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 lactose. If intolerance to certain sugars has been 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, first-trimester exposure to ondansetron 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

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 available on the effect of ondansetron on human fertility.

Ability to influence the speed of reactions while 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.

Administration and Dosage

Nausea and vomiting caused by chemotherapy and radiation therapy

The choice of dosage regimen is determined by the emetogenic potential of the antineoplastic therapy.

Adults

Emetogenic chemotherapy and radiation therapy

8 mg of ondansetron 1–2 hours before the start of chemotherapy or radiation therapy, followed by 8 mg every 12 hours for up to 5 days.

Highly emetogenic chemotherapy

24 mg of ondansetron administered orally simultaneously with 12 mg of dexamethasone orally, 1–2 hours before the start of chemotherapy.

To prevent delayed or prolonged vomiting after the first 24 hours, it is recommended to take 8 mg of ondansetron twice daily for up to 5 days following the treatment course.

Children aged 6 months and older

Dosage is calculated based on body surface area or body weight.

Based on body surface area

Ondansetron is administered immediately before chemotherapy as a single intravenous injection at a dose of 5 mg/m². The intravenous dose should not exceed 8 mg. Oral administration is started 12 hours later and continued for 5 days (see Table 1). The total daily dose of ondansetron (divided into multiple doses) should not exceed 32 mg.

Table 1

Body surface area	Day 1	Days 2 to 6
< 0.6 m²	5 mg/m² intravenously, then 2 mg* orally after 12 hours	2 mg* orally every 12 hours
≥ 0.6 m² and ≤ 1.2 m²	5 mg/m² intravenously, then 4 mg orally after 12 hours	4 mg** orally every 12 hours
> 1.2 m²	5 mg/m² or 8 mg intravenously, then 8 mg orally after 12 hours	8 mg** orally every 12 hours

* administer ondansetron in the form of an oral solution;

** administer ondansetron in the form of an oral solution or tablets.

Based on body weight

The total daily dose calculated by body weight is higher than the total daily dose calculated by body surface area.

Ondansetron is administered immediately before chemotherapy as a single intravenous injection at a dose of 0.15 mg/kg body weight. The intravenous dose must not exceed 8 mg. Subsequently, two additional intravenous injections may be given at 4-hour intervals. Oral administration should begin 12 hours after the last intravenous dose and continued for 5 days (see Table 2). The total daily dose of ondansetron (divided into several doses) must not exceed 32 mg.

Table 2

Body weight	Day 1	Days 2 to 6
≤ 10 kg	up to 3 doses of 0.15 mg/kg intravenously every 4 hours	2 mg* orally every 12 hours
> 10 kg	up to 3 doses of 0.15 mg/kg intravenously every 4 hours	4 mg** orally every 12 hours

* administer ondansetron in the form of an oral solution;

** administer ondansetron in the form of an oral solution or tablets.

Elderly patients

Dose adjustment of ondansetron is not required in elderly patients.

Postoperative nausea and vomiting

Adults

16 mg of ondansetron administered 1 hour prior to anesthesia.

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

Children from 1 month of age

For this indication, ondansetron in the form of an injection solution is recommended.

Elderly patients

There is limited experience with the use of ondansetron for the prevention and treatment of postoperative nausea and vomiting in elderly patients; however, ondansetron was well tolerated in patients aged 65 years and older who received chemotherapy.

Patients with impaired renal function

There is no need to adjust the daily dose, frequency of administration, or route of administration of ondansetron.

Patients with impaired hepatic function

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

Patients with slow metabolism of sparteine/debrisoquine

The elimination half-life of ondansetron is not altered in patients with impaired sparteine and debrisoquine metabolism. In these patients, plasma concentrations after repeated dosing are similar to those in patients with normal metabolism. No adjustment of the daily dose or frequency of administration of ondansetron is required.

Children

The drug is indicated for use in children aged 6 months and older (for the treatment of nausea and vomiting induced by chemotherapy).

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

Overdose.

Symptoms

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

Ondansetron dose-dependently prolongs the QT interval; therefore, ECG monitoring is recommended in the event of overdose.

Treatment

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

Ipecac syrup is not recommended, as the clinical response to its administration may be suppressed due to the antiemetic effect of ondansetron.

Side effects

The adverse reactions listed below are classified by system organ class and frequency of occurrence. Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Immune system disorders: rare – immediate-type hypersensitivity reactions, sometimes severe, including anaphylaxis, bronchospasm, urticaria, angioedema, laryngeal edema, stridor, laryngospasm.

Nervous system disorders: very common – headache; uncommon – movement disorders (including extrapyramidal reactions such as dystonia, oculogyric crisis, and dyskinesia)¹; rare – dizziness, convulsions; frequency not known – weakness, serotonin syndrome, neuroleptic malignant syndrome.

Eye disorders: rare – transient visual disturbances (blurred vision); very rare – transient blindness².

Cardiac disorders: common – sensation of warmth or flushing; uncommon – arrhythmia, bradycardia, hypotension; rare – myocardial infarction, myocardial ischemia, angina pectoris, chest pain (with or without ST-segment depression), arrhythmia (including ventricular or supraventricular tachycardia, premature ventricular contractions (extrasystoles), and atrial fibrillation), ECG changes (including heart block, QT interval prolongation, and Torsade de Pointes arrhythmia), palpitations and syncope; frequency not known – myocardial ischemia (see section "Special precautions for use").

Respiratory system disorders: uncommon – hiccups.

Gastrointestinal disorders: common – constipation, diarrhea; frequency not known – abdominal pain, dry mouth.

Hepatobiliary disorders: uncommon – asymptomatic elevation of liver function parameters³.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; very rare – severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome.

Metabolism and nutrition disorders: rare – hypokalemia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system and to the marketing authorization holder using the feedback form on the website: https://kusum.ua/pharmacovigilance/.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets per blister. 1 or 3 blisters per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

TOV "KUSUM FARM".

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.

or

Manufacturer.

TOV "GLEDFARM LTD".

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Hryhoriya Davydovskoho St., 54.