Instructions for Susprin tablets 4 mg No. 10
Composition
active ingredient: ondansetron;
Each film-coated tablet contains ondansetron hydrochloride dihydrate equivalent to 4 mg ondansetron or ondansetron hydrochloride dihydrate equivalent to 8 mg ondansetron.
excipients: microcrystalline cellulose, anhydrous lactose, partially pregelatinized corn starch, magnesium stearate, Opadry 03B51322 green coating*;
*Opadry 03B51322 green: hypromellose, titanium dioxide (E 171), iron oxide yellow (E 172), polyethylene glycol, indigo carmine (E 132).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, green or light green in color, round, biconvex, smooth on both sides.
Pharmacotherapeutic group
Antiemetics and antinausea drugs. Serotonin receptor antagonists (5HT3). ATC code A04A A01.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Ondansetron is a potent, highly selective serotonin (5HT3) receptor antagonist. The mechanism of action of ondansetron in nausea and vomiting is not fully understood. Radiation therapy and chemotherapy can cause the release of serotonin (5HT) in the small intestine and excitation of the afferent endings of the vagus nerve by activating 5HT3 receptors, which triggers the peripheral mechanism of the vomiting reflex. Ondansetron blocks the initiation of this reflex. Activation of the afferent endings of the vagus nerve can cause the release of 5HT in the area postrema and, accordingly, the initiation of the central mechanism of the vomiting reflex. Thus, ondansetron suppresses nausea and vomiting caused by chemotherapy and radiotherapy due to its antagonistic effect on 5HT3 receptors of neurons located in the peripheral and central nervous system.
The mechanism of action of ondansetron in postoperative nausea and vomiting has not been definitively elucidated.
Ondansetron does not affect plasma prolactin concentrations.
The role of ondansetron in opiate-induced vomiting is not fully understood.
Pharmacokinetics
After oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes presystemic metabolism. Peak plasma concentrations (approximately 30 ng/ml) are reached approximately 1.5 hours after an 8 mg dose. At doses above 8 mg, ondansetron blood levels increase disproportionately, as presystemic metabolism may be reduced. 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 is not changed when taken with antacids. The distribution of ondansetron is similar after oral, intramuscular and intravenous administration in adults, with a terminal half-life of 3 hours and a volume of distribution at steady state of 140 l. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of ondansetron.
Ondansetron is moderately bound to plasma proteins (70–76%). Ondansetron is cleared from the systemic circulation primarily by hepatic metabolism involving multiple enzyme systems. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the CYP2D6 enzyme (sparteine-debrisoquine polymorphism) does not affect the pharmacokinetics of ondansetron. The pharmacokinetic parameters of ondansetron remain unchanged after repeated administration.
Special patient groups
Sex
The pharmacokinetics of ondansetron are gender-dependent. Women have a higher rate and extent of absorption and a lower systemic clearance and volume of distribution (weight-adjusted) than men.
Children
The differences in pharmacokinetic parameters are partly explained by the higher percentage of body fluid in newborns and infants and the higher volume of distribution in children aged 1 to 4 months.
In children aged 3 to 12 years, 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 in patients aged <12 years, these values approached those in adults.
When adjusting clearance and volume of distribution for body weight, these parameters were approximated across age groups. Body weight-based dose calculation compensates for age-related changes and systemic exposure to ondansetron in children.
According to the results of the study, the area under the pharmacokinetic curve "concentration-time" (AUC) after oral and intravenous administration of the drug in children and adolescents was similar to that in adults, with the exception of infants aged 1 to 4 months. The volume of distribution was age-dependent and was 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 than in younger patients.
In patients with moderate renal impairment (creatinine clearance 15–60 mL/min), systemic clearance and volume of distribution are reduced after intravenous administration of ondansetron, resulting in a small, clinically insignificant increase in half-life (5.4 hours). Studies in patients with severe renal impairment requiring regular hemodialysis have shown no change in the pharmacokinetics of ondansetron after intravenous administration.
Patients with liver dysfunction
In patients with severe liver dysfunction, the systemic clearance of ondansetron is significantly reduced with an increase in the half-life to 15–32 hours, and the bioavailability when administered orally reaches 100% due to a decrease in presystemic metabolism.
Indication
Adults
Treatment of nausea and vomiting induced 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
Treatment of nausea and vomiting induced by cytotoxic chemotherapy for children
≥ 6 months.
There are no data from studies on the use of oral ondansetron in children aged 1 month and older for the prevention or treatment of postoperative nausea and vomiting, therefore, in this case, it is recommended to use ondansetron in the form of a solution for injection.
Contraindication
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. Ondansetron has been shown not to 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 reduction in the activity of one of them (e.g. genetic deficiency of CYP2D6) is normally compensated by the other enzymes and will have no or negligible effect on the overall clearance of ondansetron.
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 cause additional prolongation of this interval.
Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines (doxorubicin, daunorubicin) or trastuzumab), antibiotics (erythromycin), antifungals (ketoconazole), antiarrhythmics (amiodarone) and beta-blockers (atenolol or timolol) may increase the risk of arrhythmias (see section "Special warnings and precautions for use").
Serotoninergics (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs))
There are reports of serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular disorders) in patients receiving ondansetron and other serotonergic medicinal products, including SSRIs and SNRIs (see section 4.4).
Apomorphine
The use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of arterial hypotension and loss of consciousness have been observed during concomitant use.
Phenytoin, carbamazepine, and rifampicin
In patients treated with potential CYP3A4 inducers (e.g. phenytoin, carbamazepine and rifampicin), the clearance of ondansetron (when administered orally) is increased and the blood concentration is decreased.
Tramadol
Ondansetron may reduce the analgesic effect of tramadol.
Application features
Hypersensitivity reactions have been reported in patients with a history of hypersensitivity to other selective 5HT3 receptor antagonists. Respiratory disorders should be treated symptomatically and physicians should pay special attention to them, as they may be precursors of hypersensitivity reactions.
Myocardial ischemia has been reported in patients receiving ondansetron. In some patients, especially when administered intravenously, symptoms have occurred immediately after administration of ondansetron. Patients should be advised of the signs and symptoms of myocardial ischemia.
Hypokalemia and hypomagnesemia should be corrected before starting use.
There are reports of serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular disorders) in patients receiving ondansetron and other serotonergic drugs, including SSRIs and SNRIs (see Interactions with other medicinal products and other forms of interaction). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate monitoring of the patient is recommended.
Since ondansetron reduces intestinal motility, careful monitoring of patients with signs of intestinal obstruction after use of the drug is required.
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 require close monitoring after the use of ondansetron.
Continuous monitoring for liver function abnormalities is necessary in children receiving ondansetron with hepatotoxic chemotherapeutic agents.
This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Use during pregnancy or breastfeeding
Women of childbearing potential who use ondansetron should consider using contraception.
Pregnancy
Based on epidemiological studies, ondansetron is suspected of causing maxillofacial malformations when used during the first trimester of pregnancy. In a cohort study involving 1.8 million pregnancies, ondansetron use during the first trimester was associated with an increased risk of oral clefts (3 additional cases per 10,000 women exposed to ondansetron; adjusted relative risk, 1.24 (95% CI 1.03-1.48)). Available epidemiological studies of cardiac malformations 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
In experimental studies, it has been shown that ondansetron passes into breast milk in animals. If necessary, women should stop breastfeeding.
Fertility
There are no data on the effect of ondansetron on human fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Psychomotor tests have shown that ondansetron does not affect the ability to drive and use machines and does not have a sedative effect. Based on the pharmacology of ondansetron, no adverse effects on such activities are expected.
Method of administration and doses
Nausea and vomiting caused by chemotherapy and radiation therapy
The choice of dosing regimen is determined by the emetogenicity of the anticancer 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 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 2 times a day for no more than 5 days after the course of treatment.
Children aged 6 months and over
The dose is calculated by surface area or body weight.
By 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 initiated 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 32 mg.
Table 1
| Body surface area | Day 1 | From the 2nd to the 6th day |
| 2 | 5 mg/m2 intravenously, then 2 mg* orally 12 hours later | 2 mg* orally every 12 hours |
≥ 0.6 m2 and ≤ 1.2 m2 | 5 mg/m2 intravenously, then 4 mg orally 12 hours later | 4 mg** orally every 12 hours |
| > 1.2 m2 | 5 mg/m2 or 8 mg intravenously, then 8 mg orally 12 hours later | 8 mg** orally every 12 hours |
* use ondansetron in the form of a solution for oral administration;
** use ondansetron in the form of an oral solution or tablets.
By body weight
Ondansetron is administered immediately before chemotherapy as a single intravenous injection at a dose of 0.15 mg/kg body weight. The intravenous dose should not exceed 8 mg. Subsequently, two intravenous injections may be administered at 4-hour intervals. Oral administration is initiated 12 hours later and continued for up to 5 days (see Table 2). The total daily dose of ondansetron (divided into several doses) should not exceed 32 mg.
Table 2
| Body weight | Day 1 | From the 2nd to the 6th day |
| ≤ 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 |
* use ondansetron in the form of a solution for oral administration;
** use ondansetron in the form of an oral solution or tablets.
Elderly patients
No dose adjustment of ondansetron is required for elderly patients.
Nausea and vomiting in the postoperative period
Adults
16 mg of ondansetron 1 hour before anesthesia.
To stop postoperative nausea and vomiting, ondansetron is used in the form of an injectable solution.
Children from 1 month of age
For this indication, it is recommended to use ondansetron in the form of an injection solution.
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 receiving chemotherapy.
Patients with renal impairment
There is no need to adjust the daily dose, frequency of administration, or route of administration of ondansetron.
Patients with liver dysfunction
In patients with moderate to severe hepatic impairment, the clearance of ondansetron is significantly reduced and the half-life is prolonged. In such patients, the daily dose of the drug should not exceed 8 mg.
Patients with poor metabolism of sparteine/debrisoquine
The half-life of ondansetron in patients with impaired metabolism of sparteine and debrisoquine is not changed. In such patients, after repeated administration, the concentration of the drug is the same as in patients with intact metabolism. Correction of the daily dose or frequency of administration of ondansetron is not required.
Children.
The drug is intended for use in children aged 6 months and older (treatment of nausea and vomiting caused by chemotherapy).
For the prevention or treatment of postoperative nausea and vomiting in children aged 1 month and older, it is recommended to use ondansetron in the form of an injectable solution.
Overdose
Symptoms
There is limited information on overdose with ondansetron. In most cases of overdose, the symptoms were similar to those experienced by patients at recommended doses (see section 4.8). Visual disturbances, severe constipation, hypotension, and vasovagal reactions with transient second-degree atrioventricular block have been reported in patients with overdose. Serotonin syndrome has been reported in children aged 12 months to 2 years with overdose.
Ondansetron dose-dependently prolongs the QT interval, therefore ECG monitoring is recommended in case of overdose.
Treatment
There is no specific antidote for ondansetron, therefore, in case of overdose, symptomatic and supportive therapy should be used.
The use of ipecacuanha is not recommended because the clinical response to its administration may be inhibited by the antiemetic action of ondansetron.
Adverse reactions
Adverse reactions, information on which is provided below, are classified by system organ class and by frequency of occurrence. Adverse reactions are classified according to frequency as follows: very common (≥1/10), common (≥1/100 and <1/1000), uncommon (≥1/1000 to
On the part of the immune system: rarely - immediate-type hypersensitivity reactions, in a number of cases - 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; not known - weakness, serotonin syndrome, neuroleptic malignant syndrome.
On the part of the organs of vision: rarely - transient visual disturbances (blurred vision); very rarely - transient blindness2.
Cardiovascular system: often - feeling of heat or flushing; infrequently - arrhythmia, bradycardia, arterial hypotension; rarely - myocardial infarction, myocardial ischemia, angina pectoris, chest pain (with or without ST segment depression), arrhythmia (including ventricular or supraventricular tachycardia, premature ventricular contractions (extrasystole) and atrial fibrillation), ECG changes (including heart block, QT interval prolongation and Torsade de Pointes-type arrhythmia), palpitations and syncope, unknown - myocardial ischemia (see section "Special instructions").
On the part of the respiratory system: infrequently - hiccups.
From the digestive tract: often - constipation, diarrhea; unknown - abdominal pain, dry mouth.
Skin and subcutaneous tissue disorders: uncommon - rash, itching; very rare - toxic rashes such as toxic epidermal necrolysis and Stevens-Johnson syndrome.
Metabolic disorders: rarely - hypokalemia.
1Observations lack definitive data on sustained clinical outcomes.
2In most cases, transient blindness resolved within 20 minutes. Most patients were receiving chemotherapy agents containing cisplatin. Some cases of transient blindness of cortical origin have been reported.
3These cases were observed mainly in patients receiving cisplatin.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after the registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report all suspected adverse reactions via the national reporting system and to the applicant via the feedback form on the website: https://kusum.ua/pharmacovigilance/.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister. 1 or 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and address of its place of business
40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54.
