Emesetron-zdorovya

INSTRUCTION FOR MEDICAL USE of the medicinal product EMESETROn-ZDOROVYE (EMESETROn-ZDOROVYE)

Composition:

Active substance: ondansetron;

One tablet contains ondansetron 4 mg or 8 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; potato starch; magnesium stearate; povidone; colloidal anhydrous silicon dioxide; titanium dioxide (E 171); candurin (silver shimmer) containing potassium aluminosilicate, titanium dioxide (E 171); hypromellose; colorant "Sepispers dry yellow R" containing hypromellose, microcrystalline cellulose, riboflavin (E 101).

Medicinal form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, light yellow in color.

Pharmacotherapeutic group. Antiemetic agents and drugs used to relieve nausea. Serotonin receptor antagonists (5HT3). ATC code A04AA01.

Pharmacological properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective antagonist of 5-HT3 (serotonin) receptors. The drug prevents or eliminates nausea and vomiting caused by cytotoxic chemotherapy and/or radiation therapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron has not been fully elucidated. It is likely that the drug blocks the initiation of the vomiting reflex by antagonizing 5-HT3 receptors located on neurons of both the peripheral and central nervous systems. The drug does not reduce psychomotor activity and does not produce sedative effects.

Pharmacokinetics.

After oral administration of ondansetron, its Cmax in plasma is reached in approximately 1.5 hours. Bioavailability of the drug is about 60%. The majority of the administered dose undergoes hepatic metabolism. Less than 5% of the drug is excreted unchanged in urine. The half-life (T½) is approximately 3 hours (in elderly patients – 5 hours). Plasma protein binding ranges from 70% to 76%.

In patients with moderate renal impairment (creatinine clearance 15–60 mL/min), both systemic clearance and volume of distribution of ondansetron are reduced, resulting in a slight and clinically insignificant prolongation of the drug's half-life. The pharmacokinetics of ondansetron are practically unchanged in patients with severe renal impairment undergoing chronic hemodialysis (studies were conducted between hemodialysis sessions). In patients with severe chronic hepatic impairment, systemic clearance of ondansetron is markedly reduced, with an increase in T½ (15–32 hours).

Clinical characteristics.

Indications.

Prevention and treatment of nausea and vomiting associated with cytotoxic chemotherapy and radiotherapy. Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe arterial hypotension and loss of consciousness have been observed during combined administration. Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other forms of interaction.

Ondansetron does not accelerate or inhibit the metabolism of other drugs when administered concomitantly. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lignocaine, 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 have no significant effect or only a negligible effect on overall creatinine clearance.

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"). Concomitant use of the drug with other medicinal products that prolong the QT interval may result in additional QT prolongation. Combined use of the drug with cardiotoxic medicinal products (e.g., anthracyclines such as doxorubicin, daunorubicin, or trastuzumab), antibiotics (e.g., erythromycin), antifungals (e.g., ketoconazole), antiarrhythmics (e.g., amiodarone), beta-blockers (e.g., atenolol and timolol) may increase the risk of developing arrhythmias (see section "Special precautions").

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

Phenytoin, carbamazepine, and rifampicin. In patients receiving potential inducers of CYP3A4 (e.g., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron is increased and its blood concentration is reduced.

Serotonergic agents (e.g., SSRIs and SNRIs). Serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) has been reported following concomitant use of ondansetron and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (see section "Special precautions").

Tramadol. According to data from a limited number of clinical studies, ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use.

In patients with known hypersensitivity to other selective 5HT3 receptor antagonists, hypersensitivity reactions have been observed. Respiratory symptoms should be treated symptomatically, and physicians should pay special attention to them as potential precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner. Post-marketing surveillance data have reported cases of ventricular arrhythmias (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 prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medicinal products that may induce QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

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.

Serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) has been described following concomitant use of ondansetron and 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 agents is clinically justified, appropriate patient monitoring is recommended.

Since ondansetron reduces gastrointestinal motility, careful monitoring is required in patients with signs of subacute intestinal obstruction during treatment.

In patients undergoing adenotonsillar surgery, the use of ondansetron for prevention of nausea and vomiting may mask the occurrence of postoperative bleeding. Therefore, such patients require careful monitoring after ondansetron administration.

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

If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicine.

Dosing regimens

When dosing according to body weight and administering three doses at 4-hour intervals, the total daily dose will be higher than with a single 5 mg/m² intravenous injection followed by a single oral dose. The comparative efficacy of these two dosing regimens has not been evaluated in clinical trials. Comparison of results from different studies suggests similar efficacy for both dosing regimens.

Use during pregnancy or breastfeeding.

Women of childbearing potential. Women of childbearing age receiving ondansetron should consider using contraception.

Pregnancy. Based on available epidemiological studies, ondansetron is suspected to cause craniofacial malformations when used during the first trimester of pregnancy. In one 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 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 is necessary, breastfeeding should be discontinued.

Effect on ability to drive and use machines.

Psychomotor tests have shown that ondansetron does not affect the ability to operate machinery and does not have sedative effects. However, the adverse reaction profile of the drug should be taken into account when assessing a patient's ability to drive or operate machinery.

Method of Administration and Dosage

To be administered orally.

Nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.

The emetogenic potential of cancer therapy varies depending on the dose and combination of chemotherapy and radiation therapy regimens used. The choice of ondansetron dosing regimen depends on the intensity of the emetogenic effect of the anticancer therapy being administered. The maximum daily dose of ondansetron is 32 mg.

Adults.

Chemotherapy- and radiotherapy-induced nausea and vomiting. Administer 8 mg 1–2 hours before the start of therapy, followed by 8 mg every 12 hours for up to 5 days.

Highly emetogenic chemotherapy. For patients receiving highly emetogenic chemotherapy, ondansetron is recommended to be administered intravenously or intramuscularly.

For highly emetogenic chemotherapy, a single dose of 24 mg should be given concomitantly with dexamethasone 12 mg orally, 1–2 hours before the start of chemotherapy.

To prevent delayed or prolonged vomiting after the first 24 hours, oral ondansetron is recommended at a dose of 8 mg twice daily for 5 days starting from the end of chemotherapy.

Children.

Children aged 6 months and adolescents.

The dose of the drug can be calculated based on body surface area or body weight. Dosing based on body weight results in higher total daily doses compared to dosing based on body surface area (see section "Special Instructions").

There are no controlled clinical study data on the use of ondansetron for the prevention of nausea and vomiting induced by radiation therapy in children.

Dosing based on body surface area.

Ondansetron (injection solution) should be administered as a single intravenous injection at a 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 additional days. The adult maximum dose of 32 mg must not be exceeded.

Dose calculation for chemotherapy based on body surface area in children aged 6 months and adolescents:

A. The intravenous dose must not exceed 8 mg.
B. The total daily dose must not exceed the adult dose (32 mg).

Dose calculation based on body weight.

Ondansetron (injection solution) should be administered as a single intravenous injection at a dose of 0.15 mg/kg body weight, 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 may continue for up to 5 additional days. The total daily dose must not exceed the adult dose of 32 mg.

Dose calculation for chemotherapy-induced nausea and vomiting based on body weight in children aged 6 months and older and adolescents:

A. The intravenous dose should not exceed 8 mg.
B. The total daily dose should not exceed the adult dose (32 mg).

Geriatric patients. The drug is well tolerated in elderly individuals; therefore, dosage adjustment is not required.

Patients with renal impairment. Patients with impaired kidney function do not require changes in dosage regimen or route of administration.

Patients with hepatic impairment. In patients with moderate or severe hepatic impairment, ondansetron clearance is significantly reduced and the serum half-life (T½) is considerably prolonged. In such patients, the total daily dose of ondansetron should not exceed 8 mg.

Patients with impaired metabolism of sparteine/debrisoquine. The T½ of ondansetron in individuals with impaired sparteine and debrisoquine metabolism is not altered. Repeated administration in these patients results in ondansetron concentrations similar to those observed in patients with normal metabolism; therefore, dosage adjustment or change in dosing frequency is not necessary.

Postoperative nausea and vomiting.

Adults. To prevent postoperative nausea and vomiting, administer the drug at a single dose of 16 mg one hour before anesthesia. An alternative regimen is 8 mg one hour before anesthesia, followed by two additional doses administered at 8-hour intervals.

Children. In pediatric practice for this indication, ondansetron is recommended in the form of an injection solution.

Children aged 1 month to 18 years.

Oral formulation. 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).

Injection formulation. For prophylactic use in children scheduled for surgery under general anesthesia, a single dose of ondansetron should be administered slowly (over no less than 30 seconds) by intravenous injection at a dose of 0.1 mg/kg, up to a maximum of 4 mg, during or after induction of anesthesia.

For treatment of postoperative nausea and vomiting in children, ondansetron is also administered as a single slow intravenous injection (over no less than 30 seconds) at a dose of 0.1 mg/kg, up to a maximum of 4 mg.

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.

Geriatric patients

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

Patients with renal impairment. Patients with impaired kidney function do not require changes in dosage regimen or route of administration.

Patients with hepatic impairment. In patients with moderate or severe hepatic impairment, ondansetron clearance is significantly reduced and the serum half-life (T½) is considerably prolonged. In such patients, the total daily dose of ondansetron should not exceed 8 mg.

Patients with impaired metabolism of sparteine/debrisoquine. The T½ of ondansetron in individuals with impaired sparteine and debrisoquine metabolism is not altered. Repeated administration in these patients results in ondansetron concentrations similar to those observed in patients with normal metabolism; therefore, dosage adjustment or change in dosing frequency is not necessary.

Children.

The drug is indicated for use in children aged 6 months and older (during cytotoxic chemotherapy).

There are no clinical data on the use of oral ondansetron in children aged 1 month to 18 years 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).

Overdose.

Data on ondansetron overdose are limited. In most cases, symptoms are similar to those described in patients receiving recommended doses (see section "Adverse Reactions").

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

Manifestations of overdose have included visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree AV block. In all reported cases, these effects resolved completely.

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

The use of ipecacuanha to treat ondansetron overdose is not recommended, as its emetic effect may be suppressed due to the antiemetic action of ondansetron.

Children: Serotonin syndrome has been reported in infants and children aged 12 months to 2 years following accidental overdose of the oral formulation (doses exceeding the recommended level of 4 mg/kg).

Adverse reactions.

Immune system disorders: immediate-type hypersensitivity reactions, sometimes severe, up to anaphylaxis, anaphylactic reactions, angioedema, bronchospasm, anaphylactic shock, pruritus, skin rashes, urticaria.

Nervous system disorders: headache, seizures, motor disturbances (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences), gait disturbance, chorea, myoclonus, restlessness, burning sensation, tongue protrusion, diplopia, paresthesia.

Eye disorders: transient visual disturbances (blurred vision), transient blindness. In most cases, blindness resolves within 20 minutes. Some cases of transient blindness have been reported as of cortical origin.

Cardiac disorders: arrhythmias, chest pain (with or without ST-segment depression), chest discomfort, bradycardia, QT interval prolongation (including ventricular fibrillation/flutter), extrasystoles, tachycardia, including ventricular and supraventricular tachycardia, atrial fibrillation, palpitations, syncope, ECG changes, myocardial ischemia.

Vascular disorders: sensation of warmth or hot flushes, hypotension.

Respiratory, thoracic and mediastinal disorders: hiccups.

Gastrointestinal disorders: constipation.

Hepatobiliary disorders: asymptomatic elevation of liver function parameters.

These cases occur mainly in patients receiving chemotherapy containing cisplatin.

Cases of liver failure have been reported in cancer patients receiving concomitant treatment, including potentially hepatotoxic chemotherapy and antibiotics.

General disorders: increased body temperature.

Other: hypokalemia.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets № 10 in a blister pack in a box.|tablets|

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.