INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOFETRON (ZOFETRON)

Composition:

Active substance: ondansetron;

1 tablet contains 8 mg of ondansetron in the form of ondansetron hydrochloride dihydrate;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, maize starch, magnesium stearate;

tablet coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, film-coated tablets of yellow-beige color, with the imprint "OD" on one side and "8" on the other.

Pharmacotherapeutic group. Antiemetic agents and drugs for relief of nausea. 5HT3 serotonin receptor antagonists.

ATC code A04AA01.

Pharmacological properties.

Pharmacodynamics.

Ondansetron hydrochloride is a serotonin receptor antagonist of the 5HT3 subtype. The exact mechanisms of antiemetic action have not been fully established. It is known that radiation therapy and cytotoxic chemotherapy lead to the release of serotonin (5HT) from enterochromaffin cells of the small intestine. Initiation of the vomiting reflex is associated with the interaction of serotonin with 5HT3 receptors located on the afferent endings of the vagus nerve. Activation of vagal afferent nerve endings may trigger serotonin release in the central nervous system from the chemoreceptor trigger zone located in the area of the floor of the fourth cerebral ventricle. It is believed that ondansetron prevents initiation of the vomiting reflex both at the level of vagal afferent nerve endings and at serotonin receptors located in the central nervous system.

Ondansetron exerts a sedative effect but does not alter plasma prolactin levels and does not reduce psychomotor activity in patients.

The mechanisms of ondansetron’s antiemetic action in the postoperative period are not sufficiently studied.

Pharmacokinetics.

The bioavailability of ondansetron after oral administration is approximately 60%. It undergoes extensive metabolism in the body, and metabolites are excreted in feces and urine. After oral administration, maximum plasma concentration is reached within 1.5 hours. Plasma protein binding is about 73%. The majority of the administered dose is metabolized in the liver.

The elimination half-life is 3–4 hours; in elderly individuals, it may extend to 6–8 hours. Less than 10% of the active substance is excreted unchanged in urine.

In vitro metabolism studies indicate that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. Ondansetron is primarily metabolized by CYP3A4. Since ondansetron metabolism can be carried out by several cytochrome P450 enzymes, the total clearance of ondansetron is not significantly altered in the case of deficiency of one of these enzymes, as the deficiency is compensated by other enzymes.

Clinical characteristics.

Indications.

Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy.

Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

Hypersensitivity to the components of the drug and to other selective 5HT3 serotonin receptor antagonists.

Severe hepatic impairment, abdominal surgery.

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

Interaction with other medicinal products and other forms of interaction.

Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, tramadol, 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 effect or only a negligible effect on total creatinine clearance. However, despite the diversity of metabolic enzymes, in patients receiving CYP3A4 inducers (i.e., phenytoin, carbamazepine, and rifampicin), increased oral clearance of ondansetron and reduced plasma concentrations have been observed.

Medicinal products that prolong the QTc interval. When ondansetron is used concomitantly with other drugs that prolong the QTc interval, the expected therapeutic benefit and potential risk should be carefully weighed.

The list below provides examples of medicinal products associated with QTc interval prolongation and/or ventricular fibrillation ("torsade de pointes"). Not all drugs within the pharmacological classes listed necessarily have an association with QTc prolongation and/or "torsade de pointes":

Class IA antiarrhythmics (quinidine, procainamide, disopyramide);
Class III antiarrhythmics (amiodarone, sotalol, ibutilide, dronedarone);
Class 1C antiarrhythmics (flecainide, propafenone);
Antiemetics (dolasetron, droperidol, chlorpromazine, prochlorperazine);
Tyrosine kinase inhibitors (vandetanib, sunitinib, nilotinib, lapatinib);
Antipsychotic agents (chlorpromazine, pimozide, haloperidol, ziprasidone);
Antidepressants (citalopram, fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants such as amitriptyline, imipramine, maprotiline);
Opioids (methadone);
Domperidone;
Macrolide antibiotics and analogues (erythromycin, clarithromycin, telithromycin, tacrolimus);
Quinolone antibiotics (moxifloxacin, levofloxacin, ciprofloxacin);
Antimalarials (quinine, chloroquine);
Azole antifungals (ketoconazole, fluconazole, voriconazole);
Histone deacetylase inhibitors (vorinostat);
Beta-2 adrenergic agonists (salmeterol, formoterol).

Medicinal products causing electrolyte imbalance. Concomitant use of ondansetron with drugs that may disrupt electrolyte balance should be avoided. Examples of such medicinal products include:

Loop, thiazide, and thiazide-like diuretics;
Laxatives and enemas;
Amphotericin B;
High-dose corticosteroids.

The lists of potentially interacting drugs above are not exhaustive. It is necessary to monitor current information sources to identify newly recognized drugs that prolong the QTc interval or cause electrolyte disturbances.

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

Apomorphine. Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe hypotension and loss of consciousness have been observed during combined use (see section "Contraindications").

Serotonergic medicinal products. As with other serotonergic agents, serotonin syndrome—a potentially life-threatening condition—may occur when using a 5HT3 serotonin receptor antagonist antiemetic in combination with other drugs that affect the serotonergic neurotransmitter system (including triptans, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), lithium, sibutramine, fentanyl and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone, and pirtazepine, or St. John’s wort (Hypericum perforatum)), as well as with drugs that reduce serotonin metabolism (such as MAO inhibitors, including linezolid (an antibiotic that is a reversible non-selective MAO inhibitor) and methylene blue) (see section "Special precautions for use").

Special precautions for use.

Ondansetron is not effective for the prevention of nausea and vomiting caused by motion sickness.

Cross-sensitivity among various 5-HT3 receptor antagonists has been reported. Therefore, in patients with hypersensitivity to one of the 5-HT3 receptor antagonists, a similar reaction to other antagonists may be more pronounced due to cross-reactions. If even a mild hypersensitivity reaction occurs to any of the 5-HT3 receptor antagonist drugs, switching to another 5-HT3 receptor antagonist is not recommended due to the potential for an enhanced hypersensitivity reaction.

Rarely, transient ECG changes, including dose- and infusion-rate-dependent QT interval prolongation, have been observed during ondansetron administration. Post-marketing surveillance data have reported cases of ventricular tachycardia (torsade de pointes) associated with ondansetron use; therefore, the drug should be used with caution in patients who have or may develop QT interval prolongation. Cases of torsade de pointes may be asymptomatic or may present with dizziness, rapid heartbeat, syncope, or seizures; this condition may progress to ventricular fibrillation and sudden cardiac death.

Ondansetron should be avoided in patients with congenital long QT syndrome. Ondansetron should be used with caution in patients with cardiac arrhythmias or conduction disorders, in patients receiving antiarrhythmic drugs or β-blockers, and in those who have or may develop QT interval prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medications that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy.

Examples of risk factors for the development of ventricular tachycardia (torsade de pointes): female sex; age 65 years or older; baseline QT/QTc prolongation; presence of genetic ion channel or regulatory protein disorders of the heart; family history of sudden cardiac death before age 50; heart disease (myocardial ischemia or infarction, left ventricular hypertrophy, cardiomyopathy, conduction system disorders); presence of arrhythmias (especially ventricular arrhythmias, atrial fibrillation); bradycardia (less than 50 beats/min); acute neurological disorders (intracranial or subarachnoid hemorrhage, stroke, traumatic brain injury); nutritional deficiencies (eating disorders, extreme diets); diabetes mellitus; autonomic neuropathy.

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

Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic drugs, with symptoms including: mental status changes (agitation, hallucinations, coma), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (hyperreflexia, incoordination), and gastrointestinal symptoms (nausea, vomiting, diarrhea). If serotonin syndrome occurs, ondansetron therapy should be discontinued and symptomatic treatment initiated. If concomitant treatment with ondansetron and other serotonergic drugs is clinically justified, appropriate patient monitoring is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Ondansetron does not affect the cytochrome P450 enzyme system; however, the use of other drugs capable of influencing the activity of these enzymes may alter the clearance and elimination half-life of ondansetron.

Ondansetron increases colonic transit time; therefore, continuous monitoring is required in patients receiving ondansetron who show even mild signs of intestinal obstruction.

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

Since the tablets contain carbohydrates, including lactose, the product should not be administered to patients with carbohydrate intolerance or rare hereditary disorders such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Ondansetron should not be administered during pregnancy. It is unknown whether ondansetron is excreted in breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

Due to the potential for nervous system-related adverse reactions, patients should be advised to avoid driving or operating machinery during treatment with this medicinal product.

Method of Administration and Dosage.

The drug is administered orally.

Zofetron is available in tablets; therefore, when prescribing ondansetron in injectable form, refer to the monograph describing ondansetron for injection.

Ondansetron has a dose-dependent effect of prolonging the QTc interval. With intravenous administration, this effect is expected to be greater due to the rapid infusion of the drug. The use of the minimum effective dose administered by slow infusion is recommended.

Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy

The choice of dosing regimen depends on the emetogenic potential of the anticancer therapy and should be individually determined.

Nausea and vomiting caused by chemotherapy

Adults

Highly emetogenic chemotherapy (e.g., high-dose cisplatin)

Initial dose for prevention of vomiting during the first 24 hours after chemotherapy: an initial dose of ondansetron is recommended before the start of chemotherapy. The subsequent dosing regimen should be determined based on the expected severity of vomiting associated with different cancer treatments. The usual dose is 8 mg administered as a 15-minute intravenous infusion, given at least 30 minutes before chemotherapy.

Doses higher than 8 mg (up to a maximum of 16 mg) should only be administered as intravenous infusion. Single doses exceeding 16 mg must not be used due to the risk of QTc interval prolongation (see section "Special precautions for use").

The efficacy of Zofetron in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate prior to chemotherapy.

For prevention of delayed or prolonged vomiting after the first 24 hours of chemotherapy, Zofetron 8 mg orally every 8 hours for 5 days is recommended.

Moderately emetogenic chemotherapy (e.g., regimens containing cyclophosphamide, doxorubicin, epirubicin, fluorouracil, or carboplatin)

Initial dose: ondansetron 8 mg administered as a 15-minute intravenous infusion at least 30 minutes before chemotherapy, or Zofetron 8 mg orally 1–2 hours before the start of chemotherapy.

For prevention of delayed or prolonged vomiting, Zofetron 8 mg orally twice daily for 5 days is recommended.

Children

Clinical experience with ondansetron for the treatment of chemotherapy-induced nausea and vomiting in children is currently limited; however, ondansetron has been effective and well tolerated in children aged 4 years and older.

Ondansetron is administered intravenously at a dose of 3–5 mg/m² (body surface area-based dosing) over 15 minutes, at least 30 minutes before chemotherapy. After chemotherapy, ondansetron 4 mg orally every 8 hours for 5 days is prescribed.

There is insufficient information to make dosing recommendations for children under 4 years of age; therefore, ondansetron is not indicated for use in this age group.

Elderly patients

Efficacy and tolerability following oral administration in patients aged 65 years and older do not differ from those in younger patients; therefore, dose adjustment is not necessary.

For intravenous administration in patients aged 65 years and older, all intravenous doses should be diluted in 50–100 mL of 0.9% sodium chloride injection or 5% dextrose injection.

Nausea and vomiting induced by radiotherapy

For adult patients, the initial dose of Zofetron is 8 mg orally 1–2 hours before the start of radiotherapy.

After completion of the radiotherapy course, Zofetron 8 mg orally every 8 hours for 5 days is prescribed.

Children

There is no clinical trial experience in this patient population. Ondansetron is not used for the prevention or treatment of radiation-induced nausea and vomiting in children.

Elderly patients

Efficacy and tolerability in patients aged 65 years and older do not differ from those in younger patients; therefore, dose adjustment is not necessary.

Postoperative nausea and vomiting

For adults, to prevent postoperative nausea and vomiting, Zofetron may be administered orally as a single 16 mg dose one hour before the induction of anesthesia. Alternatively, a single 4 mg dose of ondansetron may be administered intravenously undiluted over 2–5 minutes, but not less than 30 seconds, at the time of anesthesia induction.

For treatment of postoperative nausea and vomiting, a single 4 mg dose of ondansetron administered intravenously undiluted over 2–5 minutes, but not less than 30 seconds, is recommended.

There is no experience with ondansetron for the prevention or treatment of postoperative nausea and vomiting in children; therefore, it is not prescribed for this indication in pediatric patients.

Elderly patients

There is limited experience with ondansetron for the prevention and treatment of postoperative nausea and vomiting in elderly patients; therefore, ondansetron is not used in this patient group.

For all types of therapy

Patients with renal impairment

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

Patients with hepatic impairment

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

Currently, there are no studies on the use of ondansetron in patients with jaundice.

Patients with impaired metabolism of sparteine/debrisoquine

The elimination half-life of ondansetron is not altered in patients with impaired sparteine and debrisoquine metabolism. Repeated administration in these patients results in drug concentrations similar to those in patients with normal metabolism. Therefore, no dose adjustment is required for this patient group.

Children

The drug in this pharmaceutical form is not administered to children under 4 years of age.

Overdose

Currently, there is limited information on ondansetron overdose. In most cases, symptoms are similar to those observed in patients receiving recommended doses.

Symptoms: In one patient, sudden blindness (amaurosis) lasting 2–3 minutes associated with severe constipation occurred after a single intravenous dose of 72 mg ondansetron. In another patient, hypotension (and loss of consciousness) occurred after oral intake of 48 mg ondansetron. A vasovagal episode with transient second-degree heart block was observed after a 4-minute infusion of 32 mg ondansetron. Neuromuscular disturbances, autonomic instability, somnolence, and brief generalized tonic-clonic seizures (which resolved after benzodiazepine administration) were observed in a 12-month-old infant who ingested 7 or 8 tablets of 8 mg ondansetron (a dose approximately 40 times higher than the recommended pediatric dose of 0.1–0.15 mg/kg). In all cases, these effects were completely reversible.

Treatment: Discontinue the drug and provide symptomatic and supportive therapy. The use of syrup of ipecac is not recommended for the treatment of ondansetron overdose, as its emetic effect may be counteracted by the antiemetic action of Zofetron. There is no specific antidote.

Further management of patients should be based on clinical judgment or, if possible, in accordance with recommendations from the national poison control center.

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

There have been reports of serotonin syndrome in young children following oral overdose.

Adverse Reactions

The adverse reactions listed below are classified by organ systems and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

In clinical trials, the most commonly reported adverse reactions were: headache (11%), constipation (4%), sensation of warmth or flushing (<1%).

Immune system disorders.

Rare: immediate-type allergic reactions, sometimes severe, including anaphylaxis, bronchospasm, urticaria, and angioneurotic edema.

Central nervous system disorders.

Very common: headache.

Uncommon: seizures, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences).

Rare: dizziness during rapid intravenous administration; central nervous system depression, paresthesia.

Eye disorders.

Rare: transient visual disturbances (blurred vision), transient blindness, mainly during intravenous administration.

Cardiovascular system disorders.

Uncommon: arrhythmias, chest pain (with or without ST-segment depression), bradycardia, arterial hypotension, arterial hypertension, tachycardia, syncope.

Common: sensation of warmth, flushing.

Respiratory, thoracic and mediastinal disorders.

Uncommon: hiccup, cough.

Gastrointestinal disorders.

Common: constipation, diarrhea, dry mouth, abdominal pain.

Hepatobiliary disorders.

Uncommon: asymptomatic elevation of liver function tests, hepatic function abnormalities.

General disorders: weakness, syncope. These cases occur primarily in patients receiving chemotherapy regimens containing cisplatin.

Metabolism and nutrition disorders.

In approximately 5% of patients, there was a transient increase in SGOT and SGPT levels by more than two times the upper limit of normal. It is unknown whether this increase is related to dose or duration of therapy.

Cases of liver failure and death have been reported in cancer patients receiving multiple drugs concurrently, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of liver failure in these cases remains unclear. Rare cases of hypokalemia have also been reported.

Post-marketing adverse reactions.

The adverse reaction profile in children and adolescents is comparable to that in adults.

Immune system disorders.

Rare: hypersensitivity reactions, sometimes severe (laryngeal edema, stridor, laryngospasm, cardiopulmonary shock/cardiac arrest).

Cardiovascular system disorders.

Uncommon: myocardial infarction (<0.01%), angina pectoris, chest pain with or without ST-segment depression, arrhythmias (including ventricular or supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), electrocardiographic changes (including second-degree atrioventricular block), palpitations, and syncope.

Rare, and predominantly with intravenous administration of ondansetron, transient ECG changes have been reported, including QT interval prolongation, cases of ventricular flutter/fibrillation, ventricular fibrillation, cardiac arrest, and sudden death.

Frequency not known: myocardial ischemia (see section "Special precautions for use").

Eye disorders.

Rare cases of transient blindness have been reported, usually within the recommended dosage range and predominantly during intravenous administration. In most cases, blindness resolved within 20 minutes.

Hepatobiliary disorders.

Asymptomatic elevation of liver function tests.

Central nervous system disorders.

Transient dizziness (<0.1%), mainly during or immediately after completion of intravenous infusion of ondansetron.

Uncommon (<1%): extrapyramidal reactions, including oculogyric crisis/dystonic reactions (oral-lingual dyskinesia, opisthotonus, tremor, etc.), movement disorders, and dyskinesias without persistent clinical consequences.

Serotonin syndrome has been reported with the use of 5-HT3 receptor antagonists (including ondansetron hydrochloride) in combination with other serotonergic agents and/or neuroleptics.

Skin and subcutaneous tissue disorders.

Very rare: bullous skin and mucosal reactions, including fatal cases, particularly toxic skin eruptions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. These reactions have been reported in patients receiving other medicinal products as well.

Shelf life. 5 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 30 °C.

Packaging. 5 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Pharmascience Inc.

Manufacturer's address.

6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada.