Ondansetron-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONDANSETRON-VISTA (ONDANSETRON-VISTA)

Composition:

Active substance: ondansetron;

1 ml of solution contains 2 mg of ondansetron (in the form of ondansetron hydrochloride dihydrate);
Excipients: sodium citrate dihydrate, citric acid monohydrate, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear colorless solution, practically free from visible particles.

Pharmacotherapeutic group. Antiemetic agents and drugs for relief of nausea. Serotonin (5HT3) receptor antagonists. ATC code A04AA01.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

The volume of distribution after parenteral administration in adults is 140 L. The majority of the administered dose undergoes hepatic metabolism. Less than 5% of the drug is excreted unchanged in urine. The elimination half-life is approximately 3 hours (in elderly patients, about 5 hours). Plasma protein binding is 70–76%. 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 increase in elimination 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 elimination half-life (15–32 hours).

Clinical characteristics.

Indications.

Nausea and vomiting caused by cytotoxic chemotherapy and radiation therapy. Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

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

Hypersensitivity to any component of the medicinal product.

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, 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 overall creatinine clearance 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 imbalances (see section "Special precautions for use").

Concomitant use of ondansetron with medicinal products that prolong the QT interval may lead to additional QT prolongation. Concomitant use of ondansetron with cardiotoxic agents (e.g., anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such as erythromycin), antifungal agents (such as ketoconazole), antiarrhythmic agents (such as amiodarone), and beta-blockers (such as atenolol or timolol) may increase the risk of developing arrhythmias (see section "Special precautions for use"). Serotonergic agents (e.g., SSRIs and SNRIs).

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

Apomorphine.

The use of ondansetron together with apomorphine hydrochloride is contraindicated, as cases of severe hypotension and loss of consciousness have been observed during concomitant 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.

Tramadol.

According to data from some clinical studies, ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use.

In patients with a history of hypersensitivity to other selective 5HT3-receptor antagonists, hypersensitivity reactions have been observed.

Respiratory reactions should be treated symptomatically. Healthcare professionals should pay special attention to such reactions, as they may be signs of hypersensitivity to the medicinal product.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section "Pharmacological properties"). Additionally, post-marketing surveillance data have reported cases of ventricular tachycardia (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 interval prolongation, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, or those receiving other medicinal products that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment. Serotonin syndrome has been reported following concomitant use of ondansetron and other serotonergic medicinal products (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.

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.

Since ondansetron may reduce gastrointestinal motility, careful monitoring is required in patients showing signs of subacute intestinal obstruction during ondansetron therapy.

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 close observation after ondansetron administration.

Children.

In children receiving ondansetron together with hepatotoxic chemotherapeutic agents, careful monitoring for possible hepatic function impairment is required.

Dosing regimens.

When dosing according to body weight and administering three doses at 4-hour intervals, the total daily dose will be higher than when using a single dose of 5 mg/m² and one dose of the medicinal product orally. The comparative efficacy of these two dosing regimens has not been evaluated in clinical trials. Comparison of results from different studies indicates similar efficacy for both dosing regimens.

Important information on excipients.

One injection of Ondansetron-VIST contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is essentially sodium-free.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential should use contraceptive methods.

Pregnancy.

Based on human experience from epidemiological studies, there is suspicion of an increased risk of craniofacial defects with ondansetron use 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 treated; adjusted relative risk 1.24 (95% CI 1.03–1.48)). Epidemiological studies on congenital heart defects have yielded conflicting results. Animal studies have not indicated direct or indirect adverse 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 medicinal product is necessary, breastfeeding should be discontinued.

Fertility.

There is no information available on the effect of ondansetron on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Psychomotor tests have shown that ondansetron does not impair the ability to operate machinery and has no sedative effect. However, the adverse effect profile of the medicinal product should be taken into account when assessing the ability to drive or operate machinery.

Dosage and Administration

Nausea and vomiting induced by chemotherapy and radiation therapy.

Adults.

The emetogenic potential of cancer therapy varies depending on the dose and combination regimens of chemotherapy and radiation therapy. The choice of dosing regimen depends on the severity of emetogenic effect. The dose of Ondansetron-Vista (range from 8 to 32 mg per day) and route of administration should be selected according to the information below.

Emetogenic chemotherapy and radiation therapy.

The recommended intravenous or intramuscular dose of Ondansetron-Vista is 8 mg administered as a slow intravenous injection over at least 30 seconds or as an intramuscular injection given immediately before treatment.

For prevention of delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the drug is recommended for up to 5 days following completion of the treatment course.

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

Ondansetron-Vista may be administered as a single 8 mg intravenous or intramuscular dose immediately before chemotherapy.

For highly emetogenic chemotherapy, 8 mg of Ondansetron-Vista or a lower dose does not require dilution and may be administered via slow intravenous or intramuscular injection (over at least 30 seconds) immediately before chemotherapy, followed by two additional intravenous or intramuscular doses of 8 mg given 2 and 4 hours later, or by continuous infusion of 1 mg/hour for 24 hours.

Doses exceeding 8 mg (up to 16 mg) must be administered only as intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable diluent (see below "Administration of injection solution"); the infusion must last at least 15 minutes. Single doses exceeding 16 mg must not be used, as higher doses increase the risk of QT interval prolongation (see section "Special precautions"). The choice of dosing regimen depends on the severity of emetogenic effect. The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate before chemotherapy.

For prevention of delayed or prolonged vomiting after the first 24 hours, oral or rectal administration of the drug is recommended.

Children aged 6 months to 17 years.

In pediatric practice, ondansetron should be administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable diluent (see below "Administration of injection solution") over at least 15 minutes. The drug dose can be calculated based on body surface area or body weight of the child.

Dose calculation according to child's body surface area.

Ondansetron-Vista should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m²; the intravenous dose must not exceed 8 mg. Oral administration of the drug may be initiated 12 hours later and may continue for up to 5 additional days. Adult dose must not be exceeded.

Ondansetron-Vista must be diluted with 5% dextrose solution, 0.9% sodium chloride solution, or another suitable infusion solution and administered by intravenous infusion over at least 15 minutes.

There are no data from controlled clinical trials regarding the use of ondansetron for prevention of delayed or prolonged chemotherapy-induced nausea and vomiting (CINV). There are no data from controlled clinical trials regarding the use of ondansetron for treatment of nausea and vomiting induced by radiation therapy in children.

Dose calculation according to child's body weight.

Ondansetron-Vista should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. 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 of the drug may be initiated 12 hours later and may continue for up to 5 additional days. Adult dose must not be exceeded.

Elderly patients.

For patients aged 65 years and older, all intravenous injection doses should be diluted and administered over 15 minutes. When repeated administration is required, the interval between injections must be at least 4 hours.

For patients aged 65 to 74 years, the initial dose of ondansetron is 8 mg or 16 mg, administered by intravenous infusion over 15 minutes, which may be followed by two additional 8 mg doses infused over 15 minutes each, with at least a 4-hour interval between infusions.

For patients aged 75 years and older, the initial intravenous dose of ondansetron must not exceed 8 mg, administered by infusion over at least 15 minutes. After the initial 8 mg dose, two additional 8 mg doses may be administered by infusion over 15 minutes each, with at least a 4-hour interval between infusions.

Patients with renal impairment.

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

Patients with hepatic impairment.

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

Patients with sparteine/debrisoquine metabolism deficiency.

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

Postoperative nausea and vomiting.

Adults.

For prevention of postoperative nausea and vomiting, the recommended dose of ondansetron is 4 mg administered as a single intramuscular or slow intravenous injection during anesthesia induction.

For treatment of postoperative nausea and vomiting, the recommended single dose of ondansetron is 4 mg administered as an intramuscular or slow intravenous injection.

Children aged 1 month to 17 years.

For prevention and treatment of postoperative nausea and vomiting in children undergoing general anesthesia, ondansetron may be administered at a dose of 0.1 mg/kg body weight (maximum up to 4 mg) by slow intravenous injection (over at least 30 seconds) before, during, or after anesthesia induction or after surgery.

Elderly patients.

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

Patients with renal impairment.

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

Patients with hepatic impairment.

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

Patients with sparteine/debrisoquine metabolism deficiency.

The elimination half-life of ondansetron in subjects with sparteine and debrisoquine metabolism deficiency is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with intact metabolism. Therefore, dose adjustment or change in administration frequency is not required.

Administration of injection solution.

Ampoules of Ondansetron-Vista do not contain preservatives and the solution must be used immediately after opening; any unused solution must be discarded. Ampoules of Ondansetron-Vista must not be autoclaved.

Compatibility with other intravenous solutions.

Intravenous solutions should be prepared immediately before infusion. However, it has been established that ondansetron solution remains stable for 7 days at room temperature (up to 25°C) under daylight or in the refrigerator when diluted in the following media: 0.9% sodium chloride solution, 5% glucose solution, 10% mannitol solution, Ringer's solution, 0.3% potassium chloride solution and 0.9% sodium chloride solution, 0.3% potassium chloride solution and 5% glucose solution.

It has been shown that ondansetron remains stable when using polyethylene and glass bottles. Ondansetron diluted with 0.9% sodium chloride or 5% glucose has been shown to remain stable in polypropylene syringes. Stability in polypropylene syringes has also been demonstrated when ondansetron is diluted with other recommended solutions.

If prolonged storage of the drug is required, dilution should be performed under appropriate aseptic conditions.

Compatibility with other medicinal products.

Ondansetron-Vista may be administered as intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, ondansetron may be co-administered with the following drugs at ondansetron concentrations ranging from 16 to 160 mcg/mL (i.e., 8 mg/500 mL or 8 mg/50 mL, respectively):

• cisplatin at concentrations up to 0.48 mg/mL, over 1–8 hours;
• 5-fluorouracil at concentrations up to 0.8 mg/mL (e.g., 2.4 g in 3 L or 400 mg in 500 mL) at a rate not exceeding 20 mL/hour. Higher concentrations of 5-fluorouracil may cause ondansetron precipitation. The 5-fluorouracil infusion solution may contain up to 0.045% magnesium chloride in addition to other compatible excipients;
• carboplatin at concentrations from 0.18 mg/mL to 9.9 mg/mL (e.g., from 90 mg in 500 mL to 990 mg in 100 mL) over 10–60 minutes;
• etoposide at concentrations from 0.14 mg/mL to 0.25 mg/mL (e.g., from 72 mg in 500 mL to 250 mg in 1 L) over 30–60 minutes;
• ceftazidime at doses from 250 mg to 2 g, diluted in water for injection (e.g., 2.5 mL per 250 mg or 10 mL per 2 g ceftazidime), administered as intravenous bolus injection over 5 minutes;
• cyclophosphamide at doses from 100 mg to 1 g, diluted in water for injection (5 mL per 100 mg cyclophosphamide), administered as intravenous bolus injection over 5 minutes;
• doxorubicin at doses from 10 mg to 100 mg, diluted in water for injection (5 mL per 10 mg doxorubicin), administered as intravenous bolus injection over 5 minutes;
• dexamethasone at a dose of 20 mg, administered as slow intravenous injection over 2–5 minutes (when co-administered with 8 mg or 16 mg ondansetron diluted in 50–100 mL of injection solution) over approximately 15 minutes. Since these drugs are compatible, they may be administered through the same infusion line, with dexamethasone phosphate (as sodium salt) concentrations ranging from 32 mcg to 2.5 mg per mL and ondansetron concentrations from 8 mcg to 1 mg per mL.

Children.

To be administered to children aged 6 months (during chemotherapy) and aged 1 month (for prevention and treatment of postoperative nausea and vomiting).

Overdose.

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

Symptoms. Overdose manifestations reported include visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree atrioventricular block. In all cases, these effects were fully reversible.

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.

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

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

The use of ipecacuanha for treatment of ondansetron overdose is not recommended, as its effect may be counteracted by 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

The adverse effects 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000).

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 without persistent clinical consequences);
Rare: Dizziness, mainly during rapid intravenous administration of the medicinal product.

Eye disorders:

Rare: Transient visual disturbances (blurred vision), mainly during intravenous administration;
Very rare: Transient blindness, mainly during intravenous administration. In most cases, blindness resolves within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient blindness have been reported as cortical in origin.

Cardiac disorders:

Uncommon: Arrhythmias, chest pain (with or without ST segment depression), bradycardia;
Rare: QT interval prolongation (including ventricular fibrillation/torsade de pointes);
Frequency not known: Myocardial ischemia (see section "Special precautions").

Vascular disorders:

Common: Feeling of warmth or flushing;
Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Hiccups.

Gastrointestinal disorders:

Common: Constipation.

Hepatobiliary disorders:

Uncommon: Asymptomatic increase in liver function parameters.

These cases occur mainly in patients receiving chemotherapy containing cisplatin.

Skin and subcutaneous tissue disorders:

Very rare: Toxic skin rashes, including toxic epidermal necrolysis.

General disorders and administration site conditions:

Common: Local reactions at the site of intravenous administration.

During post-marketing surveillance, the following adverse reactions have been observed:

Cardiovascular disorders: Chest pain and discomfort, extrasystoles, tachycardia including ventricular and supraventricular tachycardia, atrial fibrillation, palpitations, syncope, ECG changes.

Hypersensitivity reactions: Anaphylactic reactions, angioneurotic edema, bronchospasm, anaphylactic shock, pruritus, skin rashes, urticaria.

Nervous system disorders: Gait disturbance, chorea, myoclonus, restlessness, burning sensation, tongue protrusion, diplopia, paresthesia.

General disorders and administration site conditions: Increased body temperature, pain, erythema, burning sensation at the injection site.

Other: Hypokalemia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicine to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibilities.

Ondansetron-Vista must not be used in the same syringe or infusion solution with other medicinal products. Ondansetron-Vista in injectable form may be mixed only with recommended infusion solutions (see section "Dosage and administration").

Packaging.

2 ml or 4 ml in an ampoule; 5 ampoules in a blister pack in a carton.

Prescription status.

Prescription only.

Manufacturer.

PT. Novell Pharmaceuticals Laboratories

Manufacturer's address and location of business operations.

Jl. Veteran No. 35 Tlajung Udik, Gunung Putri, Bogor 16962, Indonesia