Aurodans

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AURONDANS (AURODANZ)

Composition:

Active substance: ondansetron;

1 ml of solution contains: ondansetron hydrochloride dihydrate equivalent to ondansetron 2 mg;

Excipients: citric acid monohydrate; sodium citrate (dihydrate); sodium chloride; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution, 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 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 inhibits the emetic 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 – 5 hours). Plasma protein binding ranges from 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 clinically insignificant prolongation of the drug's elimination half-life. 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, leading to an increased elimination half-life (15–32 hours).

Clinical characteristics.

Indications.

Nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy.

Prevention and treatment of postoperative nausea and vomiting.

Contraindications.

Concomitant use of ondansetron with apomorphine hydrochloride (cases of severe arterial hypotension and loss of consciousness have been observed during combined use).

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 used 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 in combination with medicinal products that prolong the QT interval and/or cause electrolyte imbalances (see section "Special precautions for use").

Concomitant use of ondansetron with drugs that prolong the QT interval may lead to additional QT prolongation. Concurrent use of ondansetron with cardiotoxic drugs (e.g., anthracyclines such as doxorubicin, daunorubicin, or trastuzumab), antibiotics (e.g., erythromycin), antifungal agents (e.g., ketoconazole), antiarrhythmic drugs (e.g., amiodarone), and beta-blockers (e.g., atenolol or timolol) increases 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 following 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

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.

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 particular 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"). Post-marketing surveillance has also 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, and patients receiving other medications 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 agents (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 administration of Aurodans.

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

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

The medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e. it is essentially sodium-free.

Children

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

Dosing regimens

When dosing according to body weight and administering three doses with 4-hour intervals, the total daily dose will be higher than with a single dose of 5 mg/m² and one oral dose. 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 regimens.

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should consider using contraception.

Pregnancy

Epidemiological studies suggest that ondansetron may 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 orofacial clefts (3 additional cases per 10,000 women treated with ondansetron; adjusted relative risk: 1.24; 95% confidence interval (CI): 1.03–1.48).

Available epidemiological data on cardiac malformations are conflicting. Animal studies do not indicate direct or indirect harmful effects related to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

Breastfeeding

Ondansetron passes into breast milk; therefore, breastfeeding must be discontinued during treatment with this medicinal product.

Fertility

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

Ability to affect driving and use of machines

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

Method of Administration and Dosage

Nausea and vomiting induced by chemotherapy and radiotherapy

Adults

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

Emetogenic chemotherapy and radiotherapy

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

To prevent 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)

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

For highly emetogenic chemotherapy, 8 mg of Aurodans or a lower dose does not need to be diluted and can 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) may only be administered as an intravenous infusion in 50–100 mL of 0.9% sodium chloride solution or another suitable diluent; the infusion must last no less than 15 minutes.

Single doses exceeding 16 mg must not be used, as increasing the dose increases the risk of QT interval prolongation (see section "Special precautions for use").

The choice of dosing regimen depends on the severity of the emetogenic effect. The efficacy of Aurodans in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium dexamethasone phosphate before chemotherapy.

To prevent 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, Aurodans should be administered via intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable diluent over at least 15 minutes. The drug dose can be calculated based on body surface area or body weight of the child.

Dosage calculation according to body surface area

Aurodans 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 may continue for another 5 days. The adult dose must not be exceeded.

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

There are no data from controlled clinical trials regarding the use of ondansetron for the prevention of delayed or prolonged vomiting and nausea induced by chemotherapy. There are also no data from controlled clinical trials regarding the use of ondansetron for the treatment of nausea and vomiting induced by radiotherapy in children.

Dosage calculation according to body weight

Aurodans should be administered as a single intravenous injection at a dose of 0.15 mg/kg immediately before chemotherapy. The intravenous dose must not exceed 8 mg. On the first day, two additional intravenous doses may be administered with a 4-hour interval.

Oral administration may be initiated 12 hours later and may continue for another 5 days. The 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 should be at least 4 hours.

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

For patients aged 75 years and older, the initial intravenous dose of ondansetron must not exceed 8 mg, administered via infusion over at least 15 minutes. After the initial 8 mg dose, two additional 8 mg doses may be administered via infusion over 15 minutes each, with an interval of at least 4 hours 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, the clearance of Aurodans 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 impaired metabolism of sparteine/debrisoquine

The elimination half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with normal metabolism. Therefore, no dosage adjustment or change in frequency of administration is required.

Postoperative nausea and vomiting

Adults

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

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

Children aged 1 month to 17 years

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

Elderly patients

Experience with the use of Aurodans for the prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, the drug 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, the clearance of Aurodans 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 impaired metabolism of sparteine/debrisoquine

The elimination half-life of ondansetron in subjects with impaired sparteine and debrisoquine metabolism is unchanged. After repeated administration, drug concentrations in these patients are similar to those in patients with intact metabolism. Therefore, no dosage adjustment or change in frequency of administration is required.

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 solutions: 0.9% sodium chloride, 5% glucose, 10% mannitol, Ringer’s solution, 0.3% potassium chloride and 0.9% sodium chloride, 0.3% potassium chloride and 5% glucose solution.

It has been demonstrated that ondansetron remains stable when using polyethylene and glass vials. Ondansetron diluted in 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 drugs

Aurodans may be administered as an intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, Aurodans at a concentration of 16 to 160 mcg/mL (i.e., 8 mg / 500 mL or 8 mg / 50 mL, respectively) may be co-administered with:

• cisplatin at a concentration up to 0.48 mg/mL, over 1–8 hours;
• 5-fluorouracil at a concentration 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 precipitation of ondansetron. The 5-fluorouracil infusion solution may contain up to 0.045% magnesium chloride in addition to other compatible excipients;
• carboplatin at a concentration 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 a concentration 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 an 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 an 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 an intravenous bolus injection over 5 minutes;
• dexamethasone at a dose of 20 mg, administered as a slow intravenous injection over 2–5 minutes (when co-administered with 8 mg or 16 mg ondansetron diluted in 50–100 mL of infusion solution) over approximately 15 minutes. Since these drugs are compatible, they may be administered through the same infusion line, with dexamethasone phosphate (as the sodium salt) concentrations ranging from 32 mcg to 2.5 mg per 1 mL and ondansetron concentrations from 8 mcg to 1 mg per 1 mL.

The diluted solution should be stored at 2–8°C for no more than 24 hours.

Ondansetron solutions in compatible intravenous infusion solutions remain stable at normal room temperature for at least 24 hours; protection from light is not required.

Sterilization of ampoules in an autoclave is prohibited.

Children

Administered to children aged 6 months and older during chemotherapy and to children aged 1 month and older for the prevention and treatment of postoperative nausea and vomiting.

Overdose

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

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

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

Cases of serotonin syndrome in young children after oral overdose have been reported.

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

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

The use of ipecacuanha for the treatment of ondansetron overdose is not recommended, as its effect may be counteracted by the antiemetic action of Aurodans.

Children: serotonin syndrome has been reported in infants and children aged 12 months to 2 years after accidental overdose of orally administered ondansetron (doses exceeding the recommended level of 4 mg/kg).

Adverse Reactions

Adverse reactions are classified by organ systems and frequency of occurrence. Frequency categories: 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).

Very common, common, and uncommon adverse reactions were identified during clinical trials. Placebo-controlled cases were taken into account. Rare and very rare adverse reactions were identified during the post-marketing period through spontaneous reporting.

The adverse reaction categories listed below were observed with ondansetron when used at recommended doses according to the approved indications.

Immune system:

Rare: Immediate-type hypersensitivity reactions, sometimes severe, up to anaphylaxis.

Nervous system:

Very common: Headache;

Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without lasting clinical consequences);

Rare: Dizziness, mainly during rapid intravenous administration.

Psychiatric disorders:

Very rare: Depression.

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 who experienced this reaction 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 elevation of liver function tests. These cases are mainly observed in patients receiving chemotherapy containing cisplatin.

Skin and subcutaneous tissue disorders:

Very rare: Toxic skin eruptions, including toxic epidermal necrolysis; hypersensitivity reactions at the site of administration (e.g., rash, urticaria, pruritus).

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 system: 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: Gait disturbances, chorea, myoclonus, restlessness, burning sensation, tongue protrusion, diplopia, paresthesia.

General disorders and local reactions: Increased body temperature, pain, redness, burning sensation at the injection site.

Other: Hypokalemia.

Pediatric population

The adverse reaction profile in children and adolescents was similar to that in adults.

Shelf life.

2 years.

Storage conditions.

Store in a place protected from light and inaccessible to children, at a temperature not exceeding 30 °C.

Incompatibilities.

Aurondans must not be used in the same syringe or infusion solution with other medicinal products. Aurondans for injection may only be combined with the recommended infusion solutions (see section "Dosage and administration").

Packaging.

2 ml or 4 ml in a vial; 5 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Eugia Pharma Specialities Limited, Unit-III /

Eugia Pharma Specialities Limited, Unit-III.

Manufacturer's address and place of business.

Plot No’s: 4, 34 to 48, EPIP, TSIIC, IDA, Pashamylaram Village, Patancheru Mandal, Sanga Reddy District, Telangana state, 502307, India /
Plot No’s: 4, 34 to 48, EPIP, TSIIC, IDA, Pashamylaram Village, Patancheru Mandal, Sanga Reddy District, Telangana state, 502307, India.