Vomicaund

INSTRUCTIONS for medical use of the medicinal product VOMIKIND (VOMIKIND)

Composition:

Active substance: ondansetron;

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

Excipients: sodium chloride, citric acid monohydrate, sodium citrate, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

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 5-HT3 (serotonin) receptor antagonist. The drug prevents or relieves nausea and vomiting caused by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The mechanism of action of ondansetron is not fully understood. It is likely that the drug blocks the initiation of the vomiting reflex by exerting an antagonistic effect on 5-HT3 receptors located on neurons of both the peripheral and central nervous systems. The drug does not reduce psychomotor activity and has no sedative effect.

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 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 prolongation of the elimination half-life. The pharmacokinetics of ondansetron are almost 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 a prolonged elimination half-life (15–32 hours).

Clinical characteristics

Indications

Adults

Ondansetron is indicated for the control of nausea and vomiting associated with cytotoxic chemotherapy and radiotherapy, as well as for the prevention and treatment of postoperative nausea and vomiting.

Children

Ondansetron is indicated for the treatment of nausea and vomiting induced by chemotherapy in children aged 6 months and older, and for the prevention and treatment of postoperative nausea and vomiting in children aged 1 month and older.

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, 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 the effect will be negligible.

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").

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

Serotonergic agents (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (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 SSRIs, SNRIs, and buprenorphine (see section "Special precautions for use").

Apomorphine

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.

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 decreased.

Tramadol

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

Special precautions for use

Hypersensitivity reactions have been observed in patients with known hypersensitivity to other selective 5HT3 receptor antagonists.

Respiratory-related reactions should be treated symptomatically. Healthcare professionals should pay special attention to such reactions, as they may be signs of increased sensitivity 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 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 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.

Hypokalaemia and hypomagnesaemia should be corrected prior to initiating treatment.

Cases of myocardial ischaemia have been reported in patients receiving ondansetron. The frequency of such events is unknown. In some patients, particularly following intravenous administration, symptoms appeared immediately after ondansetron administration. Patients should be informed about the signs and symptoms of myocardial ischaemia.

Serotonin syndrome has been described following concomitant use of ondansetron with other serotonergic medicinal products (including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and buprenorphine) (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 showing signs of subacute intestinal obstruction during treatment with Vomikind.

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

Children

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

Dosing regimens

When dosing is calculated according to body weight and three doses are administered at 4-hour intervals, the total daily dose will be higher than when using a single dose of 5 mg/m² followed by one 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.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free". However, if physiological saline (0.9% sodium chloride solution) is used to dilute the product prior to administration, the amount of sodium received will be higher.

Use during pregnancy or breastfeeding

Pregnancy

Women of childbearing potential should undergo a pregnancy test before starting treatment with this medicinal product.

Women of childbearing potential should be advised that the medicinal product may harm the developing fetus. Sexually active women of childbearing potential are advised to use effective contraception (a method that results in pregnancy rates of less than 1%) during treatment and for two days after discontinuation of treatment.

Based on human experience and epidemiological data, there is a 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 harmful effects with regard to reproductive toxicity.

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

Breastfeeding

It is unknown whether ondansetron is excreted in human breast milk. There are no data on adverse reactions in infants or effects on breast milk production. However, ondansetron has been shown to pass into the milk of lactating animals. Therefore, breastfeeding mothers are advised not to breastfeed while receiving ondansetron.

Fertility

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

Women of childbearing potential

Women of childbearing potential should use contraceptive measures.

Ability to affect performance when driving or operating machinery

Psychomotor tests have shown that ondansetron does not impair the ability to drive or 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.

Administration and Dosage

Vomikaynd for injection solution is administered by intravenous or intramuscular injection, or by intravenous infusion after dilution.

Nausea and vomiting induced by chemotherapy and radiotherapy (CINV and RINV)

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 emetogenic impact. The dose of Vomikaynd (range from 8 to 32 mg per day) and route of administration should be selected according to the information below.

Emetogenic chemotherapy and radiotherapy

The recommended intravenous or intramuscular dose of Vomikaynd 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)

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

For highly emetogenic chemotherapy, 8 mg of Vomikaynd or a lower dose does not require dilution 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 at 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 "Use of injection solution"); the infusion must last at least 15 minutes.

Single doses exceeding 16 mg should 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 the drug in highly emetogenic chemotherapy may be enhanced by additional single intravenous administration of 20 mg sodium phosphate dexamethasone 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, Vomikaynd should be administered by intravenous infusion in 25–50 mL of 0.9% sodium chloride solution or another suitable diluent (see below "Use of injection solution") over at least 15 minutes. The drug dose can be calculated based on body surface area or body weight.

Dose calculation based on body surface area

Vomikaynd should be administered as a single intravenous injection of 5 mg/m² immediately before chemotherapy; the intravenous dose must not exceed 8 mg. Oral administration of the drug may be initiated 12 hours later and may continue for another 5 days. The adult dose must not be exceeded.

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

Dose calculation based on body weight

Vomikaynd should be administered as a single intravenous injection 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 at 4-hour intervals. Oral administration of the drug 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 ondansetron dose 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 ondansetron dose 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 in patients with impaired renal function.

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, clearance of Vomikaynd is significantly reduced and serum half-life is prolonged. In 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 are similar to those in patients with normal metabolism. Therefore, no dose adjustment or change in frequency of administration is required.

Postoperative nausea and vomiting

Adults

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

For treatment of postoperative nausea and vomiting, the recommended single dose 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, Vomikaynd may be administered at a dose of 0.1 mg/kg body weight (maximum up to 4 mg) as a slow intravenous injection (over at least 30 seconds) before, during, after induction of anesthesia, or after surgery.

Elderly patients

Experience with the use of the drug for prevention and treatment of postoperative nausea and vomiting in elderly patients is limited; however, Vomikaynd 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 in patients with impaired renal function.

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, clearance of ondansetron is significantly reduced and serum half-life is prolonged. In 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 are similar to those in patients with intact metabolism. Therefore, no dose adjustment or change in frequency of administration is required.

Use of injection solution

Vomikaynd ampoules do not contain preservatives; therefore, the solution must be used immediately after opening. Any unused solution must be discarded.

Vomikaynd ampoules must not be autoclaved.

Compatibility with other intravenous fluids

Intravenous infusion 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 and 0.9% sodium chloride solution, 0.3% potassium chloride and 5% glucose solution.

It has been demonstrated that ondansetron remains stable when using polyethylene and glass bottles. 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

Vomikaynd may be administered as intravenous infusion at a rate of 1 mg/hour. Through a Y-injector, Vomikaynd may be co-administered with the following drugs at ondansetron concentrations 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 precipitation of ondansetron; 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 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 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 infusion solution) over approximately 15 minutes. Since these drugs are compatible, they may be administered through the same infusion line. In the solution, concentrations of dexamethasone phosphate (as sodium salt) will range from 32 mcg to 2.5 mg per 1 mL, and ondansetron concentrations from 8 mcg to 1 mg per 1 mL.

Children

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

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

Manifestations of overdose include visual disturbances, severe constipation, arterial hypotension, vasovagal reactions with transient second-degree atrioventricular block. In all cases, these effects were fully reversible.

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

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

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

Ipecacuanha is not recommended for treatment of ondansetron overdose, as its effect may be ineffective due to the antiemetic action of the drug.

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

Side effects

The adverse reactions listed below are classified by organ systems and frequency of occurrence. Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

Immune system disorders:
Rare: immediate-type hypersensitivity reactions, sometimes severe, up to anaphylaxis.

Nervous system disorders:
Very common: headache;
Uncommon: convulsions, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions, and dyskinesia without persistent clinical consequences);
Rare: dizziness, mainly during rapid intravenous administration.

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 were 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 for use").

Vascular disorders:
Common: sensation of warmth or flushing;
Uncommon: arterial hypotension.

Respiratory, thoracic and mediastinal disorders:
Uncommon: hiccups.

Gastrointestinal disorders:
Common: constipation.

Hepatobiliary disorders:
Uncommon: asymptomatic elevations in liver function tests.

These events occur primarily in patients receiving chemotherapy regimens containing cisplatin.

Skin and subcutaneous tissue disorders:
Very rare: toxic skin eruptions, including toxic epidermal necrolysis.

General disorders and administration site conditions:
Common: local reactions at the site of intravenous administration.

The following adverse reactions have been reported during post-marketing surveillance:

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 disorders: gait disturbance, chorea, myoclonus, restlessness, burning sensation, tongue protrusion, diplopia, paresthesia;

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

Other: hypokalemia.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Incompatibilities

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

Packaging

2 ml or 4 ml of solution in a vial. 4 vials in a plastic blister pack, 1 blister pack in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mankind Pharma Limited.

Manufacturer's address and place of business

Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmaur 173025, Himachal Pradesh, India.