Vomikaind-md 8

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VOMIKIND-MD 4 VOMIKIND-MD 8 (VOMIKIND-MD 4) (VOMIKIND-MD 8)

Composition:

Active substance: ondansetron;

1 orodispersible tablet contains ondansetron 4 mg or 8 mg;

Excipients:

tablets of 4 mg: mannitol (E 421), crospovidone, povidone, siliconized microcrystalline cellulose, sodium starch glycolate (type A), aspartame (E 951), lemon flavor, mint flavor, quinoline yellow lake (E 104), colloidal anhydrous silicon dioxide, sodium stearyl fumarate, magnesium stearate;

tablets of 8 mg: mannitol (E 421), crospovidone, povidone, siliconized microcrystalline cellulose, sodium starch glycolate (type A), aspartame (E 951), lemon flavor, mint flavor, yellow FCF lake (E 110), colloidal anhydrous silicon dioxide, sodium stearyl fumarate, magnesium stearate.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties:

tablets of 4 mg: round, biconvex yellow tablets with specks, smooth on both sides;

tablets of 8 mg: round, biconvex light orange tablets with specks, smooth on both sides.

Pharmacotherapeutic group.
Serotonin (5-HT3) receptor antagonists. ATC code A04AD01.

Pharmacological properties.

Pharmacodynamics.

Ondansetron is a potent, highly selective antagonist of 5-HT3 (serotonin) receptors. The drug prevents or relieves nausea and vomiting induced by cytotoxic chemotherapy and/or radiotherapy, as well as postoperative nausea and vomiting. The exact mechanism of action of ondansetron has not been fully elucidated. It is likely that the drug blocks the initiation of the vomiting reflex by antagonizing 5-HT3 receptors located on neurons of both the peripheral and central nervous systems.

The precise mechanism of control over nausea and vomiting is not known. Chemotherapeutic agents and radiation therapy may induce the release of 5-HT in the small intestine, thereby stimulating the vomiting reflex through activation of vagal afferent nerves via 5-HT3 receptors. Ondansetron blocks this reflex stimulation. Activation of vagal afferent nerves may also trigger the release of 5-HT in the area located at the base of the fourth ventricle (area postrema), which may also provoke vomiting via a central mechanism. Thus, the effect of ondansetron on nausea and vomiting caused by cytotoxic chemotherapy and radiotherapy is likely explained by antagonism of 5-HT3 receptors on neurons located in both the peripheral and central nervous systems. The mechanisms of action in postoperative nausea and vomiting are not known, but the mechanism may be similar to that observed in nausea and vomiting induced by cytotoxic therapy.

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in nausea and vomiting caused by opioids has not yet been established.

Pharmacokinetics.

After oral administration, ondansetron is rapidly absorbed; a minimum peak plasma concentration of approximately 30 ng/mL is reached about 1.5 hours after an 8 mg dose. The syrup and tablets are bioequivalent and have an absolute oral bioavailability of 60%. The distribution of ondansetron after oral, intravenous, and intramuscular administration is similar, as is the elimination half-life, which is approximately 3 hours, and the steady-state volume of distribution—approximately 140 L. Ondansetron is moderately bound to plasma proteins (70–76%) and is removed from systemic circulation primarily by hepatic metabolism involving enzymes. Less than 5% of the absorbed dose is excreted unchanged in urine. The absence of the CYP2D6 enzyme (debrisoquine polymorphism) has no effect on the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are not altered upon repeated administration.

Special patient groups:

Gender

Ondansetron affects men and women differently, with women showing a higher rate and extent of absorption after oral administration. Systemic clearance and volume of distribution normalized to body weight are reduced in women.

Children and adolescents (from 1 month to 17 years of age)

In pediatric postoperative patients aged 1 to 4 months (n = 19), clearance was approximately 30% slower compared to patients aged 5 to 24 months (n = 22), but similar to clearance in patients aged 3 to 12 years. The elimination half-life in patients aged 1 to 4 months averaged 6.7 hours, compared to 2.9 hours in patients aged 5 to 24 months and 3 to 12 years. Differences in pharmacokinetic parameters in patients aged 1 to 4 months are partially explained by the higher percentage of total body water in neonates and infants, and the larger volume of distribution of water-soluble drugs such as ondansetron. In pediatric patients aged 3 to 12 years undergoing planned surgery under general anesthesia, the absolute values of both clearance and volume of distribution of ondansetron were reduced compared to adult patients. Both parameters increased linearly with increasing body weight and approached values in young adults by age 12. When clearance and volume of distribution were normalized to body weight, the values of these parameters were similar across different age groups. Dosing according to body weight compensates for age-related changes and is effective in normalizing systemic exposure in children. A population pharmacokinetic analysis was conducted in 428 volunteers (oncology patients, surgical patients, and healthy volunteers) aged 1 month to 44 years after intravenous administration of ondansetron. According to the analysis results, systemic exposure (AUC) of ondansetron after oral or intravenous administration in children and adolescents was comparable to that in adults, except in children aged 1 to 4 months. The volume of distribution depended on age and was lower in adults than in infants and children. Elimination was related to body weight rather than age, except in children aged 1 to 4 months. It is difficult to conclude whether there was an additional age-related reduction in clearance in children aged 1 to 4 months or whether this was due to natural differences caused by the low number of subjects in this age group. Since patients under 6 months of age receive only a single dose for postoperative nausea and vomiting, the reduced clearance is unlikely to be of clinical significance.

Elderly patients

Early Phase I studies involving healthy elderly volunteers demonstrated a slight age-related reduction in clearance and an increase in the elimination half-life of ondansetron. However, the wide inter-subject variability resulted in substantial overlap in pharmacokinetic parameters between younger subjects (< 65 years) and elderly subjects (≥ 65 years).

Overall, no differences in safety or efficacy of ondansetron have been observed between younger and elderly oncology patients; therefore, no specific dosage recommendations are required for elderly patients.

Based on the latest ondansetron plasma concentrations and exposure-response modeling, a greater effect of ondansetron on the QTcF interval is expected in patients aged 75 years and older compared to younger patients.

Renal impairment

In patients with impaired renal function (creatinine clearance 15–60 mL/min), systemic clearance and volume of distribution are reduced, resulting in a moderate but clinically insignificant prolongation of the elimination half-life (5.4 hours). Studies in patients with severe renal impairment requiring regular hemodialysis (evaluated between dialysis sessions) showed that the pharmacokinetics of ondansetron are virtually unchanged.

Hepatic impairment

In patients with severe hepatic impairment, systemic clearance is markedly reduced, with a prolonged elimination half-life (15–32 hours), and oral bioavailability approaches 100% due to reduced first-pass metabolism.

Clinical characteristics.

Indications.

Adults

Ondansetron in the form of orally disintegrating tablets is indicated for the treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Ondansetron in the form of orally disintegrating tablets is indicated for the prevention of postoperative nausea and vomiting (PONV).

For the treatment of PONV, administration of ondansetron by injection is recommended.

Children

Ondansetron in the form of orally disintegrating tablets is indicated for the treatment of chemotherapy-induced nausea and vomiting in children aged 6 months and older.

• For the prevention and treatment of PONV in children aged 1 month and older, administration of the drug by injection is recommended.

Contraindications.

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated.

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 significantly affect overall clearance or will have only a minor effect.

Ondansetron should be used with caution together with medicinal products that prolong the QT interval and/or cause electrolyte imbalances.

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

Post-marketing reports exist describing patients with serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular disturbances) following concomitant use of ondansetron and other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Apomorphine

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as cases of severe arterial 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 some clinical studies, ondansetron may reduce the analgesic effect of tramadol.

Special precautions for use

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

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

Ondansetron prolongs the QT interval in a dose-dependent manner. Additionally, postmarketing reports have described 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 with known risk factors for QT prolongation or in whom QT prolongation may develop, including patients with electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), congestive heart failure, bradyarrhythmias, and patients receiving other medicinal products that can induce QT prolongation or electrolyte disturbances.

Myocardial ischemia has been reported in patients receiving ondansetron. In some cases, particularly following intravenous administration, symptoms occurred immediately after administration but resolved with prompt treatment. Therefore, caution should be exercised during and after ondansetron administration. Hypokalemia and hypomagnesemia should be corrected prior to initiating ondansetron therapy.

Postmarketing reports have described serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) following concomitant use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, appropriate patient monitoring is recommended.

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

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

The medicinal product contains aspartame (E 951), which may be harmful for patients with phenylketonuria.

Sodium methylparahydroxybenzoate and sodium propylparahydroxybenzoate may cause allergic reactions (possibly delayed).

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Children

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

Chemotherapy-induced nausea and vomiting

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

Use during pregnancy or breastfeeding

Pregnancy

Women of childbearing potential who are treated with ondansetron should consider using contraception.

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 cleft palate [3 additional cases per 10,000 women exposed to ondansetron; adjusted relative risk: 1.24 (95% CI: 1.03–1.48)]. Epidemiological data on cardiac malformations are inconsistent. Animal studies have not shown 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 use of 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 drive and use machines

Ondansetron has no effect or has a negligible effect on the ability to drive or operate machinery.

Psychomotor tests have shown that ondansetron does not impair the ability to operate machinery and has no sedative effect. Based on the pharmacological profile of ondansetron, a harmful effect on reaction speed during driving or operating machinery is not expected.

Administration and Dosage

Place the tablet on the tongue and allow it to dissolve completely.

Nausea and vomiting induced by chemotherapy and radiation therapy

Adults

The emetogenic potential of cancer therapy varies depending on the dose and combination of chemotherapy and radiation therapy regimens. The choice of dosage regimen depends on the severity of emetogenic effect.

Emetogenic chemotherapy and radiation therapy

The medicinal product Vomikind is administered orally (as tablets or syrup), intravenously, or intramuscularly. An 8 mg dose is taken 1–2 hours before chemotherapy or radiation therapy, followed by an additional 8 mg dose every 12 hours for up to 5 days to prevent delayed or prolonged vomiting.

Highly emetogenic chemotherapy (e.g., high-dose cisplatin): the drug should be administered as a single dose of up to 24 mg of ondansetron combined with 12 mg of sodium phosphate dexamethasone orally 1–2 hours before chemotherapy.

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

The recommended oral dosage is 8 mg twice daily.

Children

Dosage calculation for children aged 6 months to 17 years

The drug dosage can be calculated based on body surface area or body weight. In clinical studies in pediatrics, ondansetron was administered via intravenous infusion diluted in 25–50 mL of physiological saline or another compatible infusion fluid, infused over at least 15 minutes. When dosing is based on body weight, the total daily dose is higher compared to dosing based on body surface area.

There are no data from controlled clinical trials regarding the use of the medicinal product Vomikind for the prevention of delayed or prolonged nausea and vomiting induced by chemotherapy. Controlled clinical trial data on the use of Vomikind for the treatment of chemotherapy-induced nausea and vomiting in children are lacking.

Dosage calculation according to body surface area

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at a dose of 5 mg/m²; the intravenous dose must not exceed 8 mg. Oral administration may be initiated 12 hours later and may continue for another 5 days (see Table 1). The total daily dose (divided into administrations) must not exceed the adult dose of 32 mg.

Table 1

Dosage calculation according to body surface area for children aged 6 months to 17 years

Child’s body surface area	Day 1(a, b)	Day 2–6(b)
< 0.6 m²	0.5 mg/m² intravenously + syrup* at a dose of 2 mg every 12 hours	Syrup* at a dose of 2 mg every 12 hours
≥ 0.6 m² to ≤ 1.2 m²	5 mg/m² intravenously + syrup* or tablet at a dose of 4 mg every 12 hours	Syrup* or tablet at a dose of 4 mg every 12 hours
> 1.2 m²	5 mg/m² or 8 mg intravenously + syrup* or tablet at a dose of 8 mg every 12 hours	Syrup* or tablet at a dose of 8 mg every 12 hours

* Another medicinal product containing ondansetron in the form of a syrup is used.

a. The intravenous dose must not exceed 8 mg.

b. The total daily dose must not exceed the adult dose of 32 mg.

Dose calculation based on the child's body weight

If the dose is calculated according to body weight, the total daily dose is higher compared to dosing based on body surface area.

Ondansetron should be administered immediately before chemotherapy as a single intravenous injection at a dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg; two additional intravenous doses may be given at 4-hour intervals. Oral administration may be initiated 12 hours after the last intravenous dose and may continue for another 5 days (see Table 2). The total daily dose (divided into administrations) must not exceed the adult dose of 32 mg.

Table 2

Dose calculation based on body weight for children aged 6 months to 17 years

Body weight	Day 1 (a,b)	Day 2–6 (b)
≤ 10 kg	Up to 3 doses of 0.15 mg/kg IV every 4 hours	Syrup 2 mg every 12 hours
> 10 kg	Up to 3 doses of 0.15 mg/kg IV every 4 hours	Syrup or tablet 4 mg every 12 hours

a. The intravenous dose should not exceed 8 mg.

b. The total daily dose should not exceed the adult dose of 32 mg.

Elderly patients

Dosage adjustment or frequency of administration is not required.

Postoperative nausea and vomiting

Adults

For prevention of postoperative nausea and vomiting, ondansetron may be administered either orally (as tablets or syrup) or by intravenous or intramuscular injection.

For oral administration: the recommended dose is 16 mg, to be taken one hour before anesthesia.

For treatment of postoperative nausea and vomiting: the drug is recommended to be administered by intravenous or intramuscular injection.

Postoperative nausea and vomiting in children aged 1 month to 17 years

Oral formulation

No studies have been conducted on oral administration of ondansetron for prevention or treatment of postoperative nausea and vomiting; in this indication, administration of the drug by slow (over not less than 30 seconds) intravenous injection is recommended.

Injections:

For prevention of postoperative nausea and vomiting in children undergoing surgery under general anesthesia, a single dose of ondansetron may be administered by slow intravenous injection (over not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg, given before, during, or after induction of anesthesia.

For treatment of postoperative nausea and vomiting following surgical intervention in children undergoing surgery under general anesthesia, a single dose of the medicinal product Vomikaynd may be administered by slow intravenous injection (over not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg.

There are no data on the use of ondansetron for treatment of postoperative nausea and vomiting in children under 2 years of age.

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 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, ondansetron clearance is significantly reduced and serum half-life is prolonged. In such patients, the maximum daily dose should not exceed 8 mg.

Patients with impaired metabolism of sparteine/debrisoquine

The half-life of ondansetron in patients with impaired sparteine and debrisoquine metabolism is not altered. After repeated administration, drug concentrations are similar to those in patients with normal metabolism. Therefore, dosage adjustment or frequency of administration is not required.

Children

Ondansetron may be administered to children aged 6 months and older in an appropriate pharmaceutical form (see section "Method of administration and dosage").

Overdose

Symptoms

Data on ondansetron overdose are limited. In most cases, symptoms are similar to those described in patients receiving recommended doses.

Manifestations reported in overdose include visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree atrioventricular block.

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

Children

Cases of serotonin syndrome have been reported in infants and children aged 12 months to 2 years following accidental oral overdose of ondansetron (exceeding the calculated dose of 4 mg/kg).

Treatment

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

Further management should be based on clinical indications or in accordance with recommendations from the national toxicology center, if available.

Ipecacuanha should not be used to treat ondansetron overdose, as its emetic effect may be ineffective due to the antiemetic action of ondansetron.

Adverse Reactions

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 (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated based on available data). Very common, common, and uncommon adverse reactions were generally observed in clinical trials. Rare and very rare adverse reactions were primarily reported during the post-marketing period.

The frequencies listed below are assessed for standard recommended doses of ondansetron.

The adverse reaction profile in children and adolescents was the same as in adults.

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)\textsuperscript{1};
Rare – dizziness during rapid intravenous administration of the drug.

Eye disorders:
Rare – transient visual disturbances (blurred vision), mainly during intravenous administration;
Very rare – transient blindness, mainly during intravenous administration\textsuperscript{2}.

Cardiac disorders:
Uncommon – arrhythmia, chest pain (with or without ST segment depression), bradycardia;
Rare – QT interval prolongation, including ventricular flutter/fibrillation (torsade de pointes);
Frequency not known – myocardial ischemia*.

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 elevation of liver function tests\textsuperscript{3}.

\textsuperscript{1} No persistent clinical consequences were observed.
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