ONDAAR

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONDAAR (ONDAAR)

Composition:

Active substance: ondansetron;

1 orally disintegrating tablet contains 4 mg or 8 mg of ondansetron;

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, sunset yellow FCF lake (E 110), colloidal anhydrous silicon dioxide, sodium stearyl fumarate, magnesium stearate.

Pharmaceutical form. Orally disintegrating tablets.

Main physicochemical properties:

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

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

Pharmacotherapeutic group.

Antiemetics and antinausea preparations. Serotonin (5-HT3) receptor antagonists. ATC code A04AA01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

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 is not fully understood. It is likely that the drug inhibits the vomiting reflex by antagonizing 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.

The precise mechanism of control of nausea and vomiting is unknown. Cytotoxic chemotherapeutic agents and radiotherapy may induce the release of 5-HT in the small intestine, stimulating the vomiting reflex via activation of vagal afferent nerves through 5-HT₃ receptors. Ondansetron blocks the stimulation of this reflex. Activation of vagal afferent nerves may also cause 5-HT release in the area postrema located at the base of the fourth ventricle, which may trigger vomiting via a central mechanism. Thus, the effect of ondansetron on nausea and vomiting induced 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 mechanism of action in postoperative nausea and vomiting is not known, but it may be similar to that observed in chemotherapy-induced nausea and vomiting.

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 plasma concentration of approximately 30 ng/mL is reached about 1.5 hours after an 8 mg dose. 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. The steady-state volume of distribution is about 140 L. Ondansetron is moderately bound to plasma proteins (70–76%) and is eliminated from systemic circulation primarily via hepatic metabolism involving enzymes. Less than 5% of the absorbed dose is excreted unchanged in urine. In the absence of the CYP2D6 enzyme (debrisoquin polymorphism), no changes in ondansetron pharmacokinetics are observed. The pharmacokinetic properties of ondansetron are not altered upon repeated administration.

Special patient groups:

Sex

Ondansetron affects men and women differently. In women, a higher rate and extent of absorption after oral administration are observed, and systemic clearance and volume of distribution normalized to body weight are reduced.

Children and adolescents (aged 1 month to 17 years)

In pediatric postoperative patients aged 1 to 4 months (n=19), clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22), but was similar to that 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 in those aged 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 elective surgery under general anesthesia, absolute values of both clearance and volume of distribution of ondansetron were lower than in adult patients. Both parameters increased linearly with increasing body weight and by age 12 approached values seen in young adults. When clearance and volume of distribution were normalized to body weight, 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. Population pharmacokinetic analysis was performed in volunteers (oncology patients, surgical patients, and healthy volunteers) aged 1 month to 44 years after intravenous administration of ondansetron. According to the analysis, 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 small number of subjects studied 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 have clinical significance.

Elderly patients

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

In patients aged 75 years and older, a greater effect of ondansetron on the QTcF interval is expected 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 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*.

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

* The use of ondansetron in various dosage forms is described in the section "Dosage and administration", which states that treatment of children with tablets should begin when the child's body surface area reaches 0.6 m², approximately corresponding to the age of 4 years.

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 several hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6, and CYP1A2. Due to the diversity of ondansetron-metabolizing enzymes, inhibition or reduced activity of any 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 together with medicinal products that prolong the QT interval and/or cause electrolyte imbalances.

Drugs that prolong the QT interval

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 (doxorubicin, daunorubicin) or trastuzumab), antibiotics (erythromycin), antifungals (ketoconazole), antiarrhythmics (amiodarone), and β-blockers (atenolol or timolol) increases the risk of arrhythmias.

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).

Apomorphine

Concomitant use of ondansetron with apomorphine hydrochloride is contraindicated, as 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 decreased.

Tramadol

According to 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 5-HT3 receptor antagonists, hypersensitivity reactions have been observed.

Respiratory reactions should be treated symptomatically. Healthcare providers 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. Additionally, post-marketing surveillance has reported cases of ventricular fibrillation (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 or at risk of QT interval prolongation or cardiac arrhythmias, including patients with electrolyte imbalances, congestive heart failure, bradyarrhythmias, and in patients receiving other drugs that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to initiating treatment.

Serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant use of ondansetron and other serotonergic agents (including SSRIs and SNRIs). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, appropriate monitoring of the patient 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 bleeding. Therefore, such patients require careful monitoring after ondansetron administration.

The medicinal product contains aspartame (E 951), which may have a negative effect in patients with phenylketonuria.

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

Caution should be exercised when using high doses, especially in patients with hepatic or renal impairment, due to increased risk of accumulation and development of toxicity (metabolic acidosis).

Children

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

Nausea and vomiting induced by chemotherapy

When dosing according to body weight and administering three doses at 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 suggests similar efficacy for both dosing regimens.

Use during pregnancy or breastfeeding

Women of childbearing potential

When ondansetron is administered to women of childbearing potential, contraception should be considered.

Pregnancy

Epidemiological studies indicate 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 studies on cardiac malformations have shown conflicting results. Animal studies did not reveal reproductive toxicity. Ondansetron should not be used during the first trimester of pregnancy.

Breastfeeding period

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 fertility.

Ability to affect reaction speed 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.

Dosage and Administration

Tablets should be taken immediately after removal from the packaging.

Place the tablet on the tongue and allow it to dissolve completely. The tablet should be handled with dry hands.

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.

Emetogenic chemotherapy and radiotherapy

An 8 mg dose should be taken 1–2 hours before chemotherapy or radiotherapy, followed by an 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 dexamethasone phosphate 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

Dose calculation for children aged 6 months to adolescents aged up to 17 years

The drug dose can be calculated based on body surface area or body weight. If the dose is calculated by body weight, the total daily dose is higher compared to dosing based on body surface area.

Dose calculation according to body surface area in children

Ondansetron should be administered intravenously as a single 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 up to 5 additional days (see Table 1). The total daily dose (divided into doses) must not exceed the adult dose of 32 mg.

Table 1

Dose calculation according to body surface area in children aged 6 months and adolescents

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

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 according to 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. On the first day, two additional intravenous doses may be given at 4-hour intervals. Oral administration may be started 12 hours later, which 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 according to body weight for children from 6 months of age and adolescents

a. The intravenous dose should not exceed 8 mg.

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

Older patients

Ondansetron is well tolerated by patients aged 65 years and older. Dose adjustment or changes in frequency of administration are not required.

Postoperative nausea and vomiting

Adults

For prevention of postoperative nausea and vomiting, ondansetron may be administered either orally 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 recommended route is intravenous or intramuscular injection.

Postoperative nausea and vomiting in children from 1 month of age and adolescents

Oral formulation

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

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

Older 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 the 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 is not altered in patients with impaired sparteine and debrisoquine metabolism. In these patients, plasma concentrations after repeated dosing are similar to those in patients with normal metabolism. Therefore, dose adjustment or changes in frequency of administration are not required.

Children

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

Overdose.

Symptoms

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

Manifestations of overdose have included visual disturbances, severe constipation, hypotension, vasovagal reactions with transient second-degree atrioventricular block.

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

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 calculated dose of 4 mg/kg).

Treatment

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

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

Adverse Reactions

The adverse reactions listed below are classified by system organ class and frequency of occurrence. The frequency categories are defined 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). 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 adverse reaction profile in children and adolescents was generally 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)¹;
Rare – dizziness during rapid intravenous administration.

Eye disorders:
Rare – transient visual disturbances (blurred vision), mainly during intravenous administration;
Very rare – transient blindness, mainly during intravenous administration².

Cardiac disorders:
Uncommon – arrhythmia, chest pain (with or without ST segment depression), bradycardia;
Rare – QT interval prolongation, including ventricular 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 – hiccup.

Gastrointestinal disorders:
Common – constipation.

Hepatobiliary disorders:
Uncommon – asymptomatic elevation of liver function parameters³.

Skin and subcutaneous tissue disorders:
Very rare – toxic erythematous rashes, including toxic epidermal necrolysis.

¹ No persistent clinical consequences were observed.
² In most cases, blindness resolves within 20 minutes. Most patients were receiving chemotherapy regimens containing cisplatin. Some cases of transient blindness were of cortical origin.
³ These cases occur primarily in patients treated with chemotherapeutic agents containing cisplatin.

Shelf life. 3 years.

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

Packaging.
10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Mankind Pharma Limited, Unit-II.

Manufacturer's address.
Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmour 173025, Himachal Pradesh, India.

Marketing Authorization Holder.
AAR PHARMA FZ-LLC

Address of Marketing Authorization Holder.
Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates.
Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates.