Zofran - instructions for use, dose, side effects, contraindications

Component	Content (mg / 5 ml)
Active substance
Ondansetron hydrochloride dihydrate	- 5,0⁽¹⁾
Excipients
Lemon acid	25,0
Sodium citrate dihydrate	7,5
Sodium benzoate	10,0
Sorbitol	3000,0
Aromatic Strawberry	15,0
Water	up to 5 ml

Note:

1.5 mg of ondansetron hydrochloride dihydrate is equivalent to 4 mg of ondansetron.

Description:

Transparent liquid from colorless to light yellow with the smell of strawberry.

Pharmacotherapeutic group:Antiemetic, serotonin receptor antagonist

ATX: & nbsp

A.04.A.A.01 Ondansetron

Pharmacodynamics:

Mechanism of action

Ondansetron is a potent, highly selective 5HT antagonist₃receptors. The mechanism of suppressing nausea and vomiting is not exactly known. When radiotherapy and the use of cytotoxic drugs, the release of serotonin (5HT) in the small intestine, which causes a gag reflex through the activation of 5HT₃receptors and excitation of the endings of the afferent fibers of the vagus nerve. Ondansetron blocks the initiation of this reflex. Activation of the afferent endings of the vagus nerve, in turn, can cause the release of 5HT in the posterior field of the bottom of the fourth ventricle (area postrema) and the triggering of the central mechanism of the vomiting reflex. Thus, suppression of ondansetron with nausea and vomiting,caused by cytostatic chemotherapy and radiotherapy, appears to be due to antagonistic effects on 5HT₃receptors of neurons located both on the periphery and in the central nervous system.

The mechanisms of action of the drug for the relief of postoperative nausea and vomiting have not been established, but in general they correspond to those when curing cytostatic nausea and vomiting induced by chemotherapy and radiotherapy.

Ondansetron does not affect the concentration of prolactin in the blood plasma.

Pharmacokinetics:

The pharmacokinetic parameters of ondansetron do not change when it is used multiple times.

Suction

Ondansetron is completely absorbed in the gastrointestinal tract after oral administration and is metabolized by "first passage" through the liver. The maximum plasma concentration is achieved approximately 1.5 hours after administration.

When using Zofran® orally in doses greater than 8 mg, the content of ondansetron in the blood increases disproportionately, this can reduce the metabolism of oral high doses at the "first pass" through the liver.The average bioavailability in healthy male volunteers after taking one tablet of 8 mg was approximately 55-60%. Bioavailability increases somewhat with the simultaneous administration of the drug with food, but does not change with admission to antacids.

Distribution

Protein-binding ability of ondansetron is low (70-76%). The distribution of ondansetron for oral administration, intramuscular and intravenous administration in adults is similar, and the volume of distribution in the equilibrium state is about 140 liters.

Metabolism

Ondansetron is excreted from the systemic blood flow by metabolism in the liver with the participation of various enzyme systems. The absence of the CYP2D6 isoenzyme (spartein-debrisoquine-type polymorphism) does not affect the pharmacokinetics of ondansetron.

Excretion

Ondansetron is excreted from the systemic blood stream, mainly by metabolism in the liver. Less than 5% of the administered dose is excreted unchanged by the kidneys.

The distribution of ondansetron when taken orally, intramuscularly or intravenously is similar to the half-life and is about 3 hours.

Special patient groups

Floor

The pharmacokinetics of ondansetron depends on the sex of the patients. Women have a higher rate, a degree of absorption and a lower systemic clearance, the volume of distribution (the figures are corrected for body weight) than for men.

Children (aged 6 months to 18 years)

In children aged 1 to 4 months (n= 19) who underwent surgery, the clearance was approximately 30% slower than in patients aged 5 to 24 months (n= 22), but comparable with this indicator in patients aged 3 to 12 years. The half-life in the group of patients aged 1 to 4 months averaged 6.7 hours compared with 2.9 hours in the age groups from 5 to 24 months and from 3 to 12 years.

The differences in pharmacokinetic parameters are partly explained by the higher percentage of fluid in the body in newborns and infants and the higher volume of distribution of such water-soluble drugs as ondansetron, in patients aged 1 to 4 months.

In children aged 3 to 12 years who underwent planned surgical interventions under general anesthesia, the absolute values of clearance and volume distribution of ondansetron were reduced in comparison with the values in adults.Both parameters increased linearly depending on body weight, in patients under the age of 12 these values were close to those in adults. When adjusting the clearance values and volume of distribution, depending on the body weight, these parameters were close in different age groups. Calculation of the dose taking into account the body weight compensates for age changes and systemic exposure of ondansetron in children.

Based on the results of the population pharmacokinetic analysis, the AUC (area under the pharmacokinetic curve "concentration-time") after oral administration and intravenously to children and adolescents was comparable to that in adults, except for infants aged 1 to 4 months.

The volume of distribution depended on age and was lower in adults than in children.

Elderly patients

Based on the obtained data on ondansetron concentrations in blood plasma, as well as the results of modeling the dependence of clinical response on exposure, a more pronounced effect on the QTcF interval in patients aged ≥75 years is suggested than in patients of younger age.For patients over the age of 65 and over 75 years of age, special recommendations for the choice of dose for intravenous administration are presented (see section "Method of administration and dose").

Patients with impaired renal function

In patients with an average degree of renal failure (creatinine clearance 15-60 ml / min), systemic clearance and volume of distribution decrease after intravenous administration of ondansetron, which leads to a small clinically insignificant increase in the half-life (5.4 hours). Studies in patients with severe renal failure who need regular hemodialysis (studies conducted between dialysis sessions) did not show changes in the pharmacokinetics of ondansetron after its intravenous administration.

Patients with impaired hepatic function

In patients with severe liver function abnormalities, systemic clearance of ondansetron decreases with an increase in the half-life period to 15-32 hours, and oral bioavailability reaches 100% due to a decrease in presystemic metabolism.

Indications:

- Prevention and treatment of nausea and vomiting,caused by cytostatic chemotherapy and radiotherapy in adults.

- Prevention and treatment of nausea and vomiting caused by cytostatic chemotherapy in children.

- Prevention of postoperative nausea and vomiting in adults.

Studies on the use of oral dosage form of ondansetron for the prevention or treatment of postoperative nausea and vomiting in children have not been conducted. For these purposes, the use of Zofran® in the form of a drug for intravenous and intramuscular administration is recommended.

Contraindications:

- Simultaneous application of ondansetron with apomorphine;

- hypersensitivity to the active ingredient or any other component, included in the preparation

- pregnancy and the period of breastfeeding;

- children up to 6 months;

- congenital lengthening syndrome QT.

Carefully:

Care should be taken when prescribing Zofran to patients with increased sensitivity to other 5HT3 receptor antagonists. Use with caution in patients with impaired cardiac rhythm and conductivity; in patients receiving antiarrhythmic agents and beta-blockers; and in patients with significant impairment water

electrolyte balance.

Caution should be used ondansetron in patients with lengthening or the risk of lengthening the interval QTc, including patients with impaired waterelectrolyte balance, chronic heart failure, bradyarrhythmia, or in patients taking other medications that may cause lengthening of the interval QT, disturbance of water-electrolyte balance or reduction of heart rate.

Dosing and Administration:

Prevention and treatment of nausea and vomiting caused by cytostatic chemotherapy and radiotherapy in adults

The choice of the dosage regimen is determined by the emetogenicity of antitumor therapy and can differ depending of the dose and combination of the regimens used for chemotherapy and radiation therapy.

Adults

The recommended dose is 8 mg of ondansetron (10 ml of syrup) 1-2 hours before the start of cytotoxic chemotherapy or radiation therapy followed by taking 8 mg orally every 12 hours for no more than 5 days.

In highly emetogenic chemotherapy, a single dose of ondansetron orally is 24 mg (30 ml of syrup) concomitantly with dexamethasone inward at a dose of 12 mg 1-2 hours before the start of chemotherapy.

After the first 24 hours after chemotherapy or radiotherapy, Zofran® can be taken orally (in drug form syrup) or rectally (in the form of rectal suppositories) for no more than 5 days. It is recommended to take the drug Zofran® orally (in the drug form of syrup) at a dose of 8 mg (10 ml) 2 times a day.

Special patient groups

Elderly patients

Correction of the dose of Zofran® in an oral dosage form for elderly patients is not required.

Patients with impaired renal function

Correction of the daily dose, the frequency of dosing or the route of administration of ondansetron is not required.

Patients with impaired hepatic function

In patients with impaired liver function of moderate and severe severity, clearance of ondansetron is significantly reduced, the half-life is significantly increased.

In such patients, the daily dose of ondansetron should not exceed 8 mg (10 ml of syrup).

Patients with a slow metabolism of sparteine-debrisoquine

In patients with a slow metabolism of sparteine-debrisoquine, the half-life of ondansetron is not changed. Consequently, with the repeated administration of such patients to ondansetron, its plasma concentration will not differ from that in the general population.Therefore, correction of the daily dose or ondansetron dosing frequency in this case is not required.

Prevention and treatment of nausea and vomiting caused by cytostatic chemotherapy in children

At a chemotherapy at children and teenagers (at the age from 6 months till 18 years)

The dose of Zofran® in children is calculated on the basis of surface area or body weight.

Calculation of the dose based on body surface area in children aged 6 months to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

Zofran®, a solution for intravenous and intramuscular injection, can be used as a single intravenous injection at a dose of 5 mg / m2 (not more than 8 mg) immediately before chemotherapy followed by oral administration of the drug after 12 hours. The preparation Zofran® in an oral dosage form can be continued for another 5 days after the course of chemotherapy. Do not exceed the dose prescribed for adults.
Dose calculation table based on thesponges of the body surface in children aged 6 months to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

Body surface area	Day 1	Day 2-6
<0.6 m²	5 mg / m² intravenously, followed by 2.5 ml syrup (2 mg ondansetron) after 12 h	2.5 ml syrup (2 mg ondansetron) every 12 hours
≥ 0.6 m² and ≤ 1.2 m²	5 mg / m² intravenously, then 5 ml of syrup (4 mg ondansetron) after 12 h	5 ml of syrup (4 mg ondansetron) every 12 hours
> 1.2 m²	5 mg / m2 intravenously or 8 mg intravenously, followed by 10 ml syrup (8 mg ondansetron) after 12 hours	10 ml of syrup (8 mg ondansetron) every 12 hours

Calculation of dose based on body weight in children aged 6 months to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

Zofran®, a solution for intravenous and intramuscular injection should be administered once intravenously immediately before the start of chemotherapy (see instructions for use on Zofran®, solution for intravenous and intramuscular administration) followed by oral administration 12 hours after the start of therapy. Taking Zofran® in an oral dosage form can be continued for another 5 days after the course of chemotherapy. Do not exceed the doses used for adults.

Table of dose calculation based on body weight in children aged 6 months to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

Weight	Day 1	Day 2-6
≤ 10 kg	Up to 3 doses of 0.15 mg / kg intravenously every 4 hours	2.5 ml syrup (2 mg ondansetron) every 12 hours
> 10 kg	Up to 3 doses of 0.15 mg / kg intravenously every 4 h	5 ml syrup (4 mg ondansetron) every 12 hours

Prevention of postoperative nausea and vomiting in adults

Adults

For the prevention of nausea and vomiting in the postoperative period, it is recommended to take 16 mg of Zofran® preparation orally 1 h before anesthesia. To stop postoperative nausea and vomiting, Zofran®, a solution for intravenous and intramuscular injection, is used.

Special patient groups

Children aged 6 months to 18 years

Studies of taking Zofran® in an oral dosage form for the prevention or treatment of nausea and vomiting in the postoperative period have not been performed; for this purpose, the use of Zofran®, a solution for intravenous and intramuscular injection in the form of slow intravenous injections (duration of not less than 30 seconds) is recommended.

Elderly patients

There is limited experience with ondansetron for the prevention of postoperative nausea and vomiting in elderly patients, although ondansetron well tolerated by patients aged 65 years and older who received chemotherapy.

Patients with impaired renal function

Correction of the daily dose, the frequency of dosing or the route of administration of ondansetron is not required.

Patients with impaired hepatic function

In patients with impaired liver function of moderate and severe severity, clearance of ondansetron is significantly reduced, the half-life is significantly increased.

In such patients, the daily dose of ondansetron should not exceed 8 mg.

Patients with a slow metabolism of sparteine-debrisoquine

In patients with a slow metabolism of sparteine-debrisoquine, the half-life of ondansetron is not changed. Consequently, with the repeated administration of such patients to ondansetron, its plasma concentration will not differ from that in the general population. Therefore, correction of the daily dose or ondansetron dosing frequency in this case is not required.

Side effects:

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence.

Frequency of occurrence is defined as follows: Often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10,000 and <1/1 000), rarely (<1/10 000, including individual cases).

Unwanted reactions observed "very often," "often," and "infrequently," were usually determined from clinical trials. The incidence of placebo was also taken into account. Unwanted reactions, observed "rarely" and "very rarely," were determined on the basis of spontaneous reports obtained as part of post-registration surveillance.

When the standard recommended doses of ondansetron are taken, the frequency of occurrence is established. presented below. The profile of adverse reactions in children and adolescents was comparable to the profile observed in adults.

Frequency of occurrence of undesirable reactions

Immune system disorders

Rarely: immediate-type hypersensitivity reactions (hives, bronchospasm, laryngospasm, angioedema), in a number of cases of severe degree, including anaphylaxis.

Disturbances from the nervous system

Often: headache.

Infrequently: convulsions, motor disorders (including extrapyramidal symptoms such as dystonia, oculogic crisis (spasm of the eye) and dyskinesia) in the absence of persistent clinical consequences.

Rarely: dizziness, mainly during rapid intravenous administration.

Disturbances on the part of the organ of sight

Rarely: transient visual impairment (eg, blurred vision), mainly during intravenous administration.

Rarely: transient blindness, mainly during intravenous administration. Most cases of blindness were safely resolved within 20 minutes. Most patients received chemotherapeutic drugs containing cisplatin. In some cases, transient blindness was of a cortical genesis.

Heart Disease

Infrequently: arrhythmia, pain in the chest, both accompanied and not accompanied by a decrease in the ST segment, bradycardia.

Rarely: prolongation of QT interval (including ventricular pirouette tachycardia).

Vascular disorders

Often: a feeling of heat or "hot flashes".

Infrequently: lowering of blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: hiccups.

Disorders from the gastrointestinal tract

Often: constipation.

Disturbances from the liver and bile ducts

Infrequently: an asymptomatic increase in the activity of "hepatic" enzymes alanine aminotransferase (ALT), aspartate aminotransferase (ACT) (mainly observed in patients receiving cisplatin chemotherapy).

Disturbances from the skin and subcutaneous tissues

Rarely: toxic skin rash, including toxic epidermal necrolysis.

Overdose:

Symptomatology

At present, there is insufficient data on overdose with Zofran®. In most cases, the symptoms of an overdose were similar to the adverse events reported in patients receiving recommended doses (see "Side effect").

The drug Zofran® induces a dose-dependent lengthening of the QT interval. It is recommended to monitor the ECG in case of an overdose of Zofran®. In case of an overdose of Zofran® with oral administration, children reported symptoms indicative of serotonin syndrome.

Treatment

There is no specific antidote for Zofran®, so it is recommended that symptomatic and supportive therapy be provided for suspected overdose.

Further treatment should be based on the clinical situation, or in accordance with the recommendations of the National Toxicology Center, if any.

It is not recommended to use ipecacuanas for the treatment of overdose with Zofran®, as it is unlikely that patients will respond to treatment with ipecacuanas due to the antiemetic effect of Zofran®.

Interaction:

There is no data that ondansetron induces or inhibits the metabolism of other drugs commonly used in combination with it. Special studies have shown that ondansetron pharmacokinetically does not interact with ethanol, temazepam, furosemide, tramadol or propofol.

Ondansetron is metabolized by a number of isoenzymes of the cytochrome P450 system in the liver: CYP3A4, CYP2D6 and CYP1A2. In connection with the variety of isoenzymes that are able to metabolize ondansetron, inhibition of isoenzymes or a decrease in the activity of one of the isozymes (for example, in case of genetic deficiency of CYP2D6) is usually compensated by other isoenzymes, as a result of which changes in the total clearance of ondansetron are either absent or insignificant and practically do not require dose adjustment.

Caution should be exercised when using ondansetron with drugs that affect the prolongation of the QT interval and / or cause electrolyte imbalances or reduce the heart rate.

Apomorphine

Based on the data obtained on deep hypotension and loss of consciousness during the use of ondansetron with apomorphine hydrochloride, concomitant use of ondansetron with apomorphine is contraindicated.

Phenytoin, carbamazepine and rifampicin

In patients who received powerful inductors CYP3A4 (phenytoin, carbamazepine and rifampicin), clearance of ondansetron with oral administration of the drug was elevated, and ondansetron concentration in the blood was decreased.

Serotonergic drugs (eg, SSRIs (selective serotonin reuptake inhibitors) and SSRIs (norepinephrine and serotonin reuptake inhibitors))

It has been established that with the combined use of ondansetron and other serotonergic drugs, including SSRIs and SSRIs, the risk of developing serotonin syndrome (altered state of consciousness, peripheral nervous system instability and neuromuscular disorders) increases (see Fig.section "Special instructions").

Tramadol

There are data from small studies indicating that ondansetron can reduce the analgesic effect of tramadol.

Special instructions:

There are reports of hypersensitivity reactions to ondansetron in patients who have a history of hypersensitivity to other selective 5HT antagonists₃receptors. Since it is known that ondansetron increases the time of passage of the contents along the thick intestine, in the case of using the drug in patients with symptoms of subacute intestinal obstruction, regular observation of such patients is necessary.

Ondansetron causes a dose-dependent lengthening of the QT interval. In addition, during post-registration follow-up, reports of cases of ventricular pirouette tachycardia were reported among patients receiving ondansetron. Before using ondansetron, it is necessary to correct hypokalemia and hypomagnesemia.

It is established that combined use of ondansetron and other serotonergic drugs increases the risk of developing serotonin syndrome (see section "Interaction with other drugs").If combined use of ondansetron and other serotonergic drugs is clinically justified, it is necessary to ensure regular monitoring of the patient's condition.

Effect on the ability to drive transp. cf. and fur:

The drug Zofran® does not have a sedative effect and does not affect the ability of patients to drive vehicles or engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:Syrup, 4 mg / 5 ml.

Packaging:To 50 ml in a bottle of dark glass type III (European Pharmacopoeia), closed with a plastic screw cap with an anti-opening device and first opening control.
For 1 bottle together with a measuring spoon and instructions for use in a cardboard pack.

Storage conditions:

At a temperature of no higher than 30 ° C. Do not freeze.

Keep at inaccessible to children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015967 / 01

Date of registration:25.09.2009 / 01.12.2015

Expiration Date:Unlimited

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

GlaxoSmithKline, Inc. Canada

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp11.07.2016

Illustrated instructions

Instructions

Zofran® (ZOFRAN®)