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

Name components	Quantity, mg / tablet
Name components	4 mg	8 mg
Active substance
Ondansetron	4,00	8,00
Excipients
Gelatin	5,00	10,00
Mannitol	3,75	7,50
Aspartame	0,625	1,25
Methylparahydroxybenzoate sodium	0,056	0,11
Propyl parahydroxybenzoate sodium	0,0069	0,014
Aroma strawberry	0,125	0,250
Weight of a tablet	13,6	27,1

Description:

Round tablets of white color, convex on one side and flat on the other.

Pharmacotherapeutic group:Antiemetic, serotonin receptor antagonist

ATX: & nbsp

A.04.A.A.01 Ondansetron

Pharmacodynamics:Mechanism of action

Ondansetron is a potent, highly selective antagonist

5NT₃receptors. The mechanism of suppressing nausea and vomiting is not exactly known. When carrying out radiation therapy and using cytotoxic drugs, serotonin release is possible (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 nausea and vomiting caused by cytostatic chemotherapy and radiotherapy by ondansetron appears to be due to the antagonistic effect on 5HT₃receptors of neurons located both on the periphery and in the central nervous system.

Mechanisms of action of the drug for the relief of postoperative nausea and vomiting are not established, but in general they correspond to those for the suppression of nausea and vomiting induced by chemotherapy and radiation therapy.

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 concentration in plasma is reached approximately in 1,5 hours after reception. When using Zofran orally in doses exceeding 8 mg, the content of ondansetron in the blood increases disproportionately, this can reduce the metabolism of "do-it-yourself" through the liver when high oral doses are prescribed.

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 when taken orally, intramuscularly or intravenously in adults is similar, with a distribution volume in the equilibrium state of 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 3 to 18 years)

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 concentration-time curve) after oral administration and intravenous ondansetron for 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 the clinical response on exposure, a more pronounced effect on the QTcF interval in patients aged> 75 years is suggested than in younger patients. 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 impairment of liver function, the systemic clearance of ondansetron drastically decreases with an increase in the half-life to 15-32 hours, and oral bioavailability reaches 100% due to a reduction in the systemic 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 injection is recommended.

Contraindications:

Simultaneous application of ondansetron with apomorphine;

hypersensitivity to the active substance or any other component included in the formulation;

pregnancy and the period of breastfeeding;

children under 3 years;

congenital syndrome of QT interval prolongation

Carefully:

Caution should be exercised when prescribing Zofran® to patients with increased sensitivity to other 5HT antagonists₃receptors.

Use with caution in patients with impaired cardiac rhythm and conductivity; in patients receiving antiarrhythmic drugs and beta-blockers; and in patients with significant disturbances in the water electrolyte balance.

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

Dosing and Administration:

A lyophilized tablet is placed on the tip of the tongue, after dissolving it should be swallowed.

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 the antitumor therapy and can differ depending on the dose and combinations of the regimens used for chemotherapy and radiotherapy.

Adults

The recommended dose is 8 mg ondansetron 1-2 hours before the initiation of cytotoxic chemotherapy or radiotherapy followed by oral administration of 8 mg every 12 hours for no more than 5 days.

With highly emetogenic chemotherapy, a single dose of oral ondansetron is 24 mg concomitantly with dexamethasone inside at a dose of 12 mg 1-2 hours before chemotherapy begins.

After the first 24 hours after chemotherapy or radiotherapy, you can continue taking Zofran orally (in the form of a drug, lyophilized tablets) or rectally (in the form of a rectal suppository) for no more than 5 days. It is recommended to take the drug Zofran orally (in the form of medicinal form lyophilized tablets) at a dose of 8 mg 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.

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

Calculation of dose based on body surface area in children aged 2 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. Taking Zofran in an oral dosage form can be continued for 5 more days after the course of chemotherapy.Do not exceed the doses used for adults.

Dose calculation table based on body surface area in children aged 3 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 and <1.2 m²

5 mg / m² intravenously, then 4 mg of ondansetron after 12 h

4 mg

ondansetron every 12 h

> 1.2 m²

5 mg / m² intravenously or 8 mg intravenously, then

8 mg ondansetron after 12 h

8 mg ondansetron every 12 hours

Calculation of the dose based on body weight in children aged 3 to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

The drug 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, a solution for intravenous and intramuscular administration) followed by oral administration of Zofran 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.

Calculation of dose based on body weight in children aged 3 to 18 years for the prevention and treatment of nausea and vomiting caused by chemotherapy

Weight bodies	Day 1	Day 2-6
> 10 kg	Up to 3 doses of 0.15 mg / kg intravenously every 4 hours	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 that 16 mg of Zofran should be taken orally 1 h before anesthesia.

For the treatment of postoperative nausea and vomiting, Zofran is used in a medicinal form for intravenous and intramuscular administration.

Special patient groups

Children aged 3 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 is recommended, a solution of intravenous and intramuscular injection in the form of slow intravenous injections (lasting not less than 30 seconds).

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

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: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10,000 and <1/1000), very 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 shown 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 (urticaria, bronchospasm, laryngospasm, angioedema), in a number of severe cases, including anaphylaxis.

Disturbances from the nervous system

Very often: headache.

Infrequent: 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.

Very 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

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

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

Vascular disorders

Often: a sense of heat or "hot flashes"

Infrequent: lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: hiccough.

Disorders from the gastrointestinal tract

Often: constipation.

Disturbances from the liver and bile ducts

Infrequent: 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

Very rarely: toxic skin rash, including toxic epidermal necrolysis.

Overdose:Symptomatology

Currently, there is insufficient data on overdose of ondansetron. In most of the observed cases, the symptoms of an overdose coincided with the undesirable dose-related events that occur when taking Zofran in the recommended doses. Ondansetron causes a dose-dependent lengthening of the QT interval. It is recommended to monitor the ECG in case of an overdose of ondansetron.

Treatment

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

It is not recommended that ipecacuanas be used to treat an overdose of ondansetron, as patients may not respond to ipecacuano treatment due to the antiemetic effect of ondansetron.

Interaction:There is no data that ondansetron induces or inhibits the metabolism of other drugs commonly taken 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 a decrease in heart rate.

Apomorphine

Based on the data obtained on deep hypotension and loss of consciousness during the application of ondansetron with apomorphine hydrochloride, simultaneous application of ondansetron with apomorphineit 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 was found that the combined use of ondansetron and other serotonergic drugs, including SSRIs and SNRIs increased the risk of serotonin syndrome (including altered state of consciousness, instability of the peripheral nervous system and neuromuscular disorders) (see. 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 the occurrence 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 monitoring 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 the introduction of 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.

Lyophilized tablets contain aspartame, and therefore they should be taken with caution in patients with phenylketonuria.

Tablets lyophilized Zofran® should be removed from the package immediately before use. Do not squeeze out lyophilized Zofran® tablets from foil. Carefully fold the foil, as shown by the arrow on the package, and remove the freeze dried Zofran® tablet. Before removing the lyophilized tablet, make sure that the foil package is not damaged.

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

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

Form release / dosage:

Tablets for resorption, 4 mg, 8 mg.

Packaging:

For 10 tablets in a blister of laminated five-layer aluminum / PVC foil.

1 blister together with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of 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 N015809 / 01

Date of registration:14.07.2009

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

ASPEN BAD OLDESLOE, GmbH Germany

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp03.07.2015

Illustrated instructions

Instructions

Zofran® (ZOFRAN®)