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

1 ml of the preparation contains:
Active substance:
Ondansetron	2.0 mg
in the form of ondansetron hydrochloride dihydrate	- 2.49 mg
Excipients:
Sodium chloride	- 9.0 mg
Citric acid anhydrous	- 0.46 mg
Sodium citrate dihydrate	- 0.31 mg
Water for injections	- up to 1 ml

Description:Transparent colorless or colored liquid.

Pharmacotherapeutic group:Antiemetic means - 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 radiation therapy and the use of cytotoxic drugs, the release of serotonin (5HT) in the small intestine, which causes a vomitive reflex through the activation of 5HT₃receptors and excitation of the afferent fibers of the vagus nerve. Ondansetron blocks the initiation of this reflex. Activation of the afferent fibers 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, therefore, run a gag reflex through the central mechanism. Thus, ondansetron suppression of chemo- and radioinduced nausea and vomiting is most likely due to antagonistic effects on 5NT₃-Rthe receptors of neurons located both on the periphery and in the central nervous system. The mechanism of action of the drug for the relief of postoperative nausea and vomiting is unclear, it is probably analogous to that for the relief of chemo- and radioinduced nausea and vomiting.

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

Pharmacokinetics:

The pharmacokinetic parameters of ondansetron do not change with its repeated administration.

Suction

Ondansetron has the same systemic effect with intramuscular and intravenous administration.

Distribution

Ondansetron has a moderate ability to bind to plasma proteins (70-76%). The distribution of ondansetron is similar for intramuscular and intravenous administration in adults, the volume of distribution in the equilibrium state is about 140 liters.

Metabolism

Ondansetron is metabolized mainly in the liver with the participation of several enzymes. The absence of the enzyme CYP2D6 (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 through the kidneys. The half-life of ondansetron both after intramuscular injection and after intravenous administration is approximately 3 hours.

Special patient groups

Floor

The pharmacokinetics of ondansetron depends on the sex of the patients. In women, there is less systemic clearance and volume of distribution (the figures are corrected for body weight) than for men.

Children and adolescents (aged 1 month to 18 years)

In children aged 1 to 4 months (n = 19) who underwent surgery, the clearance was approximately 30% less than in patients aged 5 to 24 months (n = 22), but comparable to that in patients at the age of 3 to 12 years (with correction of indices depending on body weight).

The half-life in the group of patients aged 1-4 months averaged 6.7 hours; in the age groups 5-24 months and 3-12 years - 2.9 hours. Patients aged 1 to 4 months do not need dose adjustment, since this category of patients uses a single intravenous ondansetron for the treatment of postoperative nausea and vomiting. Differences in pharmacokinetic parameters are partly explained by a higher volume of distribution in patients aged 1 to 4 months.Simulation of the ondansetron regimen for children aged 6 months was based on an average body weight of 7.7 kg (range 5.4 to 10.7 kg) and ondansetron intravenous dose 0.15 mg / kg body weight every 4 h on day 1 followed by the appointment of ondansetron 2 mg in the form of a syrup every 12 hours on day 2. The results of the circuit simulation were compared with those in patients aged 18 months, 12 years and 30 years who used the same dosing regimen, with the exception of the day 2, when ondansetron was given in tablets of 4 or 8 mg every 12 hours. These models demonstrated that the effect of the drug on AUC (area under the pharmacokinetic curve "concentration-time") with repeated oral administration is similar in patients of different age groups. The results of the simulation are consistent with the recommendations for carrying out cytostatic chemotherapy and radiotherapy in children with body weight ≤ 10 kg. Moreover, children usually have a body weight ≤ 10 kg, receiving cytostatic chemotherapy and radiotherapy, BSA (surface area of the body) is less than 0.6 m². Thus, the dosing schedule, calculated by mass, for patients with body weight ≤ 10 kg (see table 1) currently coincides with the scheme calculated for BSA, in patients with a body surface area of less than 0.6 m² (see table 2).

In children aged 3-12 years (n = 21) 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 aged 12 years, these values were close to those in adults. When adjusting the clearance values and volume of distribution, depending on body weight, these parameters were close in different age groups. Calculation of the dose taking into account the body weight compensates for these changes and systemic exposure of ondansetron in children.

A population-wide pharamakinetic analysis was performed in 428 patients (patients with malignant diseases, surgical patients and healthy volunteers) aged 1 to 44 years who were intravenously injected ondansetron. According to the results of the study, the system exposure of ondansetron (the area under the pharmacokinetic curve "concentration-time") after ingestion and intravenously to children and adolescents was comparable to that of 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

Studies involving healthy elderly volunteers demonstrated a small, age-associated increase in bioavailability and half-life of ondansetron.

Patients with impaired renal function

Studies of the drug in oral form and solution form for intravenous and intramuscular administration with participation of patients with renal insufficiency (creatinine clearance 15-60 ml / min) showed that changes in the dose or dosing regimen of ondansetron in this category of patients are not required. Given the high therapeutic index, pharmacokinetic changes are not clinically significant.

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 of up to 15-32 hours, a decrease in presystemic metabolism occurs, and bioavailability with ingestion reaches 100%.

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 cytotoxic chemotherapy in children; prevention and treatment of postoperative nausea and vomiting in adults and children.

Contraindications:Hypersensitivity to the active substance or any other component included in the preparation, combined use with apomorphine, congenital QT prolongation syndrome, children up to 6 months of age according to the indication "Prevention and treatment of nausea and vomiting caused by cytostatic chemotherapy in children", child age up to 1 month according to the indication "Prevention and treatment of postoperative nausea and vomiting in adults and children", pregnancy and the period of breastfeeding.

Carefully:Hypersensitivity to other 5-HT3 receptor antagonists; Patients with heart rhythm and conduction disorder, patients receiving antiarrhythmic drugs and beta-blockers; patients with significant electrolyte imbalance; patients with prolonged or risk of QTc prolongation, including patients with electrolyte imbalance, chronic heart failure, bradyarrhythmia or taking other medications that can cause prolongation of the QT interval.

Pregnancy and lactation:Ondansetron is contraindicated in pregnancy.

If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Nausea and vomiting in chemotherapy or radiotherapy

The choice of dosage regimen is determined by the emetogenicity of antitumor therapy.

Adults

With moderate emetogenic chemotherapy or radiation therapy

The recommended dose is 8 mg, administered slowly intravenously or intramuscularly immediately before chemotherapy or radiotherapy.

With highly emeticogenic chemotherapy (eg, high doses of cisplatin)

A dose of 8 mg is administered immediately prior to chemotherapy once as an intravenous or intramuscular injection. The drug in a dose of 8 to 32 mg should be administered only by intravenous infusion after dissolving the drug in 50-100 ml of a 0.9% solution of sodium chloride or another compatible infusion solution for 15 minutes or more.

Another method is to administer the drug at a dose of 8 mg slowly intravenously or intramuscularly immediately before chemotherapy, followed by the administration of two injections of the drug intravenouslyor intramuscularly at a dose of 8 mg at intervals of 2-4 hours or in the use of a constant infusion of the drug at a rate of 1 mg / h for 24 hours.

In the case of highly emeticogenic antitumor therapy, the efficacy of the drug can be enhanced by an additional single intravenous injection of dexamethasone 20 mg before the start of chemotherapy. Oral or rectal dosage forms of the drug are recommended to prevent delayed or continued vomiting after the first day after the chemotherapy.

Children and adolescents (aged 6 months to 18 years)

The dose of the drug in children is calculated on the basis of the surface area or body weight. The drug can be used as an intravenous infusion after dissolving the drug in 25-50 ml of a 0.9% solution of sodium chloride or another compatible infusion solution for 15 minutes or more.

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

Ondansetron can be given as a single intravenous injection at a dose of 5 mg / m² (not more than 8 mg) immediately before the chemotherapy with the subsequent ingestion of the drug inside after 12 hours.Reception of the drug in the form of a syrup can be continued for another 5 days after the course of chemotherapy.

Table 1

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, followed by 5 ml of syrup (4 mg ondansetron) after 12 h	5 ml syrup (4 mg ondansetron) every 12 hours
> 1.2 m²	5 mg / m² intravenously or 8 mg intravenously, followed by 10 ml of syrup (8 mg ondansetron) after 12 h	10 ml of syrup (8 mg ondansetron) every 12 hours

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

The drug is usually administered as a solution for injection once intravenously immediately before the start of chemotherapy at a dose of 0.15 mg / kg. The dose should not exceed 8 mg. On the first day, two additional doses should be administered at an interval of 4 hours, followed by taking the drug in the form of a syrup inside after 12 hours. The drug intake in the form of a syrup should continue for 5 days after chemotherapy.

table 2

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

Elderly patients

Ondansetron dose adjustment is not required.

Patients with impaired renal function

Ondansetron dose adjustment is not required.

Patients with impaired hepatic function

Ondansetron clearance is significantly reduced, the half-life is increased in patients with moderate and severe liver dysfunction.

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 and debrisoquine, the half-life of ondansetron is not changed. Consequently, with repeated administration of ondansetron to such patients, its concentration in the plasma will not differ from that in the general population. Therefore, such patients do not need to adjust the daily dose or ondansetron frequency.

Nausea and vomiting in the postoperative period

Adults

To prevent nausea and vomiting in the postoperative period, a single intramuscular or slow intravenous injection (at least 30 seconds) of the drug at a dose of 4 mg during anesthesia is recommended.

For the treatment of nausea and vomiting in the postoperative period, the drug is administered once in a dose of 4 mg intramuscularly or slowly intravenously.

Children and adolescents (aged 1 month to 18 years)

To prevent nausea and vomiting in the postoperative period in children who underwent surgery under general anesthesia, the drug can be used at a dose of 0.1 mg / kg (up to max. 4 mg) as a slow intravenous injection (at least 30 seconds) before, during or after an initial anesthesia or after an operation.

To stop nausea and vomiting that developed in the postoperative period, a slow intravenous injection of the drug at a dose of 0.1 mg / kg (maximum to 4 mg) is recommended.

Elderly patients

There is limited experience with ondansetron for preventing and arresting postoperative nausea and vomiting in the elderly, although ondansetron well tolerated by patients over 65 years of age who are receiving chemotherapy.

Patients with impaired renal function

Ondansetron dose adjustment is not required.

Patients with impaired hepatic function

The clearance of ondansetron is significantly reduced, the half-life is increased in patients with impaired liver function of moderate and severedegree.

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 and 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, such patients do not need to adjust the daily dose or ondansetron frequency.

Pharmaceutical compatibility

To dilute the injection solution, the following solutions can be used:

- 0.9% solution of sodium chloride;

- 5% dextrose solution;

Ringer's solution;

- 10% mannitol solution;

- 0.3% potassium chloride solution and 0.9% sodium chloride solution;

- 0.3% potassium chloride solution and 5% dextrose solution.

The infusion solution should be prepared immediately before use. If necessary, the ready-made infusion solution can be stored for up to 24 hours at a temperature of 2-8 ° C.

During the infusion, protection from light is not required; The diluted injection solution remains stable for 24 hours under natural light or normal light.

Ondansetron at a concentration of 16-160 μg / ml is pharmaceutically compatible and can be injected intravenously via a Y-shaped injector together with the following drugs: cisplastin (at a concentration of up to 0.48 mg / ml) for 1-8 hours; fluorouracil (at concentrations up to 0.8 mg / ml at a rate of 20 ml / h - higher concentrations may cause ondansetron precipitation); carboplatin (in a concentration of 0.18-9.9 mg / ml for 10-60 min); etoposide (in a concentration of 0.14-0.25 mg / ml for 30-60 minutes); ceftazidime (in a dose of 0.25-2 g, as an intravenous bolus injection for 5 minutes); cyclophosphamide (in a dose of 10-100 mg, as an intravenous bolus injection for 5 minutes); dexamethasone: possible intravenous administration of 20 mg dexamethasone sodium phosphate slowly, for 2-5 minutes. LS can be administered through a single dropper, while the concentration of dexamethasone sodium phosphate in the solution can range from 32 to 2500 μg / ml, ondansetron - from 8 to 100 μg / ml.

The procedure for working with a polymer ampoule:

1. Take the ampoule and shake it, holding it by the neck.

2. Press the ampoule with your hand, while the drug should not be isolated, and rotate and separate the valve with rotating movements.

3. Connect the syringe to the ampoule immediately through the opening.

4.Turn the ampoule over and slowly put the contents into the syringe.

5. Put the needle on the syringe.

Side effects:

The undesirable phenomena presented below are listed according to the body systems and in accordance with the frequency of occurrence. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥1 / 100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), rarely (<1/10000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

From the immune system
Rarely:	immediate-type hypersensitivity reactions (urticaria, bronchitishospazm, laryngospasm, angioedema, edema), in a number of severe cases, including anaphylaxis.
From the nervous system
Often:	headache.
Infrequently:	convulsions, motor disorders (including extrapyramidal simptomes such as dystonia, oculogic crisis [spasm of the eye] and dyskinesia) in the absence of persistent clinical consequences.
Rarely:	dizziness during rapid intravenous administration.
From the side of the organs of sight
Rarely:	transient visual disturbances (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.
From the side of the cardiovascular system
Infrequently:	arrhythmia, chest pain, both accompanied and not accompanied bywhich is accompanied by a decrease in the ST segment, bradycardia, lowering of blood pressure.
Often:	a feeling of heat or "hot flashes".
Rarely:	prolongation of the QT interval (including bidirectional ventricular tachycardia).
On the part of the respiratory system, the organs of the thorax and the mediastinum
Infrequently:	hiccups.
From the gastrointestinal tract
Often:	constipation.
From the liver and biliary tract
Infrequently:	asymptomatic increase in hepatic enzymes alanine aminotransfertimes (ALT), aspartate aminotransferase (ACT) (mainly observed in patients receiving cisplatin chemotherapy).
General and local reactions
Often:	local reactions with intravenous administration - burning at the injection site.

Overdose:

Symptoms: increased dose-dependent adverse reactions.

Treatment: symptomatic therapy. The specific antidote is unknown.

Interaction:

Caution is required when combined: with cytochrome inducers CYP2D6 and CYP3A - barbiturates, carbamazepine, carisoprodol, glutetimide, griseofulvin, dinitrogen oxide, papaverine, phenylbutazone, phenytoin (probably, other hydantoins), rifampicin, tolbutamide; with inhibitors of the enzymes CYP2D6 and CYP3A - allopurinol, macrolide antibiotics, antidepressants (monoamine oxidase inhibitors), chloramphenicol, cimetidine, estrogen-containing oral contraceptives, diltiazem, disulfiram, valproic acid and its salts, erythromycin, fluconazole, fluoroquinolones, isoniazid, ketoconazole, lovastatin, metronidazole, omeprazole, propranolol, quinidine, quinine, verapamil. Caution should be exercised when using with drugs that extend the QT interval and / or cause electrolyte imbalance /

Apomorphine

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

Phenytoin, carbamazepine and rifampicin

In patients receiving powerful inducers of CYP3A4 (phenytoin, carbamazepine and rifampicin), the concentration of ondansetron in the blood was reduced.

Tramadol

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

With the simultaneous use of ondansetron and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and norepinephrine and serotonin reuptake inhibitors (SSRIs), the risk of developing serotonin syndrome (altered state of consciousness, peripheral nervous system instability, and neuromuscular disorders ).

Special instructions:

Patients who had previously had allergic reactions to other selective 5-HT3 receptor blockers have an increased risk of developing them against ondansetron. In patients with an increased risk of prolonging the QT interval, hypokalemia and hypomagnesemia must be corrected. Ondansetron can slow the motility of the large intestine, in connection with which its appointment to patients with signs of intestinal obstruction requires special observation.

Ondansetron clearance in children aged 1 to 4 months is reduced, and the half-life is approximately 2.5 times greater than in children aged 5 to 24 months. Therefore, careful follow-up of patients receiving ondansetron at the age from 1 month to 4 months.

Pharmaceutical Precautions

The drug should not be administered in the same syringe or in one infusion solution with other medicines, with the exception of the medicinal products indicated in the section "Method of administration and dose".

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

The drug does not adversely affect the ability to drive vehicles and work with mechanisms.

Form release / dosage:

Solution for intravenous and intramuscular injection 2 mg / ml.

Packaging:

By 2 or 4 ml into ampoules of low-density polyethylene or polypropylene.

For 5 or 10 ampoules together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date!

Terms of leave from pharmacies:On prescription

Registration number:LP-003525

Date of registration:24.03.2016

Expiration Date:24.03.2021

The owner of the registration certificate:GROTEKS, LLC GROTEKS, LLC Russia

Manufacturer: & nbsp

GROTEKS, LLC Russia

Information update date: & nbsp07.06.2017

Illustrated instructions

Instructions

Ondansetron (Ondansetron)