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

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 cytostatic chemo- and radioinduced nausea and vomiting by ondansetron is most likely due to antagonistic action on the 5HT3 receptors of neurons located both on the periphery and in the central nervous system.

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

After the introduction of rectal suppositories ondansetron, its concentration in the blood plasma begins to be determined after 15-60 minutes. Ondansetron concentration rises linearly until a peak concentration of 20-30 ng / ml is reached, usually 6 hours after application of the drug.

Further, the concentration of ondansetron in the blood plasma is reduced, and the decrease is slower than with the oral route of administration, due to prolonged absorption of ondansetron.

Absolute bioavailability of ondansetron when applied in the form of suppositories is approximately 60%.

Distribution

Ondansetron has a moderate degree of binding to plasma proteins (70-76%).

Metabolism

Ondansetron is metabolized mainly in the liver with the participation of several 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 bloodstream mainly through metabolism in the liver. Less than 5% of the administered dose is excreted unchanged by the kidneys. The half-life of ondansetron is determined by the degree of absorption, not by systemic clearance, and is approximately 6 hours.

Special patient groups

Floor

Absolute bioavailability does not depend on the sex of patients. However, women experience a clinically insignificant lengthening of the half-life compared to men.

Elderly patients

Data from clinical trials in elderly patients are limited. However, it is assumed that the half-life of ondansetron in elderly patients is similar to that of healthy volunteers, since ondansetron removal when applied in the form of rectal suppositories is not determined by systemic clearance.

Patients with impaired renal function

Data from clinical studies in patients with impaired renal function are limited. However, it is assumed that the half-life of ondansetron in patients with impaired renal function is similar to that of healthy volunteers,as deducing ondansetron when used in the form of rectal suppositories is not determined by systemic clearance.

Patients with impaired hepatic function

The pharmacokinetics of ondansetron when used in the form of rectal suppositories in patients with impaired liver function has not been studied.

Indications:

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

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 (see the section on "Application during pregnancy and during breastfeeding");
childhood;
congenital syndrome of prolongation of the QT interval.

Carefully:

Caution should be exercised when using ondansetron in patients with increased sensitivity to other 5HT antagonists₃ -receptors;
in patients with heart rhythm disturbances and conduction;
in patients receiving antiarrhythmic drugs and beta-blockers;
in patients with significant disturbances in the water-electrolyte balance;
in patients with lengthening or risk of prolonging the QTc interval, including patients with water-electrolyte balance disorders, chronic heart failure, bradyarrhythmia, or in patients taking other medications that may cause prolongation of the QT interval, disturbance of the electrolyte balance or a decrease in the heart rate ;
in patients with subacute intestinal obstruction; with simultaneous use with other serotonergic drugs.

Pregnancy and lactation:

Pregnancy

The safety of ondansetron during pregnancy in humans is not established. Preclinical studies did not reveal a direct and indirect negative impact on the development of the embryo, fetus, gestation, peri- and postanal development. However, the use of ondansetron in pregnant women is contraindicated due to the fact that the results of preclinical studies can not always be extrapolated to the safety of human use.

Breast-feeding

Studies have shown that ondansetron penetrates into the breast milk of lactating animals.When using ondansetron in nursing mothers, breastfeeding should be discontinued (see section "Contraindications").

Dosing and Administration:

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

Adults

The recommended dose of 16 mg of ondansetron (1 suppository) 1-2 hours before the start of the main therapy.

In order to prevent delayed or continued vomiting 24 hours after using Zofran, a solution for intravenous and intramuscular administration can continue to receive Zofran, rectal suppositories or in oral dosage form for no more than 5 days. The recommended daily dose of ondansetron is 16 mg (1 suppository).

Special patient groups

Children

Use of Zofran, rectal suppositories in children is not recommended. Usually, children are prescribed Zofran in an injectable and oral dosage form.

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, and the half-life is significantly increased.

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.

Method of administration

Free the intestines if necessary.

Wash your hands.

Remove the suppository from the package. To simplify the introduction of the suppository, sit down or lean forward. Insert the suppository into the rectum. Wash your hands.

Try not to empty the intestine within 1 hour after the introduction of the suppository.

It is forbidden to swallow the drug Zofran, suppositories rectal.

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 <1/1 000), 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: the reactions of hypersensitivity immediate tina (urticaria, bronchospasm, laryngospasm, angioedema), in a number of cases of severe degree, 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 vision disorders (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 feeling of hotness 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.

Frequency unknown: diarrhea.

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.

General disorders and disorders at the site of administration

Often: a burning sensation in the anus and rectum after the introduction of the suppository.

The frequency is unknown: hypokalemia.

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 prescribed 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 isoenzymes (for example,with 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 imbalance, 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 was found 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, instability of the peripheral nervous system function and neuromuscular disorders) increases (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 antagonists 5HT₃receptors.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 interval QT. In addition, during post-registration follow-up, reports of cases of ventricular pirouette tachycardia were reported among patients receiving ondansetron.

Before the introduction of ondansetroya, it is necessary to correct hypokalemia and hypomagnesemia.

It has been established that with the combined use of ondansetroids and other serotonergic drugs, the risk of developing serotonin syndrome increases (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:

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:Suppositories rectal, 16 mg.

Packaging:

One suppository in a strip of polypropylene / aluminum / low density polyethylene, sealed in a cardboard frame with a triangular notch to facilitate opening the package. For 1 or 2 strips together with instructions for medical use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 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 N016094 / 01

Date of registration:02.11.2009

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

Manufacturer: & nbsp

FARMACLAIR France

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp18.10.2017

Illustrated instructions

Instructions

Zofran® (Zofran®)