Composition, form of production and packaging
The solution for intravenous and intravenous administration is clear, colorless, practically free from foreign inclusions.
1 ml of 1 amp.
ondansetron hydrochloride dihydrate 2.5 mg 5 mg,
which corresponds to the content of ondansetron 2 mg 4 mg
Excipients: citric acid monohydrate, sodium citrate, sodium chloride, water d / and.
2 ml - ampoules glass (5) - packs cardboard.
The solution for intravenous and intravenous administration is clear, colorless, practically free from foreign inclusions.
1 ml of 1 amp.
ondansetron hydrochloride dihydrate 2.5 mg 10 mg,
which corresponds to the content of ondansetron 2 mg 8 mg
Excipients: citric acid monohydrate, sodium citrate, sodium chloride, water d / and.
4 ml - ampoules glass (5) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Antiemetic drug, a selective antagonist of serotonin 5HT 3 receptors.
Ondansetron is a potent highly selective antagonist of 5HT 3 receptors. The mechanism of suppressing nausea and vomiting is not exactly known. Radiotherapy and the use of chemotherapeutic drugs may release serotonin (5HT) in the small intestine, causing a vomitive reflex through the activation of 5HT 3 receptors and the excitation of the afferent endings 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, therefore, trigger a vomitive reflex through the central mechanism. Thus, the effect of ondansetron in suppressing nausea and vomiting, provoked by cytotoxic chemotherapy and radiotherapy, appears to be due to the antagonistic effect on 5HT 3 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 the IM and IV in the introduction.
Distribution
Ondansetron has a moderate ability to bind to plasma proteins (70-76%). The distribution of ondansetron is similar for IM and IV in adults. V d in a state of equilibrium 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 in the urine.T 1/2 of ondansetron, both after IM and after IV, is approximately 3 hours.
Pharmacokinetics in special clinical cases
The pharmacokinetics of ondansetron depends on the sex of the patients. Women have less systemic clearance and V d (the figures are corrected for body weight) than for men.
In a clinical study, children aged 1 to 24 months (51 patients) received ondansetron at a dose of 0.1 mg / kg or 0.2 mg / kg before surgery. In patients aged 1 to 4 months, the clearance was approximately 30% less than in patients aged 5 to 24 months, but comparable to that in patients aged 3 to 12 years (with correction according to weight body). T 1/2 in the group of patients aged 1-4 m on average was 6.7 h; in the age groups 5-24 months and 3-12 years - 2.9 hours. In patients aged 1 to 4 months, dose adjustment is not required, since once-daily intravenous ondansetron is used to treat postoperative nausea and vomiting in this category of patients.Differences in pharmacokinetic parameters are partly due to higher V d in patients aged 1 to 4 months.
In a study in children aged 3-12 years (21 patients) who underwent planned surgery under general anesthesia, the absolute clearance values ​​and Vd of ondansetron after a single intravenous injection at a dose of 2 mg (3 to 7 years) or 4 mg (from 8 to 12 years) 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 V d as a function of body weight, these parameters were similar in different age groups. Calculation of the dose taking into account the body weight (0.1 mg / kg, maximum to 4 mg) compensates for these changes and systemic exposure of ondansetron in children.
Population pharmacokinetic analysis was performed in 74 patients aged 6 to 48 months who received IV / d ondansetron at a dose of 0.15 mg / kg every 4 hours in the amount of 3 doses for the relief of nausea and vomiting caused by chemotherapy and in 41 patients aged from 1 to 24 months after surgical interventions administered ondansetron in a single dose of 0.1 mg / kg or 0.2 mg / kg. Based on pharmacokinetic parameters in this group for patients aged 1 to 48 months, the administration of ondansetron IV at a dose of 0.15 mg / kg every 4 hours in an amount of 3 doses should result in a systemic exposure (AUC) comparable to that observed when using the drug in the same doses in children aged 5 to 24 months with surgical interventions, as well as in previous studies in children with cancer (aged 4 to 18 years) and with surgical intervention (ages 3 to 12 years).
Studies conducted in elderly patients showed a weak, clinically insignificant, age-dependent increase in T 1/2 ondansetron.
In patients with moderate impairment of renal function (creatinine clearance 15-60 ml / min) with IV ondansetron, systemic clearance and Vd of ondansetron are reduced, resulting in a small and clinically insignificant increase in its T 1/2 (up to 5.4 h). The pharmacokinetics of ondansetron with its intravenous administration remained practically unchanged in patients with severe renal dysfunction in chronic hemodialysis (studies were conducted in between hemodialysis sessions).
In patients with severe impairment of liver function, the systemic clearance of ondansetron decreases sharply with an increase in T 1/2 to 15-32 h.
INDICATIONS
- prevention and elimination of nausea and vomiting caused by cytostatic chemotherapy or radiotherapy;
- prevention and elimination of postoperative nausea and vomiting.
DOSING MODE
Nausea and vomiting caused by chemotherapy and / or radiotherapy
The choice of dosage regimen is determined by the emetogenicity of antitumor therapy.
Adults
With moderate emetogenic chemotherapy or radiotherapy, the drug is administered at a dose of 8 mg IV (slowly) or IM just before chemotherapy or radiotherapy.
For patients receiving highly emeticogenic chemotherapy, for example, cisplatin in high doses, ZofranВ® can be administered as a single IV or IM injection at a dose of 8 mg just before chemotherapy. Zofran В® in a dose of 8 mg to 32 mg should be administered only by IV infusion after dissolving the drug in 50-100 ml of 0.9% sodium chloride solution or in another compatible infusion solution for 15 minutes or more. Another method is to administer Zofran 8 mg slowly IV or IM immediately before chemotherapy, followed by the administration of two injections IV or IM at a dose of 8 mg at intervals of 2-4 hours or using a constant infusion of the drug with at a rate of 1 mg / h for 24 hours.
In the case of highly emeticogenic antitumor therapy, the effectiveness of Zofran can be enhanced by an additional single intravenous injection of dexamethasone sodium phosphate in a dose of 20 mg prior to chemotherapy. Oral or rectal dosage forms Zofran are recommended to prevent delayed or continued vomiting after the first day after the chemotherapy.
Children and adolescents aged 6 months to 17 years
Children with body surface area less than 0.6 m 2 receive an initial dose of 5 mg / m 2 IV immediately before chemotherapy, followed by Zofran inwards at a dose of 2 mg (in the form of a syrup) after 12 hours. Within 5 days after the course of treatment Therapy is continued, taking Zofran В® inside at a dose of 2 mg 2 times / day.
Children with a body surface area of ​​0.6-1.2 m 2 Zofran ® are given iv once a dose of 5 mg / m 2 immediately before the chemotherapy, followed by taking the drug inside at a dose of 4 mg after 12 hours. Taking Zofran inside at a dose of 4 mg 2 times / day can be continued for another 5 days after the course of chemotherapy.
For children with a body surface area of ​​more than 1.2 m 2, an initial dose of 8 mg is given IV immediately before chemotherapy, followed by taking the drug inside at a dose of 8 mg after 12 hours. Zofran intake in a dose of 8 mg 2 times / day can be continued within 5 days after the course of chemotherapy.
As an alternative to children aged 6 months and older Zofran В® is administered iv once at a dose of 0.15 mg / kg (not more than 8 mg) immediately before chemotherapy. This dose can be administered repeatedly every 4 hours, not more than three doses in total. Zofran intake in a dose of 4 mg 2 times / day can be continued for another 5 days after the course of chemotherapy. Doses should not exceed those recommended for adults.
Other categories of patients
In elderly patients , dose adjustment of Zofran is not required.
Patients with renal dysfunction do not need dosage correction.
With violations of liver function, clearance of ondansetron is significantly reduced, T 1/2 is increased in patients with impaired liver function of moderate and severe degree. The daily dose of Zofran should not exceed 8 mg.
In patients with delayed metabolism of sparteine ​​and debrisoquine, T 1/2 of ondansetron is not changed. Consequently, with the repeated administration of Zofran, 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 intravenous or slow intravenous injection of Zofran in a dose of 4 mg is recommended during the initial anesthesia.
For the treatment of nausea and vomiting in the postoperative period Zofran В® is administered once in a dose of 4 mg IM or slowly IV.
Children and adolescents aged 1 month to 17 years
To prevent nausea and vomiting in the postoperative period in children undergoing surgical intervention under general anesthesia, Zofran В® can be administered at a dose of 0.1 mg / kg (up to max. 4 mg) in the form of a slow intravenous injection before, during or after an initial anesthetic or after operation.
To stop the nausea and vomiting that developed in the postoperative period , a slow intravenous injection of Zofran in a dose of 0.1 mg / kg (maximum to 4 mg) is recommended.
Other categories of patients
There is limited experience with Zofran for preventing and arresting postoperative nausea and vomiting in elderly patients , although Zofran В® is well tolerated by patients over 65 years of age who are receiving chemotherapy.
Patients with renal dysfunction do not need dosage correction.
With violations of liver function, clearance of ondansetron is significantly reduced, T 1/2 is increased in patients with impaired liver function of moderate and severe degree. The daily dose of Zofran should not exceed 8 mg.
Patients with a slow metabolism of sparteine ​​/ debrisoquine
In patients with a slow metabolism of sparteine ​​and debrisoquine, T 1/2 of ondansetron is not changed. Consequently, with the repeated administration of Zofran, 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.
Rules for the preparation of solutions and use of the preparation
To dilute the injection solution, the following solutions can be used: 0.9% sodium chloride solution, 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 В° to 8 В° C.
During the infusion, protection from light is not required; The diluted injection solution retains its stability for at least 24 hours under natural light or normal light.
SIDE EFFECT
Determination of the frequency of adverse reactions: very often (? 1/10), often (? 1/100 and <1/10), sometimes (? 1/1000 and <1/100), rarely (? 1/10 000 and <1 / 1000), very rarely (<1/10 000), including individual messages.
Allergic reactions: rarely - immediate-type hypersensitivity reactions, in a number of severe cases, including anaphylaxis.
From the nervous system: very often - headache; sometimes - convulsions, motor disorders (including extrapyramidal symptoms such as dystonia, oculogic crisis / seizure spasm / and dyskinesia) in the absence of persistent clinical consequences; rarely - dizziness during a rapid IV injection.
From the side of the organ of vision: rarely - transient visual impairment (blurred vision), mainly during IV introduction; very rarely - transient blindness, mainly during intravenous administration. Most cases of blindness were safely resolved within 20 minutes. Most patients received chemotherapy drugs containing cisplatin. In some cases, transient blindness was of a cortical genesis.
From the cardiovascular system: sometimes - arrhythmia, pain in the chest, as accompanied, and not accompanied by a decrease in the ST segment, bradycardia, lowering blood pressure; often - a feeling of hotness or hot flashes; very rarely - transient ECG changes, including prolongation of the QT interval, mainly, with IV introduction.
From the digestive system: often - constipation; sometimes an asymptomatic increase in hepatic samples (mainly observed in patients receiving cisplatin chemotherapy).
Local reactions: often - local reactions at the site of intravenous administration.
Other: sometimes - hiccups.
CONTRAINDICATIONS
- Pregnancy;
- lactation (breastfeeding);
- Hypersensitivity to the components of the drug.
Caution should be used in patients with heart rhythm and conduction disorders, patients receiving antiarrhythmic drugs and beta-blockers and patients with significant electrolyte disorders (very rarely with intravenous administration of Zofran, transient ECG changes were recorded, including prolongation of the QT interval).
PREGNANCY AND LACTATION
The drug is contraindicated for use in pregnancy and lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
In renal failure, no special dose adjustment, frequency of administration or method of administration is required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
When appointing the drug to patients with impaired liver function, the daily dose of the drug should not exceed 8 mg.
APPLICATION FOR CHILDREN
Use according to the indications and in doses that take into account the age of the patient. At present, there are limited data on the use of ondansetron in children younger than 1 month .
APPLICATION IN ELDERLY PATIENTS
In elderly patients , a change in the dosage regimen is not required.
SPECIAL INSTRUCTIONS
There are reports of hypersensitivity reactions to ondansetron in patients who have a history of hypersensitivity to other selective 5HT 3 receptor antagonists.
Since it is known that ondansetron increases the time of passage of the contents through the large intestine, in the case of using the drug in patients with symptoms of subacute intestinal obstruction, regular monitoring is necessary.
Zofran В® should not be administered in the same syringe or in one infusion solution with other medicinal products.
Use in Pediatrics
At present, there are limited data on the use of ondansetron in children younger than 1 month .
Impact on the ability to drive vehicles and manage mechanisms
Zofran В® does not have a sedative effect and does not affect the ability of patients to drive vehicles or engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.
OVERDOSE
Currently, there is little data on overdose of ondansetron.
Symptoms: in most of the cases observed, the symptoms of an overdose coincided with the adverse reactions that occur when taking Zofran В® at the recommended doses.
Treatment: there is no specific antidote for Zofran, so it is recommended that symptomatic and supportive therapy be provided for suspected overdose.
DRUG INTERACTION
There is no evidence that ondansetron induces or inhibits the metabolism of other drugs, often prescribed in combination with it.
According to special studies, it was found that ondansetron does not interact with ethanol, temazepam, furosemide, tramadol and propofol.
Ondansetron is metabolized by several isoenzymes of the cytochrome P450 system (CYP3A4, CYP2D6 and CYP1A2). Due to the variety of isoenzymes capable of metabolizing ondansetron, inhibition of isoenzymes or a decrease in the activity of one of the isozymes (for example, in case of genetic deficiency of CYP2D6), it is usually compensated by other isoenzymes, as a result of which there are no changes in the total clearance of ondansetron, or insignificant and practically do not require dose adjustment.
In patients receiving potent inducers of CYP3A4 (phenytoin, carbamazepine, and rifampicin), ondansentrona concentration in the blood was reduced.
There is evidence of small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Pharmaceutical interaction
Zofran В® at a concentration of 16 ug / ml and 160 ug / ml (which corresponds to 8 mg / 500 ml and 8 mg / 50 ml respectively), pharmaceutically compatible and can be administered through the Y-shaped injector / drip in conjunction with the following medicaments:
- cisplatin (at a concentration of 0.48 mg / ml) for 1-8 hours;
- 5-fluorouracil (at a concentration of 0.8 mg / ml at 20 ml / h - higher concentrations of 5-fluorouracil can cause loss precipitated Zofran);
- carboplatin (in a concentration of 0.18-9.9 mg / ml) for 10-60 min;
- etoposide (at a concentration of 0.144-025 mg / ml for 30-60 min);
- ceftazidime (at a dose of 0.25-2 g, in the form of I / bolus injection over 5 min);
- cyclophosphamide (at a dose of 0.1-1 g, a / in a bolus injection over 5 min);
- doxorubicin (at a dose of 10-100 mg, in the form of I / bolus injection over 5 min);
- dexamethasone (possibly in / in a 20 mg dexamethasone slowly over 2-5 min). The medicaments can be administered through one dropper, the solution at a concentration of dexamethasone sodium phosphate may be from 32 .mu.g to 2.5 mg / ml, Zofran - 8 mcg to 1 mg / ml.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature not higher than 30 В° C. Shelf life - 3 years.
