Mechanism of action
Antiemetic drug. Selective antagonist of serotonin 5HT3 receptors. It has a strong antiemetic effect, the mechanism of which is not fully established. Drugs used for Chemotherapy and radiological exposure can cause the release of serotonin in the small intestine, thereby triggering the gag reflex through activation of serotonin 5HT3 receptors and stimulation of the vagal nerve endings. Ondansetron blocks the trigger mechanisms of this reflex. Activation of the afferent endings of the vagus nerve, in turn, can cause a release of serotonin in the area of post-tense, located at the bottom of the IV ventricle, and, therefore, trigger the gag reflex through the central mechanism. Suppression of nausea and vomiting triggered by cytotoxic chemotherapy and radiotherapy, apparently, is due to the antagonistic effect of ondansetron on serotonin 5HT3 receptors of neurons of the central and peripheral nervous system.
In psychomotor testing, it is shown that ondansetron does not impair performance and does not have a sedative effect. The drug does not affect the concentration of prolactin in the blood plasma.
Suction:
After taking the drug inside Cmax is achieved in about 1.5 hours. The absolute bioavailability is about 60%.
After rectal administration of 1 suppository, ondansetron is determined in plasma in 15-60 minutes. The concentration of the active substance increases linearly, Сmax is reached after about 6 hours and is 20-30 ng / ml. The decrease in plasma concentration occurs at a slower rate than after taking the drug inside, due to the continued absorption of ondansetron. The absolute bioavailability of ondansetron with rectal administration is approximately 60% and does not depend on gender.
After i / m injection, Cmax is reached in 10 minutes.
Distribution
Vd, both after ingestion and after parenteral administration, is 140 liters.
Plasma protein binding - 70-76%.
Metabolism
Biotransforming in the liver.
Removal
As after ingestion, and after parenteral administration T1 / 2 is 3 hours.After rectal administration, T1 / 2 is determined by the rate of ondansetron absorption, rather than by systemic clearance, and is approximately 6 hours.
In unchanged form, less than 5% of the administered dose is excreted in the urine.
The pharmacokinetic parameters of ondansetron do not change with its repeated administration.
Pharmacokinetics in special clinical situations
In patients with moderate renal insufficiency (CC 15–60 ml / min), both systemic clearance and ondansetron distribution volume are reduced, resulting in a small and clinically insignificant increase in its T1 / 2. The pharmacokinetics of ondansetron practically does not change in patients with severe impaired renal function on chronic hemodialysis (the studies were conducted in the intervals between hemodialysis sessions).
In patients with impaired liver function, the pharmacokinetics of ondansetron with rectal administration has not been studied.
The absence of CYP2D6 enzyme (debrisoquine polymorphism) does not affect the pharmacokinetic parameters of ondansetron, regardless of the route of administration of Zofran.
In elderly patients after taking Zofran by mouth or parenteral administration, T1 / 2 can increase up to 5 hours. In special studies, elderly patients and patients with impaired renal function used Zofran forms only for parenteral administration and oral administration. It is assumed that in such patients T1 / 2 does not differ from this indicator in healthy volunteers, since the rate of elimination of ondansetron when administered in the form of rectal suppositories does not depend on systemic clearance.
Indications and usage
Prevention and elimination of nausea and vomiting caused by cytotoxic chemotherapy or radiotherapy;
prevention and elimination of nausea and vomiting in the postoperative period.
The emetogenic effect in the treatment of malignant tumors varies depending on the doses and combinations of the chemotherapy and radiotherapy schemes used. Dosage and administration of Zofran should be adjusted in the range of 8-32 mg / day in accordance with the following criteria.
Inside adults with nausea and vomiting caused by chemotherapy or radiotherapy, Zofran is prescribed 8 mg each (as a syrup, pills or lingual tablets) 1-2 hours before the start of antitumor therapy, followed by another 8 mg orally after 12 hours.For the prevention of late or prolonged vomiting after the first 24 hours, you should continue taking the drug 8 mg 2 times / day for 5 days after the end of the course of antitumor therapy. Instead of ingestion, Zofran can be administered rectally in the form of suppositories.
For nausea and vomiting caused by highly chemotherapy, the recommended oral dose is 24 mg (as a syrup, pills or lingual tablets) simultaneously with Dexamethasone phosphate (in the form of sodium salt) at a dose of 12 mg 1-2 h before the start of chemotherapy. Instead of ingestion, Zofran can be administered rectally in the form of suppositories or in the form of an injection solution.
For the prevention of late or prolonged vomiting after the first 24 hours, the drug should be continued on 8 mg 2 times / day for 5 days after the end of the course of chemotherapy. Instead of ingestion, Zofran can be administered rectally in the form of suppositories.
Zofran is prescribed to the children immediately before chemotherapy and then taking the drug orally as a syrup at a dose of 4 mg (as syrup, pills or lingual tablets) after 12 hours. After completing the course of chemotherapy, you should continue taking Zofran in the form of syrup at a dose of 4 mg 2 times / day for 5 days.
In case of nausea and vomiting in the postoperative period, adults are advised to take the drug orally at a dose of 16 mg (in the form of syrup, pills or lingual tablets) 1 hour prior to general anesthesia. For the treatment of nausea or vomiting in the postoperative period, parenteral administration of Zofran is recommended.
The lingual pill should be put on the tongue, where it dissolves within a few seconds, and swallowed. A large measuring spoon contains 5 ml of Zofran syrup, or 4 mg of ondansetron; a small measuring spoon contains 2.5 ml of Zofran syrup, or 2 mg of ondansetron.
Adults with nausea and vomiting caused by emetogenic chemotherapy and radiotherapy for intravenous or intramuscular administration, the recommended dose of Zofran is 8 mg immediately prior to chemotherapy or radiotherapy; the drug should be administered slowly. If nausea and vomiting persist and are observed for more than 24 hours from the start of therapy, the drug is recommended to be taken orally 8 mg 2 times / day for 5 days, or rectally.
In case of nausea and vomiting caused by high-emittogenic chemotherapy (for example, when using Cisplatin in high doses), Zofran can be administered as a single intramuscular or intravenous injection (slowly) at a dose of 8 mg just before the introduction of the emetogenic drug.Zofran in doses of more than 8 mg and up to 32 mg can be administered only by intravenous infusion, after dissolving the drug in 50-100 ml of saline or in another compatible infusion solution; infusion is carried out for at least 15 minutes.
According to a different treatment regimen, Zofran is prescribed at a dose of 8 mg as an intramuscular or intravenous (slow) injection just before chemotherapy. Next, appoint 2 injections in / in or in / m at a dose of 8 mg, each of which is carried out in 2-4 hours; or administered as a constant infusion at a rate of 1 mg / h for 24 hours. The effectiveness of Zofran can be enhanced by additional administration (before the start of chemotherapy) of dexamethasone phosphate (in the form of sodium salt) at a dose of 20 mg IV, once.
If nausea and vomiting persist and are observed for more than 24 hours from the start of therapy, the drug is recommended to be taken orally 8 mg 2 times / day for 5 days, or rectally.
Zofran children can be administered iv as an injection at a dose of 5 mg / m2 immediately before the start of chemotherapy.
Since the cardiovascular system: the feeling of warmth or rush of blood to the face and head; rarely - chest pain, arrhythmias, hypotension, bradycardia.
On the part of the digestive system: constipation, hiccups, transient asymptomatic increase in transaminase activity in the blood plasma.
From the side of the central nervous system: headache, convulsions (passing later).
Allergic reactions: rarely - immediate-type allergic reactions, in some cases - severe, up to anaphylaxis.
Local reactions: rarely - local reactions in the injection area, burning sensation in the anus and rectum after administration of the suppository.
Phypersensitivity to the drug.
The safety of using ondansetron during pregnancy has not been established. In experimental studies, it was found that ondansetron does not have a direct or indirect adverse effect on the development of the embryo and fetus, during pregnancy, as well as on perinatal and postnatal development. However, since the results of studies in animals cannot always accurately predict the nature of the action in humans, the drug is not recommended for use during pregnancy.
If necessary, the appointment of the drug during lactation should stop breastfeeding.
In patients receiving prior treatment with other selective antagonists of 5HT3 receptors, accompanied by hypersensitivity reactions, hypersensitivity reactions are also possible with Zofran.
Since ondansetron increases the time it takes for the contents to pass through the large intestine, if Zofran is used in patients with symptoms of subacute intestinal obstruction , regular observation is necessary.
For the prevention and treatment of nausea and vomiting in the postoperative period, it is recommended to inject Zofran parenterally.
Zofran Lingual pills contain aspartame, so they should be used with caution in patients with phenylketonuria.
In elderly patients, experience with Zofran for the prevention and treatment of nausea and vomiting in the postoperative period is limited. Patients over 65 years of age who receive chemotherapy are well tolerated by Zofran; special changes in dose, frequency of administration or method of administration of the drug is not required.
In people with a slow metabolism of spartein and debrisoquine (lack of the CYP2D6 enzyme), the half-life of ondansertone is unchanged. Consequently, upon repeated administration of the drug in such patients, its plasma concentrations will not differ from those in the general population. Therefore, these patients do not need to adjust the daily dose or frequency of ondansteron.
Patients with impaired renal function do not need to adjust the daily dose, frequency or route of administration of Zofran.
Zofran ampoules should not be autoclaved.
Use in pediatrics
It is not recommended to prescribe a drug to children in the form of suppositories.
Currently, data on Zofran overdose is limited.
Symptoms Two patients who received doses of 84 mg and 145 mg IV showed only mild side effects that did not require medical therapy.
Treatment. In cases of suspected overdose, symptomatic therapy is indicated. In case of an overdose of ondansetron, the use of ipecac is not recommended, since it is unlikely that this drug will be effective during the antiemetic effect of Zofran.
With simultaneous use with drugs that are inducers (barbiturates, Carbamazepine , rifampin, phenytoin, phenylbutazone) or inhibitors (cimetidine, Allopurinol , disulfiram) microsomal liver enzymes - cytochrome P450 isoenzymes, may change the clearance of ondansetron.
Pharmaceutical Interaction
Ondansetron in the form of an injection solution is compatible with the following infusion solutions: 0.9% sodium chloride solution, 5% glucose solution, 10% mannitol solution, Ringer's solution, 0.3% potassium chloride solution and 0.9% sodium chloride solution, 0.3% potassium chloride solution and 5 % glucose solution.
Zofran solution is compatible with a solution of dexamethasone phosphate and can be administered through one dropper, while in a solution the concentration of dexamethasone phosphate (in the form of sodium salt) can be from 32 μg to 2.5 g in 1 ml, ondansetron - from 8 μg to 1 mg in 1 ml.
Zofran for injection should not be injected with the same syringe or through the same dropper, through which other drugs were injected.
Tablets should be stored at a temperature not exceeding 30 [0] C. Shelf life - 3 years.
Lingual pills should be stored at a temperature not higher than 30 [0] С. Shelf life - 2 years.
Syrup should be stored in a vertical position at a temperature not higher than 30 [0] C, but not in the refrigerator. Shelf life - 3 years.
Injection solution should be stored in a dark place at a temperature not higher than 30 [0] C. Shelf life - 3 years.
Rectal suppositories should be stored at a temperature not exceeding 30 [0] C.
In accordance with the standards of pharmaceutical practice (Good Pharmaceutical Practice), solutions for iv administration should be prepared immediately before infusion and stored at a temperature of 2-8 [0] C for no more than 24 hours prior to the start of the administration.
Pharmacy sales terms
The drug is available on prescription.
|
