Ondansetron

Brand Sandoz

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Available since: 2019-09-19

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Clinical Pharmacology

Ondansetron is a selective 5-HT antagonist.₃-receptors. Drugs for cytostatic chemotherapy and radiotherapy can cause an increase in serotonin levels, which by activating vagal afferent fibers containing 5-HT₃- receptors, causes vomiting reflex. Ondansetron inhibits the appearance of the gag reflex by blocking 5-HT₃- receptors at the level of neurons of both the central nervous system and the peripheral nervous system.

Pharmacokinetics

Ondansetron is completely absorbed in the gastrointestinal tract after oral administration and is metabolized by first passing through the liver. C_max in plasma is reached approximately 1.5 hours after administration. Bioavailability increases slightly with simultaneous ingestion of food, but does not change when taking antacids.

The distribution of ondansetron is the same when administered orally, in a / m and in / in the introduction; T_1/2is approximately 3 hours, in elderly patients it can reach 5 hours, and in case of severe renal failure, it is 15–20 hours. The volume of distribution when the equilibrium concentration is reached is about 140 liters. Plasma protein binding - 70–76%. After rectal administration, ondansetron is determined in plasma in 15–60 minutes. The concentration of the active substance increases linearly, C_max is reached in about 6 hours and is 20–30 ng / ml. The decrease in plasma concentration occurs at a slower rate than after ingestion (due to continued absorption). T_1/2 - 6 hours. Absolute bioavailability with rectal administration - 60%.

From the systemic blood flow, it is eliminated mainly as a result of metabolism in the liver, which proceeds with the participation of several enzyme systems. The absence of CYP2D6 enzyme (a sparteine-debrisoquine type polymorphism) does not affect the pharmacokinetics of ondansetron. In unchanged form, less than 5% of the administered dose is excreted in the urine.

In doses above 8 mg, the blood level increases disproportionately, because with the appointment of high doses inside can decrease metabolism during the first passage through the liver.

The pharmacokinetic parameters of ondansetron do not change upon repeated administration.

In patients with moderate renal insufficiency (Cl creatinine - 15–60 ml / min), both systemic clearance and ondansetron distribution are reduced, resulting in a small and clinically insignificant increase in its T_1/2 (up to 5.4 hours). The pharmacokinetics of ondansetron remains almost unchanged in patients with severe renal dysfunction on chronic hemodialysis. In patients with severely impaired liver function, systemic clearance of ondansetron is sharply reduced, resulting in an increase in its T_1/2 (up to 15–32 h), and oral bioavailability reaches 100% due to a decrease in first-pass metabolism.

Special patient groups

Floor

The pharmacokinetics of ondansetron depend on the gender of the patient. Women have less systemic clearance and volume of distribution (indicators are adjusted for body weight) than men.

Children and adolescents (aged 1 month to 17 years)

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, Cl was approximately 30% less than in patients aged 5 to 24 months, but comparable with this indicator in patients aged 3 to 12 years (with correction of indicators depending on body weight ). T_1/2 in the group of patients aged 1–4 months, the average was 6.7 hours; in age groups 5–24 months and 3–12 years - 2.9 hours. Patients aged 1–4 months do not need dose adjustment, since a single IV administration of ondansetron is used to treat postoperative nausea and vomiting in this category of patients . The differences in pharmacokinetic parameters are partly due to a higher distribution volume in patients aged 1 to 4 months.

In a study of children aged 3–12 years (21 patients) who underwent planned surgical interventions under general anesthesia, the absolute values of Cl and the volume of distribution of ondansetron after a single IV dose of 2 mg (from 3 to 7 years) or 4 mg (from 8 to 12 years) were reduced in comparison with values in adults. Both parameters increased linearly depending on body weight, in patients aged 12 years, these values approached the values in adults. When correcting the values of clearance and volume of distribution depending on body weight, these parameters were close in different age groups. The dose, calculated taking into account body weight (0.1 mg / kg, up to a maximum of 4 mg), compensates for these changes and the systemic ondansetron exposure in children.

A population-based pharmacokinetic analysis was conducted in 74 patients aged from 6 to 48 months who were given IV ondansetron at a dose of 0.15 mg / kg every 4 hours in an amount of 3 doses to relieve nausea and vomiting caused by chemotherapy, and in 41 patients at the age of 1 to 24 months after surgical interventions, in which ondansetron was administered in a single dose of 0.1 or 0.2 mg / kg. Based on the pharmacokinetic parameters of this group for patients aged 1 to 48 months, administration of ondansetron IV dose of 0.15 mg / kg every 4 hours in an amount of 3 doses should result in a systemic exposure comparable to that observed in use of the drug in the same doses in children aged from 5 to 24 months in surgical interventions, as well as in previous studies in children with cancer (aged 4 to 18 years) and in surgical intervention (aged 3 to 12 years ).

Elderly patients

Studies have shown a weak, clinically insignificant, age-dependent increase in T_1/2ondansetron.

Patients with impaired renal function

In patients with moderately impaired renal function (Cl of creatinine 15–60 ml / min) with ondansetron in / infusion, both systemic clearance and distribution of ondansetron are reduced, resulting in a small and clinically insignificant increase in T_1/2 (up to 5.4 hours). The pharmacokinetics of ondansetron with the on / in the introduction remained almost unchanged in patients with severe impaired renal function, who are on chronic hemodialysis (the studies were conducted in the intervals between hemodialysis sessions).

Patients with impaired liver function

In patients with severely impaired liver function, systemic clearance of ondansetron sharply decreases with an increase in T_1/2 up to 15–32 hours

Indications

Prevention and elimination of nausea and vomiting caused by conducting cytotoxic chemotherapy or radiotherapy; prevention and elimination of postoperative nausea and vomiting.

Ondansetron is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Undantor	Sandoz	Switzerland	pills
Ondansetron	NovosibirskChemPharm	Russia	ampoules
Ondansetron-Teva	Teva	Israel	pills
Ondansetron-Altfarm	Altfarm	Russia	rectal suppositories
Ondansetron	Sotex	Russia	ampoules
Emetron	Gedeon Richter	Hungary	ampoules
Latran	Pharmaceutical NPC	Russia	pills
Latran	Pharmaceutical NPC	Russia	ampoules
Zofran	Novartis	Switzerland	ampoules
Zofran	Novartis	Switzerland	rectal suppositories

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Dosage and Administration

Cytostatic therapy

The choice of the dosage regimen is determined by the severity of the emetogenic effect of the antitumor therapy being administered.

For adults the daily dose, as a rule, makes 8-32 mg, the following modes are recommended.

With moderate emetogenic chemotherapy or radiotherapy: 8 mg i / v jet slowly or intramuscularly, immediately before the start of therapy; or 8 mg orally for 1-2 hours before the start of therapy, then another 8 mg orally after 12 hours after the start of therapy.

With highly ehnetogennoy chemotherapy: 8 mg IV in a jet (slowly) immediately before the start of chemotherapy, and then another 2 IV flux injections of 8 mg, each of which takes 2-4 hours; or continuous 24-hour infusion of the drug in a dose of 24 mg at a rate of 1 mg / h; or 16-32 mg, diluted in 50-100 ml of the appropriate infusion solution, in the form of a 15-minute infusion, immediately before the start of chemotherapy.

The effectiveness of ondansetron can be increased by a single intravenous glucocorticoid (for example, 20 mg of dexamethasone) prior to the start of chemotherapy; when taken orally to enhance the effect, a single dose can be increased to 24 mg and administered simultaneously with 12 mg of dexamethasone 1-2 hours before the start of chemotherapy.

To prevent delayed vomiting that occurs 24 hours after the start of chemotherapy or radiotherapy, It is recommended to continue the use of the drug inside 8 mg 2 times / day for 5 days.

Children over 2 years old the drug is administered at a dose of 5 mg / m² body surfaces IV, immediately before the start of chemotherapy, followed by ingestion in a dose of 4 mg after 12 hours; after the end of chemotherapy, it is recommended to continue treatment with 4 mg 2 times / day orally for 5 days.

Prevention of postoperative nausea and vomiting

For adults A single dose of 4 mg is administered intramuscularly or intravenously in a jet, slowly at the start of anesthesia, or 16 mg is administered orally for 1 hour before the start of anesthesia.

For the relief of nausea and vomiting It is recommended intramuscularly or slow intravenous injection of 4 mg of the drug.

IM in the same area of the body ondansetron can be administered in a dose not exceeding 4 mg.

Children to prevent postoperative nausea and vomiting ondansetron is used exclusively parenterally in a single dose of 0.1 mg / kg (up to a maximum of 4 mg) as a slow intravenous injection during or after anesthesia.

For the treatment of advanced postoperative nausea and vomiting in children a slow i.v. administration of a single dose of 0.1 mg / kg (up to a maximum of 4 mg) is recommended. Regarding the prevention and treatment of postoperative nausea and vomiting in children under 2 years there is not enough experience.

Elderly patients no dosage change is required.

With kidney damage change the usual daily dose and frequency of drug administration is not required.

With liver damage the ondansetron clearance decreases significantly, with T increasing_1/2 from plasma, so do not exceed the daily dose of 8 mg / day.

The following solutions can be used to dilute the injection solution: 0.9% sodium chloride solution, 5% dextrose solution, Ringer's solution, 0.3% potassium chloride solution and 0.9% sodium chloride solution, 0.3% potassium chloride solution and 5 % solution of dextrose.

Adverse reactions

Allergic reactions: urticaria, bronchospasm, laryngospasm, angioedema, anaphylaxis.

From the digestive system: hiccups, dry mouth, diarrhea, constipation; sometimes - asymptomatic transient increase in the level of aminotransferases in the serum.

Since the cardiovascular system: chest pain, in some cases with depression of the ST segment, arrhythmias, bradshardia, decrease in blood pressure.

From the side of the central nervous system: headache, dizziness, spontaneous movement disorders and cramps. Local reactions: pain, burning and redness at the injection site.

Other: blood flow to the face, feeling hot, temporary visual acuity; rarely, hypokalemia (the connection with the intake of the drug has not been clearly established).

Contraindications

Pregnancy;
lactation period;
children's age up to 2 years (safety and efficacy have not been studied);
hypersensitivity to any component of the drug.

Drug interactions

Since ondansetron is metabolized by the liver enzyme system (cytochrome P450), and caution is required when using it together:

with enzymatic inductors P450 (CYP2D6 and CYP3A) (barbiturates, carbamazepine, carisoprodol, glutethimide, griseofulvin, nitrous oxide, papaverine, phenylbutazone, phenytoin (probably other hydantoins), rifampicin, tolbutamide);
with an inhibitor of P450 (CYP2); lovastatin, metronidazole, omeprazole, propranolol, quinidine, quinine, verapamil).

Does not interact with ethanol, temazepam, furosemide, tramadol and propofol.

Ondansetron at a concentration of 16-160 mcg / ml is pharmaceutically compatible with the following drugs, which can be administered through a Y-shaped injector:

cisplastin (at a concentration of up to 0.48 mg / ml) for 1-8 hours;
5-fluorouracil (at a concentration of up to 0.8 mg / ml at a rate of 20 ml / h - higher concentrations can cause ondansetron precipitation);
carboplatin (at a concentration of 0.18–9.9 mg / ml for 10–60 min);
etoposide (at a concentration of 0.14-0.25 mg / ml for 30-60 minutes);
ceftazidime (at a dose of 0.25-2 g, in the form of intravenous bolus injection for 5 minutes); cyclophosphamide (in a dose of 0.1-1 g, in the form of intravenous bolus injection for 5 minutes);
doxorubicin (at a dose of 10-100 mg, in the form of intravenous bolus injection for 5 minutes);
dexamethasone: possibly IV the introduction of 20 mg of dexamethasone slowly for 2-5 minutes Drugs can be administered through a single dropper, with the concentration of dexamethasone sodium phosphate in the solution can be from 32 μg to 2.5 mg / ml, ondansetron - from 8 μg to 1 mg / ml.

Pregnancy and Lactation

Contraindicated in pregnancy and lactation.

Special instructions

In patients who have previously used other selective antagonists of serotonin 5HT3 receptors, hypersensitivity reactions have been observed, while using ondansetron, similar reactions can also develop.

Since ondansetron causes constipation, patients with signs of intestinal obstruction after the use of the drug require regular monitoring.

Infusion solution should be prepared immediately before use. If necessary, the finished infusion solution can be stored until use for a maximum of 24 hours at a temperature of 2-8 ° C.

No protection from light is required during the infusion; diluted injection solution maintains its stability for at least 24 hours in natural light or artificial light.

In the presence of lactose intolerance, it should be borne in mind that the 4 mg tablet contains 59.25 mg of lactose, 8 mg - 118.5 mg, respectively.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

It does not have a sedative effect and does not affect the psychomotor abilities necessary for driving and other mechanisms.