medicalmeds.eu Medicines The antiemetic drug of the central action blocking serotoninovy receptors. Zofran

Zofran

Препарат Зофран. Glaxo Operetaions UK Limited (Глаксо Оперейшнс ЮК Лимитед) Великобритания

Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain

Code of automatic telephone exchange: A04AA01

Release form: Liquid dosage forms. Solution for injections.

General characteristics. Structure:

Solution for in/in and introductions in oil transparent, colourless, almost free from foreign inclusions.

Active ingredient: an ondansetrona of a hydrochloride a dihydrate of 2.5 mg 5 mg that corresponds to the maintenance of an ondansetron of 2 mg 4 mg

Excipients: citric acid monohydrate, sodium citrate, sodium chloride, water for and.

Solution for in/in and introductions in oil transparent, colourless, almost free from foreign inclusions.

Active ingredient: an ondansetrona of a hydrochloride a dihydrate of 2.5 mg 10 mg that corresponds to the maintenance of an ondansetron of 2 mg 8 mg

Excipients: citric acid monohydrate, sodium citrate, sodium chloride, water for and.

Pharmacological properties:

Antiemetic drug, the selection antagonist of serotoninovy 5HT3-receptors.

Ondansetron is a strong high-selection antagonist of 5HT3-receptors. The mechanism of suppression of nausea and vomiting is definitely not known. At radiation therapy and use of chemotherapeutic drugs release of the serotonin (5HT) in a small intestine causing an emetic reflex through activation of 5HT3-receptors and initiation of the afferent terminations of a vagus nerve is possible. Ondansetron blocks initiation of this reflex. Activation of the afferent terminations of a vagus nerve, in turn, can cause emission of 5HT in the back field of a bottom of the fourth ventricle (area postrema), and, therefore, start an emetic reflex via the central mechanism. Thus, action of an ondansetron for suppression of nausea and vomiting, provoked by cytotoxic chemotherapy and radiotheraphy, most likely, is carried out thanks to antagonistic impact on 5HT3-receptors of the neurons located both on the periphery and in TsNS.

The mechanism of effect of drug when stopping postoperative nausea and vomiting is not clear probably it is similar to that when stopping himio-and the radio induced nausea and vomiting.

Ondansetron does not influence concentration of prolactin in a blood plasma.

Pharmacokinetics. Pharmacokinetic parameters of an ondansetron do not change at its repeated introduction.

Absorption

Ondansetron possesses identical system influence at in oil and in introduction.

Distribution

Ondansetron has moderate ability to contact proteins of plasma (70-76%). Distribution of an ondansetron is similar at in oil and in introduction at adults. Vd in equilibrium state makes about 140 l.

Metabolism

Ondansetron is metabolized, mainly, in a liver with the participation of several enzymes. Lack of CYP2D6 enzyme (polymorphism sparteine / дебризохинового type) does not exert impact on pharmacokinetics of an ondansetron.

Removal

Ondansetron is brought from a system blood-groove, generally by means of metabolism in a liver. Less than 5% of the entered dose are removed in not changed view with urine. T1/2 of an ondansetron as after in oil, and later in/in introductions makes about 3 h.

Pharmacokinetics in special clinical cases

The pharmacokinetics of an ondansetron depends on a sex of patients. At women the smaller system clearance and Vd (indicators are corrected on body weight), than at men are noted.

In clinical trial children aged from 1 up to 24 months (51 patients) received ондансетрон in a dose 0.1 mg/kg or 0.2 mg/kg to surgical intervention. At patients aged from 1 up to 4 months the clearance was about 30% less, than at patients aged from 5 up to 24 months, but is comparable to this indicator at patients aged from 3 up to 12 years (with correction of indicators depending on body weight). T1/2 in group of patients at the age of 1-4 m averaged 6.7 h; in age groups of 5-24 months and 3-12 years - 2.9 h. Aged from 1 up to 4 months of dose adjustment it is not required from patients as it is applied single in/in introduction of an ondansetron to treatment of postoperative nausea and vomiting at this category of patients. Distinctions of pharmacokinetic parameters partially are explained by higher Vd at patients aged from 1 up to 4 months.

In a research at children at the age of 3-12 years (21 patients) which were exposed to planned surgical interventions under the general anesthesia, absolute values of clearance and Vd of an ondansetron after single in/in introductions in a dose of 2 mg (from 3 to 7 years) or 4 mg (from 8 to 12 years) were lowered in comparison with values at adults. Both parameters increased linearly depending on body weight, at patients at the age of 12 years these values approached values at adults. At correction of values of clearance and Vd depending on body weight these parameters were close in various age groups. Calculation of a dose taking into account body weight (0.1 mg/kg, as much as possible to 4 mg) compensates these changes and system exposure of an ondansetron at children.

The population pharmacokinetic analysis at 74 patients aged from 6 up to 48 months to which in/in it was entered ондансетрон in a dose of 0.15 mg/kg each 4 h in number of 3 doses for the stopping of nausea and vomiting caused by chemotherapy and at 41 patients aged from 1 up to 24 months after surgical interventions to which it was entered ондансетрон in a single dose of 0.1 mg/kg or 0.2 mg/kg was carried out. On the basis of pharmacokinetic parameters at this group for patients aged from 1 up to 48 months introduction of an ondansetron in/in in a dose of 0.15 mg/kg each 4 h in number of 3 doses has to lead to achievement of system exposure (AUC) comparable to that which is observed at use of drug in the same doses at children aged from 5 up to 24 months at surgical interventions, and also in the previous researches at children with oncological diseases (aged from 4 up to 18 years) and at surgical intervention (aged from 3 up to 12 years).

The researches conducted at patients of advanced age showed increase in T1/2 of an ondansetron, weak, clinically insignificant, dependent on age.

At patients with moderate renal failures (clearance of creatinine of 15-60 ml/min.) at in introduction of an ondansetron both the system clearance, and Vd of an ondansetron what small and clinically insignificant increase in its T1/2 is result of are reduced (to 5.4 h). The pharmacokinetics of an ondansetron at it in introduction remained almost invariable with the patients with heavy renal failures who are on a chronic hemodialysis (researches were conducted in breaks between hemodialysis sessions).

At patients with heavy abnormal liver functions the system clearance of an ondansetron with increase in T1/2 up to 15-32 h sharply decreases.

Indications to use:

— the prevention and elimination of nausea and vomiting, caused by cytostatic chemotherapy or radiotheraphy;

— prevention and elimination of postoperative nausea and vomiting.

Route of administration and doses:

The nausea and vomiting caused by chemotherapy and/or radiotheraphy

The choice of the mode of dosing is defined by an emetogennost of antineoplastic therapy.

Adults

At moderate emetogenny chemotherapy or radiotheraphy the drug is administered in a dose 8 mg in/in (slowly) or in oil just before the beginning himio-or radiotheraphy.

To the patients receiving vysokoemetogenny chemotherapy, for example, Cisplatinum in high doses, it is possible to appoint Zofran® in the form of single in/in or injections in oil in a dose of 8 mg just before carrying out chemotherapy. Зофран® in a dose from 8 mg to 32 mg it is necessary to enter only in the way to infusions after dissolution of drug into 50-100 ml 0.9% of solution of sodium of chloride or in other compatible infusion solution within 15 min. and more. Other way consists in Zofran's introduction in a dose of 8 mg slowly in/in or in oil just before chemotherapy with the subsequent purpose of two injections of drug in/in or in oil 8 mg in a dose with an interval of 2-4 h or use of continuous infusion of drug with a speed of 1 mg/h during 24 h.

In case of performing vysokoemetogenny antineoplastic therapy Zofran's efficiency can be increased additional single in/in administration of dexamethasone of sodium of phosphate in a dose of 20 mg prior to the beginning of chemotherapy. Peroral or rectal dosage forms of Zofran are recommended for prevention of the delayed or proceeding vomiting after the first days after carrying out chemotherapy.

Children and teenagers aged from 6 months up to 17 years

To children with body surface area less than 0.6 sq.m enter an initial dose of 5 mg/sq.m in/in just before carrying out chemotherapy, with the subsequent reception of Zofran inside in a dose of 2 mg (in the form of syrup) in 12 h. Within 5 days after a course of treatment therapy is continued, accepting Zofran® inside in a dose of 2 mg 2

To children with the surface area of a body of 0.6-1.2 sq.m of Zofran® enter in/in once in a dose of 5 mg/sq.m just before carrying out chemotherapy, with the subsequent administration of drug inside in a dose of 4 mg in 12 h. Zofran's reception inside in a dose of 4 mg 2 can be continued within 5 days after carrying out a course of chemotherapy.

To children with body surface area more than 1.2 sq.m enter an initial dose of 8 mg in/in just before carrying out chemotherapy, with the subsequent administration of drug inside in a dose of 8 mg in 12 h. Zofran's reception inside in a dose of 8 mg 2 can be continued within 5 days after carrying out a course of chemotherapy.

As an alternative to children at the age of 6 months Zofran® is also more senior enter in/in once in a dose of 0.15 mg/kg (no more than 8 mg) just before carrying out chemotherapy. This dose can be entered repeatedly each 4 h, in total no more than three doses in total. Zofran's reception inside in a dose of 4 mg 2 can be continued within 5 days after carrying out a course of chemotherapy. Doses should not exceed recommended for adults.

Other categories of patients

Dose adjustment of Zofran is not required from patients of advanced age.

Dose adjustment of Zofran is not required to patients with a renal failure.

At abnormal liver functions the clearance of an ondansetron is significantly reduced, T1/2 is increased at patients with abnormal liver functions of moderate and heavy degree. The daily dose of Zofran should not exceed 8 mg.

At patients with the slowed-down metabolism of sparteine and T1/2 debrisoquine of an ondansetron it is not changed. Therefore, at repeated introduction of Zofran its concentration in plasma will not differ from that in the general population. Therefore it is not required to such patients of correction of a daily dose or frequency of reception of an ondansetron.

Nausea and vomiting in the postoperative period

Adults

For prevention of nausea and vomiting in the postoperative period it is recommended single in oil or slow in/in Zofran's injection in a dose of 4 mg during an introduction anesthesia.

For treatment of nausea and vomiting in the postoperative period of Zofran® enter once in a dose 4 mg in oil or slowly in / century.

Children and teenagers aged from 1 month up to 17 years

For prevention of nausea and vomiting in the postoperative period at the children who are exposed to an operative measure under the general anesthesia, Zofran® it is possible to appoint in a dose 0.1 mg/kg (as much as possible to 4 mg) in the form of slow in/in an injection to, in time either after an introduction anesthesia or after operation.

For stopping of the nausea and vomiting which developed in the postoperative period it is recommended slow in/in Zofran's injection in a dose of 0.1 mg/kg (as much as possible to 4 mg).

Other categories of patients

There is a limited experience of use of Zofran for prevention and stopping of postoperative nausea and vomiting for patients of advanced age though Zofran® is well transferred by patients 65 years, receiving chemotherapy are more senior.

Dose adjustment of Zofran is not required to patients with a renal failure.

Patients with slow metabolism of sparteine/debrisoquine

At patients with slow metabolism of sparteine and T1/2 debrisoquine of an ondansetron it is not changed. Therefore, at repeated introduction of Zofran its concentration in plasma will not differ from that in the general population. Therefore it is not required to such patients of correction of a daily dose or frequency of reception of an ondansetron.

Rules of preparation of solutions and use of drug

The following solutions can be applied to cultivation of injection solution: 0.9% solution of sodium of chloride, 5% dextrose solution, Ringer's solution, 10% solution of Mannitolum, 0.3% solution of potassium of chloride and 0.9% solution of sodium of chloride, 0.3% solution of potassium of chloride and 5% dextrose solution.

Infusion solution has to be prepared just before use. In case of need ready infusion solution can be stored before use as much as possible during 24 h at a temperature from 2 ° up to 8 °C.

During performing infusion of protection against light it is not required; divorced injection solution keeps the stability at least during 24 h at natural light or normal lighting.

Features of use:

There are messages on emergence of reactions of hypersensitivity to an ondansetron for the patients having in the anamnesis hypersensitivity to other selection antagonists of 5HT3-receptors.

As it is known what ондансетрон increases time of passing of contents on a large intestine, in case of use of drug for patients with symptoms of subacute intestinal impassability regular observation is necessary.

Зофран® it is not necessary to enter in one syringe or in one infusion solution with other medicines.

Use in pediatrics

Now there are limited these uses of an ondansetron for children is aged younger 1 month.

Influence on ability to driving of motor transport and to control of mechanisms

Зофран® does not possess sedation and does not influence ability of patients to manage vehicles or to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Determination of frequency of side reactions: very often (≥1/10), it is frequent (≥1/100 and <1/10), sometimes (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1000), is very rare (<1/10 000), including separate messages.

Allergic reactions: seldom - reactions of immediate hypersensitivity, in some cases heavy degree, including an anaphylaxis.

From a nervous system: very often - a headache; sometimes - spasms, motive frustration (including extrapyramidal symptoms, such as dystonia, okulogirny crisis / spasm of a look / and dyskinesia) in the absence of resistant clinical effects; seldom - dizziness during bystry in/in introductions.

From an organ of sight: seldom - passing visual disturbances (the obscured sight), mainly, in time in/in introductions; very seldom - a tranzitorny blindness, mainly, in time in/in introductions. The majority of cases of a blindness were safely resolved within 20 min. Most of patients received the chemotherapeutic drugs containing Cisplatinum. In certain cases the tranzitorny blindness was cortical genesis.

From cardiovascular system: sometimes - the arrhythmia, the thorax pain which both is followed, and which is not followed by decrease in a segment ST, bradycardia, decrease in the ABP; often - feeling of heat or inflows; very seldom - tranzitorny changes of an ECG, including lengthening of an interval of QT, preferential, at in introduction.

From the alimentary system: often - a lock; sometimes - asymptomatic increase in hepatic tests (it was generally observed at the patients receiving chemotherapy Cisplatinum).

Local reactions: often - local reactions in the place in/in introductions.

Others: sometimes - a hiccups.

Interaction with other medicines:

There are no data on what ондансетрон induces or inhibits metabolism of other drugs which are often appointed in a combination with it.

According to special researches it is established what ондансетрон does not interact with ethanol, temazepam, furosemide, tramadoly and propofoly.

Ondansetron is metabolized by several isoenzymes of system of P450 cytochrome (CYP3A4, CYP2D6 and CYP1A2). Due to the variety of the isoenzymes capable to metabolize ондансетрон, the inhibition of isoenzymes or reduction of activity of one of isoenzymes (for example, at genetic deficit of CYP2D6) is usually compensated by other isoenzymes therefore changes of the general clearance of an ondansetron either are absent, or are insignificant and practically do not demand dose adjustment.

The patients receiving the powerful inductors CYP3A4 (Phenytoinum, carbamazepine and rifampicin), in blood had a lowered concentration of an ondansentron.

There are data of small researches indicating what ондансетрон can reduce analgeziruyushchy effect of a tramadol.

Pharmaceutical interaction

Зофран® in concentration of 16 mkg/ml and 160 mkg/ml (that corresponds to 8 mg / 500 ml and 8 mg / 50 ml respectively) pharmaceutical it is compatible and it can be entered through a Y-shaped injector in/in kapelno jointly with the following medicines:

— Cisplatinum (in concentration to 0:48 mg/ml) during 1-8 h;

— 5-ftoruratsit (in concentration to 0.8 mg/ml with a speed of 20 ml/h - higher concentration of a 5-ftoruratsil can cause Zofran's loss in a deposit);

— карбоплатин (in concentration of 0.18-9.9 mg/ml) within 10-60 min.;

— этопозид (in concentration of 0.144-025 mg/ml within 30-60 min.);

— a ceftazidime (in a dose of 0.25-2 g, in a look in a bolyusny injection within 5 min.);

— cyclophosphamide (in a dose of 0.1-1 g, in a look in a bolyusny injection within 5 min.);

— doxorubicine (in a dose of 10-100 mg, in a look in a bolyusny injection within 5 min.);

— dexamethasone (20 mg of dexamethasone slowly, within 2-5 min. are possible in/in introduction). Medicines can be entered through one dropper, at the same time in solution of concentration of dexamethasone of sodium of phosphate can make from 32 mkg to 2.5 mg/ml, Zofran - from 8 mkg to 1 mg/ml.

Contraindications:

— pregnancy;

— lactation (breastfeeding);

— hypersensitivity to drug components.

With care it is necessary to use drug at patients with disturbances of a cordial rhythm and conductivity, the patients receiving antiarrhytmic means and beta adrenoblockers and patients with considerable electrolytic disturbances (very seldom at in Zofran's introduction tranzitorny changes of an ECG, including lengthening of an interval of QT were registered).

Use of the drug ZOFRAN® at pregnancy and feeding by a breast

Drug is contraindicated to use at pregnancy and in the period of a lactation (breastfeeding).

Use at abnormal liver functions

At purpose of drug to patients with abnormal liver functions the daily dose of drug should not exceed 8 mg.

Use at renal failures

At a renal failure special dose adjustment, frequency of reception or a route of administration is not required.

Use for elderly patients

It is not required from patients of advanced age of change of the mode of dosing.

Use for children

Use according to indications and in the doses considering age of the patient. Now there are limited these uses of an ondansetron for children is aged younger 1 month.

Overdose:

Now there are not enough data on overdose of an ondansetron.

Symptoms: in the majority of observed cases symptoms of overdose matched the side reactions arising at administration of drug of Zofran® in the recommended doses.

Treatment: there is no specific antidote for Zofran therefore at suspicion on overdose it is recommended to carry out a symptomatic and maintenance therapy.