Zofran syrup

General characteristics. Structure:

Syrup transparent, from colourless till light yellow color, with a strawberry smell.

5 mg operating a veshchestvo:ondansetrona of a hydrochloride a dihydrate that corresponds to the maintenance of an ondansetron of 4 mg

Excipients: citric acid - 25 mg, citrate sodium a dihydrate - 7.5 mg, Natrium benzoicum - 10 mg, sorbitol - 3000 mg, fragrance strawberry - 15 mg, the water purified - to 5 ml.

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. Absorption

After intake ондансетрон it is completely absorbed from a GIT and is exposed to effect of "the first passing" through a liver. Cmax is reached approximately in 1.5 h after reception. Bioavailability increases at a concomitant use of food a little, but does not change at reception of antacids.

After rectal administration ондансетрон is defined in plasma in 15-60 min. Concentration of active agent increases linearly, Cmax is reached approximately in 6 h after introduction and makes 20-30 ng/ml. Decrease in concentration in plasma happens to smaller speed, than after administration of drug inside (owing to the continuing absorption). Absolute bioavailability makes 60% and does not depend on a floor.

Distribution

Distribution of an ondansetron is identical at intake, in oil and in introduction; Vd at achievement of an equilibrium state — about 140 l. Linkng with proteins of plasma — 70-76%.

Pharmacokinetic parameters of an ondansetron do not change at its repeated use inside, parenterally or rektalno.

Metabolism

From a system blood-groove ондансетрон it eliminirutsya mainly as a result of metabolism in a liver with the participation of several fermental systems.

At use in the doses exceeding 8 mg, the content in blood of an ondansetron increases disproportionately since at reception in high doses reduction of his metabolism at "the first passing" through a liver is inside possible.

Lack of CYP2D6 enzyme (polymorphism of a debrisokvin) does not influence pharmacokinetics of an ondansetron.

Removal

In not changed view with urine less than 5% of the entered dose are removed. T1/2 after intake, in oil and in/in introductions makes about 3 h.

T1/2 after rectal administration is 6 h.

Pharmacokinetics in special clinical cases

Distribution of an ondansetron depends on a sex of patients. So, at women at administration of drug the high speed and extent of absorption of an ondansetron, and also decrease in system clearance and Vd is inside noted.

At patients with KK of 15-60 ml/min. both the system clearance, and Vd of an ondansetron what small and clinically insignificant increase in T1/2 is result of are reduced (to 5.4 h). The pharmacokinetics of an ondansetron practically does not change at the patients with a heavy renal failure who are on a hemodialysis.

At patients with a heavy abnormal liver function the system clearance of an ondansetron sharply decreases, as a result of it its T1/2 increases (to 15-32 h), and bioavailability at oral administration reaches 100% owing to decrease in presistemny metabolism.

Researches at healthy volunteers of advanced age showed increase in bioavailability and T1/2, insignificant, clinically insignificant, dependent on age, which can reach 5 h.

When studying action of an ondansetron at children it turned out that after drug, single in/in introductions, in a dose of 2 mg (children at the age of 3-7 years) or 4 mg (children of 8-12 years) absolute values of clearance and Vd were lowered, at the same time the size of change depended on age. So, at children at the age of 12 years the clearance made 300 ml/min., and children at the age of 3 years have 100 ml/min., Vd - 75 l and 17 l respectively. Dose adjustment taking into account the body weight of patients (0.1 mg/kg, as much as possible to 4 mg) compensates these changes and normalizes system exposure of an ondansetron at children.

Experience of use of Zofran for patients of advanced age and at patients with a renal failure is limited in/in and in the peroral ways of introduction, however it is possible to assume that it when using drug in the form of T1/2 suppositories at such patients will not differ from T1/2 at healthy volunteers as the speed of removal of an ondansetron at administration of suppositories does not depend on system clearance.

Indications to use:

— the prevention and elimination of nausea and vomiting, caused by carrying out cytostatic himio-or radiotheraphy;

— the prevention and elimination of nausea and vomiting in the postoperative period.

Route of administration and doses:

Nausea and vomiting at cytostatic chemotherapy or radiation therapy

Adults

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

At moderate emetogenny chemotherapy or radiation therapy drug appoint in a dose 8 mg (10 ml of syrup) for 1-2 h prior to performing the main therapy with the subsequent reception of 8 more mg in 12 h.

At vysokoemetogenny chemotherapy (for example, high doses of Cisplatinum) the recommended dose makes 24 mg (30 ml of syrup) along with phosphate sodium dexamethasone reception inside in a dose of 12 mg for 1-2 h prior to carrying out chemotherapy.

For prevention of the late or long vomiting arising in 24 h after himio-or radiation therapy, it is necessary to continue Zofran's reception in a dose of 8 mg (10 ml) 2 within 5 days.

Children and teenagers aged from 6 months up to 17 years

The drug Zofran® dose at children and teenagers is calculated on the basis of the surface area or body weight.

Зофран® usually enter in the form of solution for injections once in/in just before the beginning of chemotherapy with the subsequent reception of Zofran inside in the form of syrup in 12 h. Reception of Zofran® syrup should be continued within 5 days after chemotherapy.

Table 1. Calculation of a dose on the basis of body surface area at children aged from 6 months up to 17 years for the treatment of nausea and vomiting caused by chemotherapy

 
                Put surface area 1                    Day 2-6
bodies
<0.6 sq.m             of 5 mg/sq.m in/in + 2 mg of syrup on      2 mg of syrup each 12 h
                       pro-procession of 12 h 
≥ 0.6 sq.m to ≤1.2  sq.m 5 mg/sq.m in/in + 4 mg of syrup on      4 mg of syrup each 12 h
                       pro-procession of 12 h
> 1.2 sq.m of 5 mg/sq.m in/in
or 8 mg in/in +       8 mg of syrup after 12 h     8 mg of syrup each 12 h

Table 2. Calculation of a dose on the basis of body weight at children aged from 6 months up to 17 years for the treatment of nausea and vomiting caused by chemotherapy

Body weight                   Put 1                    Day 2-6
≤ 10 kg       To 3 doses on 150 mkg/kg each 4 h  2 mg of syrup each 12 h
> 10 kg       To 3 doses on 150 mkg/kg each 4 h  4 mg of syrup each 12 h

Nausea and vomiting in the postoperative period

Adults for prevention of nausea and vomiting in the postoperative period are recommended to appoint Zofran® in a dose of 16 mg (20 ml of syrup) for 1 h before carrying out an anesthesia. For stopping of postoperative nausea and vomiting apply Zofran® in the form of solution to injections (use of this dosage form is caused by a condition of the patient in the postoperative period).

To children aged from 6 months up to 17 years for prevention and stopping of postoperative nausea and vomiting of Zofran® appoint in a look in/in an injection (use of this dosage form is caused by a condition of the patient in the postoperative period).

Other categories of patients

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

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

At patients with abnormal liver functions of moderate and heavy degree the clearance of an ondansetron is significantly reduced, T1/2 is increased. The daily dose of drug should not exceed 8 mg (10 mg of syrup).

Correction of a daily dose or frequency of reception of an ondansetron is not required to patients with the slowed-down sparteine/debrisoquine metabolism.

Features of use:

In some cases at the persons having in the anamnesis hypersensitivity to other antagonists of serotoninovy 5HT3-receptors allergic reactions to an ondansetron are noted.

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.

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 (a small tortoiseshell, a bronchospasm, a laryngospasm, a Quincke's disease), in some cases heavy degree, including an anaphylaxis.

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

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: infrequently - 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 (including ventricular tachycardia like "pirouette").

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

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.

Data on deep arterial hypotension and loss of consciousness are obtained during use of an ondansetron with Apomorphini Hydrochloridum, considering it, this combination is contraindicated.

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.

Contraindications:

— pregnancy;

— lactation (chest feedings);

— children's age up to 6 months;

— simultaneous use with Apomorphinum;

— 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; with risk of development or already available lengthening of an interval of QT; an inborn syndrome of the extended QT interval; to the patients accepting other medicines which lead to lengthening of an interval of QT; with reaction of hypersensitivity to other antagonists of 5HT3-receptors.

 

Drug ZOFRAN® use syrup 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

Irrespective of a way of introduction, it is not required from elderly people of change of the mode of dosing.

 

Use for children

Drug in the form of suppositories rectal is not intended for use udety.

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.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity – 3 years.

Issue conditions:

According to the recipe

Packaging:

50 ml - bottles of dark glass (1) complete with a measured spoon - packs cardboard.