Tropisetron

 

International not patented name

Tropisetron

 

Pharmacotherapeutic group

Serotoninergic preparations, anti-vomiting preparations

 

Composition

Tropisetron hydrochloride (calculated for tropisetron) – 1 g in 1 liter of the preparation.

 

Pharmacologic action

Pharmacodynamics

It blocks the peripheral neurons presynaptic 5-HT3 receptors and the CNS thus the vomiting reflex is blocked. It blocks the vomiting reflex (and the nausea feeling accompanying the same) provoked by chemotherapeutic anti-tumor preparations stimulating the serotonin (5-HT3) throw from the enterochromaffine-like cells in the gastro-intestinal tract mucous membrane as well as the postoperative nausea and vomiting syndrome (PONV). The effect duration is 24 hours allowing the preparation to be taken once a day. It is efficient when used again during the repeated courses of chemotherapy. Unlike a number of other preparations applied for preventing nausea and vomiting tropisetron does not provoke extrapyramidal effects (movements coordination changing manifesting by their volume reduction and tremor). It has an additional direct effect on the CNS 5-HT3 serotonin receptors transmitting impulses to the target cell by n. vagus.

Pharmacokinetics

Tropisetron is absorbed from the gastro-intestinal tract almost completely (more than 95%). The period of half absorption is about 20 minutes in the average.

The tropisetron non-specific fixation on plasma proteins (mostly on alpha1-glicoproteins) is 71%. The distribution volume in adults is from 400 l to 600 l; in children aged 3 – 6 years – about 145 l, in children aged 7 – 15 years – approximately 265 l.

The plasma maximal concentration is achieved within 3 hours. The bioavailability depends on the dose size: when the preparation dose taken is 5 mg it is approximately 60% and increases (up to 100%) when 45 mg of the preparation is taken. The bioavailability and the final period of half elimination significance in children is similar the respective indices observed in healthy volunteers. The tropisetron metabolism is realized through hydroxylating in the indole ring positions 5, 6 or 7 and the subsequent conjugation with glucuronide or sulphate formation and elimination with urine or with bile (the metabolites ratio in the urine and the feces is 5 : 1). The tropisetron metabolites activity concerning the 5-HT3 receptors is reduced significantly and they do not participate in the preparation pharmacologic action realization. The tropisetron metabolism is connected with the genetically determined polymorphism of sparteine/debrisoquine. It is known that about 8% of europeoid persons have a low metabolism of sparteine/debrisoquine.

When tropisetron is prescribed again in doses exceeding 10 mg two times a day the liver enzymes system participating in the tropisetron metabolism may become saturated thus resulting in the plasma tropisetron concentration dose depending increase. In persons metabolizing tropisetron badly appliance of the preparation such doses does not lead to the preparation plasma concentration increase over the tolerable values. In case tropisetron is applied for nausea and vomiting prevention during the anti-tumor chemotherapy for 6 days and more in the dose of 5 mg once a day the tropisetron accumulation has no clinical significance.

The period of half elimination (beta-phase) in persons metabolizing tropisetron quickly is about 8 hours; in persons metabolizing tropisetron badly this value may increase to about 45 hours.

The tropisetron general clearance is about 1 l/min the renal clearance being about 10% of the value. In persons metabolizing tropisetron badly the general clearance reduces to 0.1 – 0.2 l/min the renal clearance index remaining unchanged. The non-renal clearance reduction results in the approximately 4 – 5-fold prolongation of the period of half elimination and in the 5 – 7-fold increase of the area under the curve “concentration – time” (AUC). The maximal concentration value and the distribution volume in such patients do not differ from the corresponding indices of the patients metabolizing tropisetron quickly. The unchanged tropisetron portion eliminated with the urine is larger in patients with the tropisetron metabolism low level than in patients metabolizing tropisetron quickly.

 

Indications for appliance

Preventing nausea and vomiting developing because of anti-tumor chemotherapy.

Stopping nausea and vomiting developing in the postoperative period.

Preventing nausea and vomiting developing after gynecologic intra-abdominal surgeries. When the preparation is prescribed for optimizing the ratio “effect/risk” it should be applied exclusively by the females having data about postoperative nausea and vomiting in the anamnesis.

 

Mode of appliance and dosage regime

Preventing nausea and vomiting developing because of anti-tumor chemotherapy.

Adults. Adults are prescribed tropisetron in form of 6 days courses the dose being 5 mg/24 hours. The preparation is introduced intravenous on the first day short time before the anti-tumor chemotherapy is to be started: in form of an infusion (after the preparation has been diluted) or in form of a slow injection (for not less than 1 minute). When the preparation is to be applied in form of i/v infusions it is diluted by such conventional solutions for infusions as the sodium chloride isotonic solution, Ringer’s solution, 5% glucose solution. Then beginning from the 2nd day till the 6-th day the preparation is taken per os.

When the tropisetron alone intake does not exert a sufficient anti-vomiting effect the preparation therapeutic effect may be enhanced by dexamethasone prescription. The preparation should be taken per os with water in the morning immediately after getting up 1 hour before the meal.

Children. The tropisetron dose recommended for children older 2 years is 0.2 mg/kg; the 24 hours maximal dose is not more than 5 mg. The preparation i/v infusion (after the preparation has been diluted) is recommended on the first day a short time before the anti-tumor therapy is to be started. Then beginning from the 2nd day till the 6-th day the preparation is taken per os.

Tropisetron may prescribed in form of a solution for being taken per os immediately after diluting the necessary quantity of the preparation from the vial by the orange juice or by another beverage in the morning 1 hour before the meal.

Stopping nausea and vomiting developing in the postoperative period.

Adults. A 2 mg of tropisetron i/v infusion (after the preparation has been diluted) or slow injection (for not less than 30 seconds) is recommended. When nausea and vomiting  develop in the postoperative period should be prevented tropisetron should be taken a short time before the narcosis introduction.

 

Special warnings

Each glass vial contains 5 mg of tropisetron in 5 ml of water solution. The solution in the vials is compatible with the following solutions for injecting (1 mg of tropisetron is diluted in 20 ml): glucose 5%; mannitol 10%; Ringer’s solution; sodium chloride 0.9%; potassium chloride 0.3%. The solution in the vials is compatible with the containers for infusions of usual type (made of glass, PVC) and with kits for infusions as well.

Only fresh prepared solutions may be used.

 

Side effects

When the preparation is applied in the recommended doses the undesirable side effect are transitory. When tropisetron is received headache, constipation, dizziness, tiredness, abdominal pain, diarrhea are possible.

As in cases of appliance of other 5-HT3-receptors antagonists hypersensitivity reactions (“reactions of I type”) characterized by one or several of the following symptoms: feeling of blood rash to face and/or a generalized urticaria, feeling of heaviness behind the breast bone, dyspnea, bronchospasm developing acutely, arterial hypertension are rare.

There are publications about very rare cases of collapse, syncope or heart arrest but the causal relation with tropisetron is not determined. Some of those side effects may be provoked by the accompanying therapy or by the basal disease.

 

Contraindications

Hypersensitivity, pregnancy and lactation (breast feeding should be stopped for the period of treatment), childish age younger 2 years.

Appliance during pregnancy and lactation

Tropisetron is contraindicated during pregnancy. Breast feeding should be stopped for the period of treatment.

 

Caution measures

Care should be taken when the preparation is prescribed on the background of a not controlled hypertension, the reactions reduction possibility should be considered too.

 

Interaction with other medicinal preparations

The liver microsomal enzymes inductors (rifampycin, phenobarbital) reduce the blood tropisetron concentration. That is why patients metabolizing tropisetron quickly should receive the preparation larger doses (it is not necessary for patients metabolizing tropisetron slowly). Cytochrome P450 enzymic system inhibitors such as cimetidine influence on the tropisetron plasma levels are insignificant; no need to change the preparation dose in such cases. Studies of tropisetron interaction with preparations for anesthesia were not performed.

The QT interval lengthening was observed in several patients receiving tropisetron in combination with preparations provoking this interval lengthening. At the same time in the same studies it was determined that when tropisetron alone was applied in the therapeutic doses no QT interval lengthening was observed. Nevertheless when prescribing tropisetron and preparations provoking QT interval lengthening care should be taken.

 

Overdosing

Symptoms: In case tropisetron very high doses are prescribed repeatedly visual hallucinations may occur; in patients with preceding arterial hypertension – the arterial pressure may increase.

Treatment: A symptomatic therapy under a permanent control of vital functions and of the patient state is indicated.

 

Dosage form

5 ml vials made of neutral glass. 5 vials in a contour cellular pack.

1 or 2 contour cellular packs in a vial.