Авомит®

General characteristics. Structure:

Active ingredient: 1 mg of a granisetron in the form of a granisetron of a hydrochloride.

Excipients: sodium chloride, citric acid monohydrate, Acidum hydrochloricum to pH 5,3 ± 0,3, sodium hydroxide to pH 5,3 ± 0,3, water for injections.

Pharmacological properties:

Pharmacodynamics. Granisetron is the selection antagonist of the serotoninovy 5-HT3-retseptorov located in the terminations of a vagus nerve and a trigger zone of a bottom of the IV ventricle of a brain (practically does not influence other receptors of serotonin), with the expressed antiemetic effect. Researches showed that at a granisetron low affinity to other types of receptors, including other subtypes of serotoninovy receptors and dopamine D2 receptors. Eliminates the vomiting arising at excitement of a parasympathetic nervous system owing to serotonin release with enterokhromaffinny cells.
 
Granisetron eliminates the nausea and vomiting caused by cytotoxic chemotherapy, radiation therapy and also postoperative nausea and vomiting. Granisetron does not influence concentration of prolactin and Aldosteronum in a blood plasma. Granisetron has no mutagen effect of in vivo and in vitro. At lifelong introduction in high doses increases risk of developing of hepatocellular tumors at animals.

Pharmacokinetics. Distribution. Granisetron is distributed on bodies and fabrics (including plasma and erythrocytes), the average volume of distribution makes 3 l/kg. Communication with proteins of a blood plasma makes about 65%.
 
Metabolism. Biotransformation happens generally in a liver by N-demethylation and oxidation of an aromatic ring to the subsequent conjugation. In vitro of a research showed what кетоконазол inhibits metabolism of a granisetron that assumes participation of an isoenzyme of CYP3A of system of P450 cytochrome. Other in vitro of a research showed what гранисетрон does not influence activity of metabolizing isoenzymes of CYP3A4.

Removal. Kidneys in not changed look remove, on average, 12% and in the form of metabolites of 47% of a dose. The remained 41% of a dose are removed by intestines in the form of metabolites.
 
The elimination half-life makes 9 hours, with wide individual variability. Concentration of a granisetron in plasma poorly correlate with its antiemetic action. The therapeutic effect is observed even then when гранисетрон it is not found in plasma any more. The pharmacokinetics of a granisetron keeps linear character in the range of the doses, to 2,5 and 4 times exceeding recommended respectively.
 
Pharmacokinetics at special groups of patients. At patients of advanced age pharmacokinetic parameters after single intravenous administration did not differ from those at patients of young age.
 
At patients with a heavy renal failure pharmacokinetic parameters after single intravenous administration did not differ from those at patients with normal renal function.
 
At patients with the liver failure caused by neoplastic changes, the general plasma clearance makes about a half in comparison with patients with normal function of a liver. Despite these changes, dose adjustment is not required.
 
At children: at introduction of a granisetron in a dose of 20 mkg/kg of body weight clinically significant difference in pharmacokinetics at adults and children was absent.

Indications to use:

- Prevention and treatment of nausea and vomiting when carrying out cytostatic chemotherapy at adults and children are more senior than 2 years;
 
- prevention and treatment of nausea and vomiting when performing radiation therapy at adults;
 
- treatment of postoperative nausea and vomiting at adults.

Route of administration and doses:

The drug Avomit® is administered intravenously. Adults. Nausea and vomiting at cytostatic and/or radiation therapy. With the preventive purpose:
 
- patients with body weight more than 50 kg: one bottle (3 mg / 3 ml) is parted in 20-50 ml of infusion solution and entered intravenously kapelno within 5 minutes or in not divorced look intravenously struyno within 30 seconds prior to the beginning of chemotherapy or radiation therapy.

- to patients with body weight less than 50 kg: the drug Avomit® is administered in a dose of 20-40 mkg/kg.
 
In most cases single use of the drug Avomit® is enough for control of nausea and vomiting within 24 hours.
 
With the medical purpose:
 
- if necessary in addition to preventive administration of the drug Avomit® it is possible to carry out 2 additional infusions (on 5 minutes), everyone in a dose no more than 3 mg, with an interval not less than 10 minutes within 24 hours. The maximum daily dose should not exceed 9 mg.
 
Therapy of postoperative nausea and vomiting: once 1 mg intravenously (without cultivation by solution for infusions) slowly (not less than 30 seconds). There is an experience of use of drugs of a granisetron in a dose to 3 mg at the patients who transferred an elective operative measure under anesthesia.
 
Children from 2 to 16 years. Nausea and vomiting at cytostatic chemotherapy. With the preventive purpose:
 
- 20 mkg/kg in 10-30 ml of solution for infusions within 5 minutes intravenously kapelno prior to cytostatic therapy.
 
With the medical purpose:
 
- if necessary in addition to preventive administration of the drug Avomit® it is possible to carry out no more than 2 additional infusions (on 5 minutes), everyone in a dose of 20 mkg/kg, with an interval not less than 10 minutes. The maximum daily dose should not exceed 60 mkg/kg.

Postoperative nausea and vomiting. There are not enough data to recommend гранисетрон for prevention and treatment of postoperative nausea and vomiting at children.
 
Nausea and vomiting at radiation therapy. There are not enough data to recommend гранисетрон for prevention and treatment of nausea and vomiting at radiation therapy at children.
 
Patients with a renal or liver failure, elderly patients. Dose adjustment is not required.

Preparation of solution for intravenous infusion. For receiving solution of the drug Avomit® for intravenous drop administration use the following infusion solutions: 0,9% solution of sodium of chloride, 0,18% solution of sodium of chloride and 4% solution of a dextrose, 5% dextrose solution, Hartman's solution, solution of sodium of a lactate or solution of Mannitolum. Use of other solutions is not allowed. Solution for infusions is recommended to be entered right after its preparation. Ready solution is stable within 24 hours at the room temperature (15-25 °C) at normal room lighting. Intravenous administration of drug without cultivation is allowed.

Features of use:

As Avomit® can oppress motility of intestines, patients with signs of partial obstruction of intestines after administration of the drug Avomit® have to be under observation of the doctor.
 
Granisetron is safe for use at elderly and patients with a renal or liver failure.

Granisetron at intravenous administration in a dose to 200 mkg/kg does not exert clinically significant impact on the electroencephalogram or results of psychometric tests. As well as at use of other 5-HT3 antagonists, at therapy by drugs of a granisetron it was reported about changes of the ECG parameters, including cases of increase in an interval of QT. These changes were insignificant and, as a rule, had no clinical value, in particular had no signs of proaritmogenny action. However at patients with already existing arrhythmias or diseases which are followed by disturbance of cordial conductivity observed changes of the ECG parameters at therapy granisetrony can lead to clinically significant effects. In this regard the patients with the accompanying heart diseases who are receiving cardiotoxic chemotherapy and/or having the accompanying electrolytic disturbances should show care at purpose of drug.
 
It was reported about cases of development of cross sensitivity between antagonists of serotoninovy 5-HT3-retseptorov. It is necessary to watch a condition of the patient in case of clinical need of simultaneous use of a granisetron with other serotonergic drugs.

Influence on ability to manage vehicles and mechanisms. Data on influence of the drug Avomit® on ability to driving of the vehicle are absent. However it is necessary to remember possible emergence of drowsiness and other undesirable phenomena from a nervous system at therapy by the drug Avomit®. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

In most cases side effects at use of a granisetron were not heavy and were transferred by patients without therapy interruption. Hard cases of manifestation of hypersensitivity are celebrated rare and sometimes (for example, an anaphylaxis).
 
Frequency of the side reactions given below was defined according to the following criteria: very often (≥ 10%), it is frequent (≥ 1% and <10%), infrequently (≥ 0,1% and <1%), is rare (≥ 0,01% and <0,1%), is very rare (<0,01%), including separate messages.
 
Disturbances from a nervous system: very often - a headache; infrequently - a serotoninovy syndrome (including change of a mental state, vegetative dysfunction and disturbances from nervous and muscular systems); seldom - alarm, concern, dizziness.
 
Disturbances from digestive tract: very often - a lock; seldom - heartburn, change of flavoring feelings.
 
Disturbances from a liver and biliary tract: often - increase in activity of "hepatic" transaminases (ALT, ACT) usually within their normal values.

Disturbances from immune system: infrequently - hypersensitivity reactions, including an anaphylaxis and urticaria.
 
Disturbances from heart and vessels: infrequently - increase in an interval of QT.

Disturbances from outside knives and hypodermic fabrics: infrequently - skin rash; very seldom - the face edema swelled/.
 
General frustration and disturbances and injection site: very seldom - a grippopodobny syndrome (including fever and a fever).
 
Post-marketing observation
 
Disturbances from a nervous system: sleeplessness, drowsiness, weakness.

Disturbances from the alimentary system: abdominal pain, diarrhea, meteorism, dyspepsia.
 
Disturbances from immune system: hyperthermia, bronchospasm, itch.

Disturbances from cardiovascular system: arrhythmia, stethalgia, decrease or increase in arterial pressure.

Interaction with other medicines:

Granisetron does not influence activity of an isoenzyme of CYP3A4 (which is responsible for metabolism of some narcotic analgetics). Efficiency of a granisetron can be increased by intravenous administration of dexamethasone (8-20 mg) prior to the beginning of chemotherapy.
 
In vitro of a research showed what кетоконазол inhibits metabolism of a granisetron that assumes participation of an isoenzyme of CYP3A4. Special researches on interaction with means for the general anesthesia were not conducted, but гранисетрон it is well transferred at co-administration with similar drugs and narcotic analgetics.
 
At induction of liver enzymes phenobarbital observed increase in clearance of a granisetron (at in introduction) approximately on a quarter.
 
Ne it is revealed interactions at co-administration with the benzodiazepines, tranquilizers, antiulcerous drugs and cytostatic medicines causing vomiting.
 
At the patients receiving the accompanying therapy by drugs with the known ability to prolong an interval of QT and/or aritmogenny activity observed changes on an ECG at therapy granisetrony can lead to clinically significant effects.
 
As well as when using other antagonists of serotoninovy 5-HT3-retseptorov, at use of a granisetron in a combination with other serotonergic drugs cases of development of a serotoninovy syndrome (including change of a mental state, vegetative dysfunction and disturbances were noted from nervous and muscular systems).

Contraindications:

- Hypersensitivity to a granisetron or any of drug components in the anamnesis;
 
- reactions of hypersensitivity to other selection antagonists of serotoninovy 5HT3-receptors in the anamnesis;
 
- breastfeeding period;

- children's age up to 2 years (there are no data on efficiency and safety).

With care:
- partial intestinal obstruction;
 
- pregnancy (to women during pregnancy гранисетрон it is appointed only in that case when the estimated advantage for mother exceeds potential risk for a fruit; гранисетрон has no teratogenic effect on animals, researches at pregnant women were not conducted);
 
- associated diseases of heart, cardiotoxic chemotherapy and/or the accompanying electrolytic disturbances.

Overdose:

Specific antidotes for a granisetron do not exist. In case of overdose, a symptomatic treatment. Use of 38 mg of a granisetron in the form of a single intravenous injection was not followed by development of serious undesirable effects, except a slight headache.

Storage conditions:

In the dry place protected from light at a temperature not above 30 °C. Not to freeze. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

1 mg / 1 ml and 3 mg / 3 ml (1 mg/ml) in the bottles of neutral glass which are hermetically corked by rubber bungs with a running in caps aluminum. On 1 or 5 bottles (1 ml of a concentrate) in a blister strip packaging with the application instruction in a pack from a cardboard. On 1 bottle (3 ml of a concentrate) with the application instruction in a pack from a cardboard. On 5 bottles (3 ml of a concentrate) in a blister strip packaging with the application instruction in a pack from a cardboard.