Kitril

General characteristics. Structure:

Active agent: гранисетрон 1 mg (in the form of a granisetron of a hydrochloride of 1.12 mg);

Excipients: sodium chloride – 9.0 mg, citric acid monohydrate – 2.0 mg, Acidum hydrochloricum, sodium hydroxide – q.s. to рН 5.3 (±0.3), water for injections to 1 ml.

Pharmacological properties:

Pharmacodynamics. Granisetron is the selection antagonist of the 5-gidroksitriptaminovy (5-HT3) receptors located in the terminations of a vagal nerve and a trigger zone of a bottom of the IV cerebral cavity (practically does not influence other receptors of serotonin), with the expressed antiemetic effect. Researches showed that at the drug Kitril® low affinity to other types of receptors, including 5-HT and dopamine D2 receptors. Eliminates the vomiting arising at excitement of a parasympathetic nervous system owing to serotonin release by enterokhromaffinny cells.
Китрил® eliminates the nausea and vomiting caused by cytotoxic chemotherapy, radiation therapy and also postoperative nausea and vomiting.
Китрил® does not influence concentration of prolactin and Aldosteronum in a blood plasma.
Китрил® 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. Китрил® it is distributed on bodies and fabrics, the average volume of distribution makes 3 l/kg. It is distributed in plasma and in erythrocytes. Communication with proteins of 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 drug Kitril® metabolism that assumes participation of an isoenzyme 3A of system of P450 cytochrome. Other in vitro of a research showed that Kitril® does not influence activity of metabolizing enzymes of a subfamily 3A4 of system of P450 cytochrome.

Removal. Kidneys in not changed look remove on average 12% and in the form of metabolites of 47% of a dose. The remained 41% are removed by intestines in the form of metabolites.
The elimination half-life at intravenous administration makes 9 hours, with wide individual variability.
Concentration of a granisetron in plasma not accurately 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 at intravenous administration 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 level of 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 therapy of nausea and vomiting when carrying out cytostatic chemotherapy at adults and children are more senior than 2 years.
Prevention and therapy of nausea and vomiting when performing radiation therapy at adults.
Therapy of postoperative nausea and vomiting at adults.

Route of administration and doses:

Intravenously.
Standard mode of dosing
Adults
Cytostatic chemotherapy (prevention)
Patients with body weight more than 50 kg: one ampoule (3 mg / 3 ml) is parted in 20-50 ml of infusion solution and entered within 5 minutes prior to the beginning of cytostatic chemotherapy; one ampoule (3 mg / 3 ml) can also is entered bolyusno (within 30 seconds);
Patients with body weight less than 50 kg: 20-40 mkg/kg; infusion should be finished prior to cytostatic therapy.
In clinical trials it was shown that for control of nausea and vomiting for 24 hours most of patients needed only one dose of drug.
Radiation therapy (prevention)
The mode of dosing is similar to that see. "Cytostatic chemotherapy (prevention)".
Cytostatic chemotherapy and radiation therapy (therapy)
The small number of patients can have a pernicious vomiting and the expressed nausea.
In case of need 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.
Postoperative nausea and vomiting (therapy)
Once 1 mg slowly (not less than 30 seconds). There is an experience of use of the drug Kitril® in a dose to 3 mg at the patients who transferred an elective operative measure under anesthesia.
To the patients receiving drug Kitril® infusions after elimination of nausea and vomiting for the purpose of their prevention tablets can be appointed.
Special mode of dosing
Children
Cytostatic chemotherapy (prevention)
Single infusion in a dose of 20 mkg/kg in 10-30 ml of solution for infusions within 5 minutes, prior to cytostatic therapy.
Cytostatic chemotherapy (therapy)
No more than 2 additional infusions (within 5 minutes), each 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 (therapy)
Data on use of the drug Kitril® for therapy of postoperative nausea and vomiting at children are absent.
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 Kitril® 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:

Patients with signs of partial obstruction of intestines after administration of the drug Kitril® have to be under observation of the doctor as Kitril® can reduce motility of intestines.
Китрил® it is safe for use at elderly and patients with a renal or liver failure.
Китрил® 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 the drug Kitril® 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 by the drug Kitril® 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.

Influence on ability to driving of vehicles and work with cars and mechanisms
Data on influence of the drug Kitril® on ability to driving of the vehicle are absent. However it must be kept in mind what in isolated cases at therapy by the drug Kitril® was reported about drowsiness and other undesirable phenomena from a nervous system.

Side effects:

In most cases side effects at use of the drug Kitril® 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 (not less than 1/10); often (more than 1/100, less than 1/10); sometimes (more than 1/1000, less than 1/100); seldom (more than 1/10000, less than 1/1000); very seldom (less than 1/10000), including separate messages.
From a nervous system: seldom - alarm, concern, dizziness.
From the alimentary system: seldom - heartburn, change of flavoring feelings.
From immune system: seldom - hypersensitivity reactions.
From skin and a hypodermic fatty tissue: very seldom - skin rash, a hypostasis/face edema.
From an organism in general: very seldom - a grippopodobny syndrome, including fever and a fever.
Post-marketing observation
From a nervous system: headache, sleeplessness, drowsiness, weakness.
From the alimentary system: an abdominal pain, a lock, diarrhea, a meteorism, increase in activity of hepatic transaminases (ALT, nuclear heating plant) usually within their normal values, dyspepsia.
From immune system: skin rash, hyperthermia, bronchospasm, small tortoiseshell, itch.
From cardiovascular system: arrhythmia, stethalgia, decrease or increase in arterial pressure.
As well as at use of other 5-HT3 antagonists, at therapy by the drug Kitril® it was reported about cases of changes of parameters of the electrocardiogram (ECG), 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.

Interaction with other medicines:

Китрил® the system of P450 cytochrome (some narcotic analgetics which are responsible for metabolism) does not influence activity of metabolizing enzymes of a subfamily 3A4. Efficiency of the drug Kitril® 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 drug Kitril® metabolism that assumes participation of an isoenzyme 3A of system of P450 cytochrome. Special researches on interaction with means for the general anesthesia were not conducted, but Kitril® 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 intravenous administration) approximately on a quarter.
Interaction at co-administration with the benzodiazepines, tranquilizers, antiulcerous drugs and cytostatic medicines causing vomiting is not revealed.
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 by the drug Kitril® can lead to clinically significant effects.

Contraindications:

Hypersensitivity to a granisetron or any of drug components.
Reactions of hypersensitivity to other selection antagonists of 5-HT3 receptors in the anamnesis.
Feeding by a breast.
Data on efficiency and safety at use of drug for children are younger than 2 years are absent.

With care
Partial intestinal obstruction.
Pregnancy (to women during pregnancy of Kitril® it is appointed only in that case when the estimated advantage for mother exceeds potential risk for a fruit; Китрил® 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:

The specific antidote for the drug Kitril® is not known. 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:

To store at a temperature not above 30 °C in the place protected from light.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 1 mg / 1 ml and 3 mg / 3 ml
On 1 or 3 ml in the ampoules made of glass of a hydrolytic class 1 (EF), hermetically soldered. On ampoules there is a point of blue color; on an ampoule tip with a dosage of 1 mg / 1 ml are available two rings of green color, on an ampoule with a dosage of 3 mg / 3 ml – one ring of green color.
5 ampoules together with the application instruction place in a cardboard pack with partitions.