Irinotekan

General characteristics. Structure:

Active ingredient: 20 mg of an iridotekan of a hydrochloride of trihydrate.

Excipients: D-sorbitol, lactic acid, sodium hydroxide to pH 3,5, water for injections.

Pharmacological properties:

Pharmacodynamics. Irinotekan - semi-synthetic derivative a kamptotetsina - is specific inhibitor of cellular enzyme of topoisomerase I. In fabrics drug is metabolized by SN-38, karboksilesterazy with formation of an active metabolite, which surpasses in the activity иринотекан. Irinotekan and his metabolite SN-38 stabilize a topoisomerase I complex with DNA, causing linear damages of DNA that interferes with its replication. In experiences of in vivo it was shown that иринотекан it is also active concerning the tumors expressing the R-glycoprotein of multiple medicinal resistance (Vincristinum - and doxorubicine - resistant leukemias of P388).
 
Other pharmacological effect of an irinotekan is its ability to inhibit acetylcholinesterase.

Pharmacokinetics. The pharmacokinetics of an irinotekan and SN-38 (its active metabolite) was studied at 30-minute intravenous infusion of drug in a dose of 100-750 mg/sq.m. The pharmacokinetic profile of an irinotekan does not depend on a dose.

Distribution of drug in plasma of two - or three-phase. Distribution volume - 157 l/sq.m. The maximum plasma concentration of an irinotekan and SN-38 is reached by the end intravenous infusions in the recommended dose of 350 mg/sq.m of a body surface and makes 7,7 mkg/ml and 56 ng/ml, respectively, and the area under a curve "concentration time" (AUC) - 34 mkg/h/ml and 451 нг/ч/мл. In a blood plasma иринотекан is in the basic in not changed look. Communication with proteins of a blood plasma for an irinotekan makes about 65%, for SN-38 - 95%.

Irinotekan is metabolized in a liver in two ways: under the influence of karboksilesteraza enzyme to an active metabolite of SN-38 with the subsequent glyukuronirovaniye and under the influence of CYP3A4 isoenzyme with formation of derivatives of aminopentanoic acid and amines. Significant cytotoxic activity only SN-38 has.

The average elimination half-life of drug in plasma in the first phase of three-phase model makes 12 minutes, in the second phase - 2,5 hours, in the last phase - 14,2 hours, Average value of plasma clearance - 15 l/h/sq.m. It is removed by kidneys in not changed look (on average 19,9%) and a type of a metabolite of SN-38 (0,25%). With bile about 30% of an irinotekan, both in not changed look, and in the form of SN-38 glucuronide are removed.

Pharmacokinetic researches confirmed lack of influence of a ftoruratsil and calcium of a folinat on pharmacokinetics of an irinotekan. Removal of an irinotekan is reduced approximately by 40% at patients with the concentration of bilirubin exceeding the upper bound of norm by 1,5-3 times.

Indications to use:

Locally-spread or metastatic cancer colonic and rectum:

- in a combination with ftoruratsily and calcium folinaty at the patients who were earlier not receiving chemotherapy;
 
- in the form of monotherapy at patients with progressing of a disease after performing standard antineoplastic therapy.

Route of administration and doses:

Drug is intended only for adults. Drug Irinotekan is used both in the form of monotherapy, and in a combination with ftoruratsily and calcium folinaty. At the choice of a dose and mode of introduction it is necessary to address special literature. The drug Irinotekan is administered in the form of intravenous infusion lasting not less than 30 minutes and no more than 90 minutes.
 
In the monotherapy mode drug Irinotekan is used in a dose of 125 mg/sq.m of a body surface weekly within 4 weeks in the form of 90-minute intravenous infusion with a break in 2 weeks, and also in a dose of 350 mg/sq.m in the form of hour intravenous infusion each 3 weeks.
 
As a part of the combined chemotherapy with ftoruratsily and calcium folinaty a drug dose Irinotekan makes at weekly introduction - 125 mg/sq.m, at introduction by long infusion of 1 times to 2 weeks - 180 mg/sq.m. Doses and the mode of introduction of a ftoruratsil and calcium of a folinat are in detail described in special literature.

Recommendations about modification of a dose. In the monotherapy mode decrease in an initial dose of drug Irinotekan from 125 mg/sq.m to 100 mg/sq.m and from 350 mg/sq.m to 300 mg/sq.m, and also the dose decline from 125 mg/sq.m to 100 mg/sq.m and from 180 mg/sq.m to 150 mg/sq.m in the mode of a combination therapy can be recommended at patients at the age of 65 years and is more senior, at the previous extensive radiation therapy, at an indicator of the general condition of the patient on a scale of WHO, equal 2, at the increased concentration of bilirubin in blood.
 
Administration of drug Irinotekan should not be carried out until the quantity of neutrophils in peripheral blood does not exceed 1500 cells / мкл blood, and such complications as nausea, vomiting and especially diarrhea will not be completely stopped yet. Administration of drug Irinotekan until permission of all by-effects can be postponed for 1-2 weeks. If against the background of treatment the expressed oppression of a marrowy hemopoiesis develops (quantity of neutrophils less 500/mkl blood, and/or quantity of leukocytes less 1000/mkl blood, and/or quantity of thrombocytes less 100000/mkl), or a febrile neutropenia (quantity of neutrophils 1000/mkl, and less in combination with fervescence more than 38 °C), either infectious complications, or heavy diarrhea, or other not hematologic toxicity Irinotekan and in need of a ftoruratsil it is necessary to lower 3-4 degrees, the subsequent doses of drug by 15-20%.
 
At emergence of objective signs of progressing of a tumoral disease, or development of inadmissible toxic manifestations therapy by drug Irinotekan should be stopped.
 
Patients with an abnormal liver function. At concentration of bilirubin in blood serum, exceeding the upper bound of norm no more than by 1,5 times, in connection with the increased risk of development of the expressed neutropenia it is necessary to control carefully indicators of the general blood test at the patient. At increase in concentration of bilirubin more than by 3 times treatment by drug Irinotekan should be stopped.
 
Patients with a renal failure. Data on use are absent. Patients of advanced age. Any features on drug use Irinotekan at elderly people are absent. The drug dose in each case should be selected with care.

Rules of preparation of solution for infusions. Drug solution Irinotekan has to prepare in aseptic conditions. The necessary amount of drug should be diluted in 250 ml 5% of solution of a dextrose or 0,9% of solution of sodium of chloride and to mix the received solution, by rotation of a container or a bottle. Before introduction solution has to be visually examined on transparency. In case of detection of a deposit drug has to be utilized.
 
Drug solution Irinotekan has to be used at once after cultivation. If cultivation is executed with observance of rules of an asepsis (for example, in installation of a laminar air flow), solution of drug can be used in case of storage at the room temperature within 12 hours (including infusion time) and at a temperature of 2-8 °C - within 24 hours after opening of a bottle with a concentrate.

Features of use:

Pregnancy and lactation. Drug Irinotekan is contraindicated for use at pregnancy and during breastfeeding.

Treatment by drug Irinotekan has to be carried out in specialized chemotherapeutic departments under observation of the doctor having experience with antineoplastic drugs.
 
At the patients receiving drug Irinotekan it is necessary to make weekly developed clinical blood test and to monitor function of a liver.
 
The diarrhea arising as a result of cytotoxic effect of drug Irinotekan (the delayed diarrhea) is usually noted not earlier than 24 hours after administration of drug (at most of patients on average in 5 days). At emergence of the first episode of a liquid chair purpose of the plentiful drink containing electrolytes, and immediate carrying out, the antidiarrheal therapy including reception of loperamide in high doses is necessary (4 mg on the first reception and then on 2 mg each 2 hours). This therapy is continued within not less than 12 hours after the last episode of a liquid chair, but by no more than 48 hours because of a possibility of development of paresis of a small bowel. If diarrhea is regarded as heavy (more than 6 episodes of a liquid chair within a day or the expressed tenesmus), and also if it is followed by vomiting or fever, the patient has to be urgently hospitalized for performing the complex treatment including introduction of antibiotics of a broad spectrum of activity. At moderate or slight diarrhea (less than 6 episodes of a liquid chair within a day and moderate tenesmus) which is not stopped within the first 48 hours, it is necessary to begin reception of antibiotics of a broad spectrum of activity inside, at the same time the patient is recommended to be hospitalized. At simultaneous developing of diarrhea and the expressed neutropenia (quantity of leukocytes less than 500 cells / мкл blood) in addition to antidiarrheal therapy with the preventive purpose antibiotics of a broad spectrum of activity are inside appointed.
 
It is not necessary to appoint loperamide preventively, including to patients at whom diarrhea was noted during the previous introductions of an irinotekan.
 
The patient needs to be warned about the possibility of development in it delayed diarrheas in advance. Patients have to inform the doctor on developing of diarrhea at once and immediately begin the corresponding treatment.
 
At inadequate treatment of diarrhea the state, life-threatening the patient, especially can develop if diarrhea developed against the background of a neutropenia.
 
To patients with a febrile neutropenia (body temperature> of 38 °C and quantity of neutrophils <1000 cells / мкл) introduction of antibiotics of a broad spectrum of activity in the conditions of a hospital has to be urgently begun.
 
At development of an acute cholinergic syndrome which signs of development are emergence of early diarrhea and set of such symptoms as perspiration spastic abdominal pains, dacryagogue, a miosis and the increased salivation, in the absence of contraindications introduction of 0,25 mg of atropine subcutaneously is shown. It is necessary to be careful at use of drug for patients with bronchial asthma. At patients with instructions in the anamnesis on development of an acute cholinergic syndrome including in a severe form, before purpose of drug Irinotekan preventive administration of atropine is recommended.
 
Before each cycle of therapy by drug Irinotekan is recommended preventive purpose of antiemetics.
 
As the dosage form of drug as excipient contains sorbitol, drug Irinotekan it is impossible to use at patients with hereditary intolerance of fructose.

During treatment by drug Irinotekan it is not necessary to accept drugs on the basis of the St. John's Wort of made a hole (Hypericum perforatum), antiepileptic drugs (carbamazepine, phenobarbital and Phenytoinum), атазанавир and кетоконазол which change clearance of an irinotekan.
 
During treatment by drug Irinotekan and at least within 3 months after the termination of therapy reliable methods of contraception have to be applied.
 
At drug solution preparation Irinotekan and the treatment of drug as well as when using other antineoplastic means, it is necessary to be careful. It is necessary to use gloves, a mask and glasses.
 
At drug solution hit Irinotekan or infusion solution on skin at once wash out it water with soap. At hit of drug or its solution on mucous membranes immediately wash out them water.
 
All materials used for preparation of solution and for its introduction have to be subjected to utilization according to the standard procedure of utilization of cytotoxic drugs adopted in this hospital.

Influence on ability to manage vehicles and mechanisms. Patients need to be warned about a possibility of emergence during treatment by drug Irinotekan of dizziness and visual frustration which develop during 24 h after administration of drug. At emergence of the specified symptoms patients are recommended to refrain from driving and other mechanisms, and also to be careful at occupation potentially dangerous types of activity.

Side effects:

Frequency of side effects is specified below according to the following gradation: very often (more than 10%), it is frequent (more than 1%, but less than 10%), infrequently (more than 0,1%, but less than 1%), is rare (more than 0,01%, but less than 0,1%), is very rare (less than 0,01%).
 
From system of a hemopoiesis: very often - a neutropenia, a leukopenia, anemia; often - a febrile neutropenia, thrombocytopenia at purpose of drug as a part of monotherapy; very seldom - formation of antithrombocytic antibodies.
 
The neutropenia was observed at 78,7% of patients at monotherapy (at the combined chemotherapy at 82,5%), including 22,6% of patients had it expressed (quantity of neutrophils less than 500 cells / мкл). The neutropenia was reversible and had no cumulative character. The complete recovery of quantity of neutrophils came usually for the 22nd day at use of an irinotekan in monotherapy and for 7-8 day at use of an irinotekan as a part of the combined chemotherapy. Fever in combination with the expressed neutropenia was noted at 6,2% and 3,4% of patients respectively. Infectious complications at monotherapy took place at 10,3% of patients, at 5,3% of patients they were combined with the expressed neutropenia.
 
At use of an irinotekan moderate anemia developed in monotherapies at 58,7% of patients. At uses of an irinotekan as a part of the combined chemotherapy anemia was observed at 97,2%.
 
At use of an irinotekan in monotherapy thrombocytopenia (<100 000 cells / мкл) it was observed at 7,4% (at the combined chemotherapy at 32,6%) patients. At use of an irinotekan as a part of the combined chemotherapy of the expressed thrombocytopenia it was not observed. The quantity of thrombocytes is recovered by 22nd day. One case of thrombocytopenia in combination with formation of antithrombocytic antibodies was observed.
 
From system of digestion: very often - late diarrhea; often - nausea, vomiting, locks; sometimes - pseudomembranous colitis (in one case S. was revealed by difficile), intestinal impassability, gastrointestinal bleeding; seldom - colitis, including a typhlitis, ischemic and ulcer colitis, perforation of intestines, anorexia, an abdominal pain, an inflammation of mucous membranes, pancreatitis.
 
The diarrhea arising more, than in 24 hours after drug use (the delayed diarrhea), is dozolimitiruyushchy toxic effect of an irinotekan. At use of drug in monotherapy heavy diarrhea was observed at 20% of patients (at a combination therapy at 13,1%). Average time before emergence of the first liquid chair after introduction of an irinotekan made 5 days.
 
At use of drug in monotherapy approximately at 10% of the patients applying antiemetics the expressed nausea and vomiting took place. At use of an irinotekan as a part of the combined chemotherapy the expressed nausea and vomiting were observed less often: at 2,1% and 2,8% of patients respectively.
 
The acute cholinergic syndrome, the shown such symptoms as early diarrhea, abdominal pains, conjunctivitis, rhinitis, a lowering of arterial pressure, bradycardia, a vazodilatation, an intestines hyperperistalsis, the strengthened sweating, a fever, an indisposition, dizziness, a visual disturbance, a miosis, dacryagogue, hypersalivation was observed at 9% of the patients receiving иринотекан in monotherapy and as a part of the combined chemotherapy only at 1,4% of patients. All these symptoms disappeared after administration of atropine.
 
From the central nervous system: seldom - involuntary muscular twitchings or spasms, paresthesias, an adynamy; very seldom - tranzitorny disturbance of the speech.
 
From cardiovascular system: sometimes - a lowering of arterial pressure, hypovolemic shock because of dehydration; seldom - increase in arterial pressure in time or after infusion.
 
From a respiratory organs: sometimes - short wind, fever, pulmonary infiltrates.
 
Allergic reactions: sometimes - skin rash; seldom - development of an acute anaphylaxis.
 
From skin and a hypodermic fatty tissue: very often - a reversible alopecia; sometimes - easy skin reactions.
 
From laboratory indicators: very often - tranzitorny increase in activity of serumal transaminases, an alkaline phosphatase or concentration of bilirubin (combination therapy); often - tranzitorny increase in activity of serumal transaminases, an alkaline phosphatase or concentration of bilirubin, (monotherapy), increase in concentration of serumal creatinine; seldom - a hypopotassemia and a hyponatremia; very seldom - increase in activity of serumal amylase and/or a lipase.
 
Others: very often - fervescence; often - increased fatigue; seldom - local post-infusional reactions, accession of consecutive infections.

Interaction with other medicines:

As иринотекан has antikholinesterazny activity, increase in duration of neuromuscular blockade at combined use with salts of succinylcholine and antagonistic interaction concerning neuromuscular blockade is possible at a combination to not depolarizing muscle relaxants.
 
At combined use of an irinotekan with myelosuppressive medicines and radiation therapy toxic action on marrow (a leukopenia, thrombocytopenia) is aggravated.
 
At combined use of an irinotekan with glucocorticosteroid drugs (for example, with dexamethasone) the risk of development of a hyperglycemia (especially at patients with a diabetes mellitus or with reduced tolerance to glucose) and lymphocytopenias increases.
 
At combined use of an irinotekan with diuretics dehydration arising owing to diarrhea and vomiting can be aggravated.

Combined use of laxative drugs against the background of therapy irinotekany can aggravate the frequency or weight of diarrhea.
 
Joint reception of an irinotekan and prochlorperazine increases probability of manifestation of symptoms of an akathisia.
 
At combined use of an irinotekan with drugs of a plant origin on the basis of the St. John's Wort of made a hole (Hypericum perforatum), and also with anticonvulsant drugs - CYP3A4 isoenzyme inductors (carbamazepine, phenobarbital and Phenytoinum) - concentration in plasma of an active metabolite SN-38 decreases. Joint reception of an irinotekan with atazanaviry, inhibitor of isoenzymes of CYP3A4 and UGT1A1, and also with ketokonazoly can cause increase in concentration in a blood plasma of an active metabolite of SN-38.
 
Drug Irinotekan should not be mixed with other drugs rolled into one.
 
Introduction of live attenuirovanny vaccines to the patients who are receiving medical treatment for antineoplastic means including иринотекан, can lead to serious or fatal infections. It is necessary to avoid vaccination by live vaccines of patients, poduchayushchy drug Irinotekan. The killed or inactivated vaccine can be entered, however the answer to such vaccine can be weakened.

Contraindications:

- hypersensitivity to an irinotekan or other components of drug;
- chronic inflammatory diseases of intestines and/or disturbance of intestinal passability;
- the expressed oppression of a marrowy hemopoiesis;
- the concentration of bilirubin in blood serum exceeding more than by 3 times the upper bound of norm (UBN);
- the general condition of patients estimated on a scale of WHO> 2;
- pregnancy and period of feeding by a breast;
- children's age (data on safety and efficiency at children are absent);
- a renal failure (data on safety are absent).

With care:
- The general condition of the patient on a scale of WHO, equal 2;
- leukocytosis;
- radiation therapy (in the anamnesis) on area of an abdominal cavity or a basin;
- female patients (the risk of development of diarrhea increases);
- abnormal liver function;
- hypovolemia;
- simultaneous use of pneumotoxic drugs;
- therapy by colony stimulating factors;
- tendency to fibrinferments and thromboembolisms;
- advanced age.

Overdose:

The main expected overdose manifestations - a neutropenia and diarrhea. The specific antidote to an irinotekan is unknown. Symptomatic treatment. In case of overdose of the patient it is necessary to hospitalize and to carefully control functions of vitals.

Storage conditions:

In the place protected from light, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Release form / дозировка:Концентрат for preparation of solution for infusions, 20 mg/ml. Packaging: on 40 mg / 2 ml and 100 mg / 5 ml in the bottles of dark neutral glass corked by rubber bungs with a running in caps aluminum. On 1 bottle on 2 ml in a blister strip packaging from a PVC film with the application instruction in a pack from a cardboard. On 1 bottle on 5 ml with the application instruction in a pack from a cardboard.