Irinotecan - instructions for use, dose, side effects, contraindications

Irinotecan, a semi-synthetic derivative of camptothecin, is a specific inhibitor of the cellular enzyme of topoisomerase I. In tissues, the drug is metabolized by carboxyl esterase to form an active metabolite SN-38, which surpasses in its activity irinotecan. Irynotekan and its metabolite SN-38 stabilize the topoisomerase I complex with DNA, causing linear DNA damage, which prevents its replication. In the experiments in vivo It was. shown, that irinotecan is also active against tumors expressing the P-glycoprotein of multiple drug resistance (vincristine and doxorubicin-resistant leukemias P388).

Another pharmacological effect of irinotecan is its ability to inhibit acetylcholinesterase.

Pharmacokinetics:

The pharmacokinetics of irinotecan and SN-38 (its active metabolite) was studied with a 30-minute intravenous infusion of the drug in a dose 100-750 mg / m².

The pharmacokinetic profile of irinotecan is dose independent.

The distribution of irinotecan in plasma is two- or three-phase.The volume of distribution is 157 l / m².

The maximum plasma concentration of irinotecan and SN-38 was achieved by the end of intravenous infusion at a recommended dose of 350 mg / m² body surface area and is 7.7 μg / ml and 56 ng / ml, respectively, and the area under the concentration-time curve (AUC) - 34 μg / h / ml and 451 ng / h / ml. In the blood plasma irinotecan is basically unchanged. The association with blood plasma proteins for irinotecan is approximately 65%, for SN-38 - 95 %.

Irinotecan is metabolized in the liver in two ways: under the action of an enzyme carboxyl esterase to the active metabolite SN-38 with subsequent glucuronation and under the action of the isoenzyme CYP3A4 with the formation of aminopentanoic acid derivatives and amines. Significant cytotoxic activity has only SN-38. The average half-life of the drug in plasma in the first phase of the three-phase model is 12 minutes, in the second phase - 2.5 hours, in the last phase - 14.2 hours. The average value of the plasma clearance is 15 l / h / m². It is excreted by the kidneys in an unchanged form (an average of 19.9%) and in the form of a metabolite SN-38 (0.25%). With bile, about 30% of the drug is excreted, both in unchanged form and in the form of glucuronide SN-38. Pharmacokinetic studies confirmed the absence of the effect of fluorouracil and calcium folinate on the pharmacokinetics of irinotecan. Excretion of irinotecan was reduced by approximately 40% in patients with bilirubin concentration exceeding the upper limit of the norm by 1.5-3 times.

Indications:

Locally or metastatic colorectal cancer;

- in combination with fluorouracil and calcium folinate in patients who had not previously received chemotherapy;

- in monotherapy in patients with disease progression after standard antitumor therapy.

Contraindications:

- Hypersensitivity to irinotecan or other components of the drug;

- chronic inflammatory bowel disease and / or intestinal obstruction;

- severe oppression of bone marrow hematopoiesis;

- the concentration of bilirubin in the serum, exceeding the upper limit of the norm (VGN) by more than 3 times;

- general condition of patients, assessed by WHO scale> 2;

- simultaneous application with the yellow fever vaccine;

- pregnancy and the period of breastfeeding;

- children's age (data on safety and effectiveness in children are absent);

- kidney failure (safety data not available).

Carefully:

General condition of the patient on the WHO scale, equal to 2; leukocytosis; radiation therapy (in the anamnesis) on the abdominal cavity or pelvis; female patients (increased risk of diarrhea); abnormal liver function; hypovolemia; simultaneous use of pneumotoxic drugs; therapy with coli-stimulating factors; propensity to thrombosis and thromboembolism; elderly age.

Pregnancy and lactation:A drug Irynotekan contraindicated for use in pregnancy and during breastfeeding.

Dosing and Administration:The drug is intended only for adults.

A drug Irynotekan is used both in the form of monotherapy, and in combination with fluorouracil and calcium folinate. When choosing a dose and mode of administration, you should refer to the special literature. A drug Irynotekan is administered as an intravenous infusion lasting at least 30 minutes and not more than 90 minutes.

In the monotherapy regime a drug Irynotekan is used in a dose of 125 mg / m² body surface weekly for 4 weeks in the form of a 90-minute intravenous infusion with a break of 2 weeks,as well as in a dose of 350 mg / m² in the form of a one hour intravenous infusion every 3 weeks.

As part of combined chemotherapy with fluorouracil and calcium folinate dose of the drug Irynotekan when administered weekly - 125 mg / m², when administered by continuous infusion once every 2 weeks - 180 mg / m². Doses and administration of fluorouracil and calcium folinate are described in detail in the literature.

Recommendations for dose modification

In the monotherapy regimen, a decrease in the initial dose of the drug Irynotekan from 125 mg / m²up to 100 mg / m² and from 350 mg / m² up to 300 mg / m², as well as a reduction in the dose of 125 mg / m² up to 100 mg / m²and from 180 mg / m² up to 150 mg / m² in the regime of combination therapy, it can be recommended in patients aged 65 years and older, with previous extensive radiotherapy, with an indicator of the general condition of the patient on a WHO scale of 2, with an increased concentration of bilirubin in the blood.

Administration of the drug Irynotekan should not be carried out until the amount of neutrophils in the peripheral blood exceeds 1500 cells / μl of blood, and until such complications as nausea, vomiting and especially diarrhea are completely eliminated. Administration of the drug Irynotekan before the resolution of all side effects can be deferred for 1-2 weeks.If the expressed inhibition of bone marrow hematopoiesis develops (the number of neutrophils is less than 500 / μl of blood and / or the number of white blood cells is less than 1000 / μl of blood, and / or the number of platelets is less than 100,000 / μl), or febrile neutropenia (neutrophil count 1000 / μl and less in combination with an increase in body temperature of more than 38 ° C), or infectious complications, or severe diarrhea, or other non-hematological toxicity of 3-4 degrees, subsequent doses of the drug Irynotekan and if necessary, fluorouracil should be reduced by 15-20%.

When there are objective signs of progression of the tumor disease, or the development of unacceptable toxic manifestations of drug therapy Irynotekan should be discontinued.

Patients with impaired hepatic function

At a concentration of bilirubin in the blood serum that exceeds the upper limit of the norm no more than 1.5 times, in connection with an increased risk of development of severe neutropenia, the parameters of the general blood test in the patient should be closely monitored. With an increase in the concentration of bilirubin more than 3 times, treatment with the drug Irynotekan should be discontinued.

Patients with impaired renal function

There is no application data. The drug is not recommended for patients receiving hemodialysis.

Elderly patients

Any features on the use of the drug Irynotekan the elderly are absent. The dose of the drug in each case should be selected with caution.

Rules for the preparation of a solution for infusion

Solution of the drug Irynotekan should be prepared in aseptic conditions.

The required amount of the drug should be diluted in 250 ml of a 5% solution of dextrose or 0.9% solution of sodium chloride and mix the resulting solution by rotating the container or vial. Before administration, the solution should be visually inspected for clarity. If a sediment is found, the preparation must be disposed of.

Solution of the drug Irynotekan should be used immediately after dilution.

If the dilution is carried out in accordance with aseptic rules (for example, in a laminar air flow installation), the solution of the preparation can be used in case of storage at room temperature for 12 hours (including infusion time), and at 2 ° C - 8 ° C - in for 24 hours after opening the vial with concentrate.

Side effects:

The frequency of side effects is given below in accordance with the following gradation: very often (more than 10%), often (more than 1% but less than 10%), infrequently (more than 0.1% but less than 1%), rarely (more than 0, 01%, but less than 0.1%), very rarely (less than 0.01%).

On the part of the hematopoiesis system: very often - neutropenia, leukopenia, anemia; often - febrile neutropenia, thrombocytopenia with the appointment of the drug as part of monotherapy; very rarely - the formation of antiplatelet antibodies.

Neutropenia was observed in 78.7% of patients mri monotherapy (with combined chemotherapy in 82.5%), including 22.6% of patients it was severe (neutrophil count less than 500 cells / μl). Neutropenia was reversible and did not have a cumulative character. The complete recovery of neutrophil counts usually occurred on day 22 with irinotecan in monotherapy and on day 7-8 with irinotecan as part of combined chemotherapy. Fever in combination with severe neutropenia was noted in 6.2% and 3.4% of patients, respectively. Infectious complications with monotherapy took place in 10.3% of patients, in 5.3% of patients they were combined with severe neutropenia.

When irinotecan was used in monotherapy, moderate anemia developed in 58.7% of patients.With the use of irinotecan in the combination chemotherapy, anemia was observed in 97.2%.

When irinotecan was used in monotherapy of thrombocytopenia (<100 000 cells / μl), 7.4% (with combined chemotherapy in 32.6%) patients was observed. When irinotecan was used as part of combined chemotherapy, severe thrombocytopenia was not observed. The number of platelets is restored by day 22. One case of thrombocytopenia was observed in combination with the formation of antiplatelet antibodies.

On the part of the digestive system: very often - late diarrhea; often - nausea, vomiting, constipation, candidiasis of the gastrointestinal tract, hiccough; sometimes - pseudomembranous colitis (in one case, C. difficile), intestinal obstruction, gastrointestinal bleeding; rarely - colitis, including tiflitis, ischemic and ulcerative colitis, intestinal perforations, anorexia, abdominal pain, mucosal inflammation, pancreatitis.

Diarrhea that occurs later than 24 hours after the drug is used (delayed diarrhea) is a dose-limiting toxic effect of the drug Irynotekan.

When using the drug in monotherapy, severe diarrhea was observed in 20% of patients (with combined therapy in 13.1%).The average time before the appearance of the first liquid stool after the administration of irinotecan was 5 days.

When using the drug in monotherapy, approximately 10% of patients using anti-emetics had pronounced nausea and vomiting. When irinotecan was used as part of combined chemotherapy, severe nausea and vomiting were less common: in 2.1% and 2.8% of patients, respectively.

Acute cholinergic syndrome, manifested by such symptoms as early diarrhea, abdominal pain, conjunctivitis, rhinitis, lowering of arterial pressure, bradycardia, vasodilation, increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lacrimation, salivation was observed in 9% of patients who received irinotecan in monotherapy and as part of combined chemotherapy in only 1.4% of patients. All these symptoms disappeared after the administration of atropine.

From the central nervous system: rarely - involuntary muscle twitching or cramping, paresthesia, asthenia, gait disturbance, confusion, headache; very rarely - a transient speech disorder.

From the cardiovascular system: sometimes - lowering blood pressure, hypovolemic shock due to dehydration; rarely - high blood pressure during or after infusion.

On the part of the respiratory system: sometimes - shortness of breath, pulmonary infiltrates, rhinitis.

Allergic reactions: sometimes - a skin rash; rarely - the development of anaphylactic shock.

From the skin and subcutaneous fat: very often - reversible alopecia; sometimes - mild skin reactions.

From the laboratory indicators: very often - a transient increase in the activity of serum transaminases, alkaline phosphatase or bilirubin concentrations (combination therapy); often - transient increase in serum transaminase, alkaline phosphatase or bilirubin concentration (monotherapy), increased serum creatinine concentration; rarely - hypokalemia and hyponatremia; very rarely - an increase in the activity of serum amylase and / or lipase.

Other: very often - fever; frequency - increased fatigue; rarely - local post-fusion reactions, attachment of secondary infections.The following reactions were also observed: increased activity of gamma glutamyltransferase, serum urea nitrogen concentration, hypomagnesemia, weight loss, dehydration, hypovolemia, sepsis, syncope, urinary tract infections, chest pain, lysis of the tumor.

Overdose:The main expected manifestations of an overdose are neutropenia and diarrhea. The specific antidote to irinotecan is unknown. Treatment is symptomatic. In case of an overdose, the patient should be hospitalized and closely monitor the function of vital organs.

Interaction:

As irinotecan has anticholinesterase activity, it is possible to increase the duration of neuromuscular blockade when combined with suxamethonium salts and antagonistic interaction with neuromuscular blockade when combined with nondepolarizing muscle relaxants.

With the combined use of irinotecan with myelosuppressive drugs and radiation therapy, the toxic effect on the bone marrow (leukopenia, thrombocytopenia) is aggravated.

When combined with irinotecan with glucocorticosteroid drugs (eg, with dexamethasone), the risk of developing hyperglycemia (especially in patients with diabetes mellitus or with reduced glucose tolerance) and lymphocytopenia increases.

With the combined use of irinotecan with diuretics, dehydration, resulting from diarrhea and vomiting, can be aggravated. Joint use of laxatives against irinotecan therapy may aggravate the frequency or severity of diarrhea.

Joint intake of irinotecan and prochlorperazine increases the likelihood of manifestation of signs of akathisia.

In the joint application of irinotecan with preparations of plant origin on the basis of St. John's wort (Hypericum perforatum), as well as with anticonvulsants - isoenzyme inducers CYP3A4 (carbamazepine, phenobarbital and phenytoin) is the concentration in the plasma of the active metabolite SN-38 decreases.

Joint reception of irinotecan with atazanavir, inhibitor of isoenzymes CYP3A4 and UGT1A1, as well as with ketoconazole may cause an increase in the concentration in the blood plasma of the active metabolite SN-38.

Irinotecan should not be mixed with other drugs in one bottle.

Introduction of live attenuated vaccines to patients undergoing treatment with antitumour agents, including irinotecan, can lead to serious or fatal infections. Vaccination with live vaccines should be avoided in patients receiving irinotecan. A killed or inactivated vaccine can be administered, but the response to such a vaccine can be weakened.

Special instructions:

Treatment with drug Irynotekan should be carried out in specialized chemotherapeutic departments under the supervision of a doctor who has experience working with antitumor drugs.

Patients receiving the drug Irynotekan, it is necessary to perform a detailed clinical blood test on a weekly basis and monitor liver function.

Diarrhea resulting from the cytotoxic effect of the drug Irynotekan (delayed diarrhea), usually occurs no earlier than 24 hours after drug administration (in most patients an average of 5 days). When the first episode of a liquid stool appears, it is necessary to administer an abundant drink containing electrolytes and immediately conduct antidiarrheal therapy,including the reception of loperamide in high doses (4 mg for the first dose and then 2 mg every 2 hours). This therapy is continued for at least 12 hours after the last episode of a loose stool, but no more than 48 hours because of the possibility of developing a small intestine paresis. If diarrhea is regarded as severe (more than 6 episodes of loose stool during the day or pronounced tenesmus), and if accompanied by vomiting or fever, the patient should be urgently hospitalized for complex treatment, including the introduction of broad-spectrum antibiotics. With moderate or mild diarrhea (less than 6 episodes of loose stool during the day and moderate tenesmus), which does not stop within the first 48 hours, it is necessary to start taking broad-spectrum antibiotics inside, while the patient is recommended to be hospitalized. With the simultaneous occurrence of diarrhea and severe neutropenia (the number of leukocytes less than 500 cells / μl of blood) in addition to antidiarrheal therapy with a preventive purpose, antibiotics of a wide spectrum of action are prescribed internally. Loperamide should not be prescribed prophylactically, including patients who have had diarrhea during previous injections of irinotecan.

The patient must be warned in advance about the possibility of developing delayed diarrhea. Patients should immediately inform their doctor about the occurrence of diarrhea and immediately begin appropriate treatment.

If the treatment of diarrhea is inadequate, a condition threatening the patient's life may develop, especially if diarrhea develops against a background of neutropenia.

Patients with febrile neutropenia (body temperature> 38 ° C and neutrophil count <1000 cells / μL) should be urgently initiated antibiotics of a wide spectrum of action in the conditions of a hospital.

With the development of acute cholinergic syndrome, the development of which is the appearance of early diarrhea and a combination of such symptoms as sweating, abdominal cramps, lacrimation, miosis and increased salivation, in the absence of contraindications, the administration of 0.25 mg of atropine subcutaneously is indicated. Care should be taken when using the drug in patients with bronchial asthma. Patients with a history of developing an acute cholinergic syndrome, including severe ones, before prescribing the drug irinotecan recommended preventive administration of atropine.

Before each cycle of drug therapy Irynotekan preventive administration of antiemetics is recommended.

As a drug form of the drug as an auxiliary substance, it contains sorbitol, a drug Irynotekan Do not use in patients with hereditary intolerance to fructose.

During the period of drug treatment Irynotekan Do not take drugs based on St. John's Wort Perforated (Hypericum perforatum), antiepileptic drugs (carbamazepine, phenobarbital and phenytoin), atazanavir and ketoconazole, which alter the clearance of irinotecan.

During treatment with the drug Irynotekan and, at least 3 months after discontinuation of therapy, reliable methods of contraception should be used.

When preparing the drug solution Irynotekan and handling of the drug, as well as with the use of other antitumour agents, care should be taken. It is necessary to use gloves, a mask and glasses.

If the drug solution falls Irynotekan or infusion solution on the skin, immediately wash it with soap and water. If the drug is ingested Irynotekan or its solution on mucous membranes, immediately rinse with water.

All materials used to prepare the solution and for its administration must be disposed of in accordance with the standard procedure for cytotoxic drug disposal adopted in this hospital.

Effect on the ability to drive transp. cf. and fur:Patients should be warned about the possibility of appearance during treatment with the drug Irynotekan dizziness and visual disorders that develop within 24 hours after drug administration. Application of the drug Irynotekan can provoke the development of seizures. If these symptoms occur, patients are advised to refrain from driving and other mechanisms, and also to be careful when dealing with potentially hazardous activities.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 20 mg / 4 ml and 100 mg / 5 ml (20 mg / ml).

Packaging:

Concentrate for the preparation of a solution for infusions of 20 mg / 4 ml and 100 mg / 5 ml (20 mg / ml) in bottles of dark neutral glass, corked with rubber stoppers with the rolling off of aluminum caps.

For 1 bottle of 2 ml each in a planar cell pack of PVC film with instructions for use in a pack of cardboard.

For 1 bottle of 5 ml with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008822/10

Date of registration:27.08.2010 / 17.02.2012

Expiration Date:Unlimited

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp30.11.2017

Illustrated instructions

Instructions

Irynotekan (Irinotecan)