Index of drugs

Treatment of advanced colorectal cancer (colon and rectum): in combination with 5-fluorouracil and folinic acid in patients who have not previously received chemotherapy due to advanced disease and as monotherapy, in patients who failed treatment based on the 5-drug regimen fluorouracil. The use of irinotecan in combination with cetuximab in the treatment of colorectal (colorectal) metastases caused by expression of epithelial growth factor receptor after failure of cytotoxic therapy with irinotecan is recommended. The use of irinotecan in combination with 5- Fluorouracil, folinic acid and bevacizumab as a first-line agent in the treatment of patients with metastatic carcinoma of the colon or rectum is recommended.

1 vial 2 ml (5 ml) contains 40 mg (100 mg) of irinotecan hydrochloride trihydrate. The preparation contains sorbitol.

Irinotecan is a semi-synthetic derivative of camptothecin. It is an anticancer drug that acts as a specific inhibitor of topoisomerase I DNA. It is metabolized in most tissues to SN-38, a compound with greater activity than irinotecan in relation to purified topoisomerase I and showing a stronger cytotoxic activity against numerous cell lines of murine and human tumors. Inhibition of topoisomerase I by irinotecan or SN-38 results in the formation of single-stranded DNA segments blocking DNA replication and provides the proper cytotoxic effect of the drug. The cytotoxic effect of irinotecan and SN-38 is time-dependent and specific for the S phase. In addition to the antitumor effect, the drug has acetylcholinesterase inhibitory activity. The pharmacokinetic parameters of irinotecan and SN-38 are independent of the number of previously administered chemotherapy courses and dosing regimen. Irinotecan and SN-38 bind to plasma proteins at 65% and 95%, respectively. The mean half-life in the first phase of the three-phase model is 12 minutes, in the second phase - 2.5 hours and in the delay phase - 14.2 hours. Over 50% of the dose is excreted unchanged, 33% in the faeces through bile 22% are excreted in the urine. Two metabolic pathways have been characterized, each of which involves at least 12% of the administered dose of drug: hydrolysis with carboxyl esterase to the active metabolite SN-38; oxidative transformations of the final piperidine ring with the participation of cytochrome P450 3A enzymes.

Hypersensitivity to irinotecan or other components of the drug. Chronic inflammatory bowel disease and / or intestinal obstruction. Pregnancy, breast-feeding. Concentration of bilirubin more than 3-fold higher than the upper limit of normal (ULN). Severe bone marrow dysfunction. General condition according to the WHO classification> 2. Concomitant use of St. John's wort. Children. Contraindications of other drugs should be considered during combination therapy.

It is used after considering the benefit in relation to the risk: in patients at risk of complications, in particular in patients with a general condition of WHO classification and in a small number of cases when patients may be suspected that they will not be able to follow the recommendations. regarding the management of adverse reactions (the need to implement immediate and long-term anti-diarrheal treatment, combined with the adoption of a large amount of fluids after the onset of delayed diarrhea), close supervision of the hospital is recommended. Patients should be informed about the risk of delayed diarrhea after more than 24 hours after irinotecan or at any time prior to the start of the Next course of treatment. Patients with an increased risk of diarrhea include: persons with prior radiotherapy of the abdominal cavity and / or pelvis, patients with initial elevated leucocytosis, patients with a WHO status index ≥2 and women. Immediately after the first liquid stool, the patient should start taking large amounts of electrolyte-containing fluids and immediately apply appropriate antidiarrheal treatment (loperamide - initial dose is 4 mg, followed by 2 mg every 2 hours, treatment should be continued for 12 hours after the last liquid stool, do not use Loperamide in other doses and for more than 48 consecutive hours, nor less than 12 hours). If diarrhea is accompanied by severe neutropenia, prophylactically antibiotics with a broad spectrum of activity should also be used.In addition to antibiotic therapy, it is recommended to treat hospital diarrhea in the following cases: diarrhea is accompanied by fever, severe diarrhea (requiring intravenous hydration), diarrhea persisting after 48 hours after initiating loperamide treatment at high doses. It is recommended to reduce the dose in subsequent treatment cycles in patients who have experienced severe diarrhea. In case of neutropenic fever (temperature> 38st.C and neutrophil counts ≤1000 cells / mm³) immediate treatment with broad-spectrum antibiotics administered intravenously in the hospital is necessary. Before each administration of the drug, prophylactic treatment with antiemetics is recommended. If the patient suffers from vomiting in addition to diarrhea, he should be treated as soon as possible with hospital treatment. In the event of an acute cholinergic syndrome (early diarrhea, sweating, abdominal spasms, tearing, pupil stenosis and increased salivation), atropine sulphate (subcutaneously 0.25 mg) should be administered, unless clinically contraindicated. Caution should be exercised when treating patients with asthma and elderly patients. In patients who have previously had an acute and severe cholinergic syndrome, prophylactic treatment with atropine sulphate is recommended during subsequent doses of irinotecan. Patients with risk factors for the development of interstitial lung disease should be monitored (use of pneumotoxic drugs, radiotherapy, administration of colony stimulating factors). No studies have been conducted in the group of patients with impaired renal function, therefore the use of the drug is not recommended. The simultaneous administration of a potent CYP3A4 inhibitor (eg ketoconazole) or its inducer (eg rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort) and irinotecan should be avoided. Due to the presence of sorbitol, do not use in patients with rare hereditary problems of fructose intolerance.

There are no adequate data from the use of irinotecan in pregnant women. Embryotoxic, fetotoxic and teratogenic effects of irinotecan have been demonstrated in rabbits and rats. Therefore, the drug should not be used in pregnant women. It is recommended to use effective contraception during treatment and up to 3 months after completion. Due to the potential for side effects in breastfed infants, breast-feeding should be discontinued during treatment with irinotecan.

Adverse reactions in monotherapy and combination therapy. Very often: severe diarrhea; nausea, vomiting (including severe in patients treated with antiemetics); neutropenia (including severe neutropenia), anemia, thrombocytopenia; transient alopecia; transient increase in ALT, AST, alkaline phosphatase or increase in serum bilirubin (Grade 1 and 2). Common: dehydration associated with diarrhea and / or vomiting; constipation; infection; Severe, transient acute cholinergic syndrome (main symptoms occurred during or within 24 h after drug administration: early diarrhea, abdominal pain, conjunctivitis, rhinitis, hypotension, vasodilatation, sweating, chills, malaise, dizziness, impaired vision, miosis, tearing and increased salivation, symptoms disappear after administration of atropine); asthenia, severe febrile neutropenia, fever without infection and without associated severe neutropenia; transient and mild to moderate increase in serum creatinine. Uncommon: pseudomembranous colitis, impaired renal function, hypotension, cardiovascular failure (in patients who have experienced dehydration through diarrhea and / or vomiting); intestinal obstruction or bleeding from the stomach and intestines; mild local reactions; interstitial lung disease (manifesting in the form of infiltration in the lungs, dyspnoea was observed among early symptoms), mild skin reactions; mild allergic reactions. Rare: colitis (including appendicitis, ischemic and ulcerative colitis), symptomatic or asymptomatic pancreatitis, anorexia, abdominal pain, mucositis; hypertension during or after the infusion; anaphylactic and / or anaphylactoid reactions; muscle cramps, paresthesia; hypokalemia, hyponatremia (most commonly due to diarrhea and vomiting).Very rare: increased amylase and / or lipase activity; transient speech disorders associated with infusion. In patients with sepsis, renal failure, hypotension or cardiovascular failure were uncommon. In addition, one case of peripheral thrombocytopenia has been described.

The drug should be administered only under the supervision of a doctor experienced in the conduct of cancer chemotherapy, in units specialized in the administration of cytotoxic chemotherapy. Adults, intravenously (into a peripheral or main vein).monotherapy (in previously treated patients): 350 mg / m² pc, once every 3 weeks as an infusion lasting 0.5-1.5 hours.Combination therapy (in previously untreated patients): 180 mg / m² once every 2 weeks as an infusion lasting 0.5-1.5 hours, followed by folinic acid and 5-fluorouracil. Dose and method of administration data in combination with cetuximab are included in the Summary of Product Characteristics for this medicine. Typically, the same dose of irinotecan is given as in the last cycle of the previous irinotecan-containing treatment. It must not be given until at least 1 hour after the end of the cetuximab infusion. Dose and method of administration of bevacizumab are included in the Summary of Product Characteristics for this medicine.Dosage modifications. Irinotecan should be administered after the reduction of all adverse reactions to Grade 0 or 1 according to the NCI-CTC toxicity scale and complete resolution of treatment induced diarrhea. The dose should be reduced at the beginning of the next course of treatment, depending on the highest severity of adverse reactions observed prior to the infusion. Treatment should be delayed by 1-2 weeks to allow the side effects associated with drug administration to resolve. Decrease the dose of the drug by 15-20% if the following adverse reactions occur: haematological toxicity (grade 4 neutropenia, febrile neutropenia (grade 3-4 neutropenia and grade 2-4 fever), thrombocytopenia and leukopenia (grade 4)); non-hematologic toxicity (grade 3-4). Patients with impaired liver function. Monotherapy: bilirubin is 1.5-fold higher than GGN - 350 mg / m² pc .; 1.5-3 times higher than GGN - 200 mg / m² pc .; bilirubin concentration exceeds 3-fold GGN - do not use irinotecan. Combination treatment: no data available.
Treatment with irinotecan should be continued until objective development of disease or unacceptable toxicity. The drug should not be administered by rapid infusion or infusion in less than 0.5 hours or longer than 1.5 hours.