Index of drugs

Treatment of patients with advanced stage of colorectal cancer: in combination with 5-fluorouracil and folinic acid in patients who have not been subjected to advanced chemotherapy; as monotherapy in patients who have failed treatment with 5-fluorouracil. Irinotecan in combination with cetuximab is indicated for the treatment of metastatic colorectal cancer-expressing EGFR, wild-type KRAS, in patients who have not previously received metastases and after failure of treatment with irinotecan. Irinotecan in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated for the first-line treatment of metastatic colorectal cancer. Irinotecan in combination with capecitabine and with or without bevacizumab is indicated for the first-line treatment of metastatic colorectal cancer.

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 diseases and / or bowel 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.

It is used after considering the benefit in terms of risk: in patients with a high risk of toxicity, especially in the WHO WHO status and in a small number of cases where patients are unable to follow the recommendations for dealing with side effects ( necessity of immediate and prolonged use of anti-diarrheal therapy and drinking large amounts of beverages after the occurrence of delayed diarrhea), close supervision of the hospital is recommended. Patients should be informed about the possibility of delayed diarrhea, which may occur more than 24 hours after administration of irinotecan, at any time before the next administration. Patients with an increased risk of diarrhea include those with previous radiotherapy of the abdominal / pelvic region, with hyperleukocytosis in the baseline study, patients in the general condition of the WHO classification ≥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 h after the last liquid stool , do not use loperamide in other doses and for more than 48 consecutive hours or 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) hospital treatment should be started immediately, using intravenous antibiotics with a broad spectrum of action. In patients who have serious side effects from the hematopoietic system, it is recommended to reduce the dose in the next cycle. 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 case of an acute cholinergic syndrome (early diarrhea, sweating, painful abdominal cramps, tearing, pupillary constriction and 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 developing interstitial lung disease should be monitored (use of pneumotoxic drugs, radiotherapy, administration of granulocyte 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. Do not administer to patients until the bowel obstruction disappears. 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 data on 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 for at least 3 months after completion. Due to the potential for side effects in breastfed infants, breast-feeding should be discontinued during treatment with irinotecan.

Monotherapy. Very often: nausea, vomiting. Common: thrombocytopenia. Combination chemotherapy. Very common: thrombocytopenia. Common: nausea, vomiting. Other adverse reactions classified at the same frequency for monotherapy and for combination chemotherapy. Very often: severe diarrhea; neutropenia (including severe neutropenia), anemia, transient alopecia; transient increase in ALT, AST, alkaline phosphatase or increase in serum bilirubin. 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, weakness, dizziness, 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, slight or moderate increase in serum creatinine. Uncommon: pseudomembranous enterocolitis, renal failure, hypotension or cardiovascular failure (in patients who have been dehydrated due to diarrhea and / or vomiting); intestinal obstruction or gastrointestinal bleeding; mild reactions at the infusion site; interstitial pneumonia, pneumonia with associated infiltrations; mild skin reactions; mild allergic reactions.Rare: colitis, including inflammation of the caecum, ischemic and ulcerative colitis, and perforation of the intestine, symptomatic or asymptomatic pancreatitis, loss of appetite, abdominal pain, inflammation of the mucous membrane; hypertension during or after an intravenous infusion; anaphylactoid reactions (anaphylactoid); 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.

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 side effects 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 progression of neoplastic process or a significant increase in side effects. The drug should not be administered by rapid infusion or infusion in less than 0.5 hours or longer than 1.5 hours.