Index of drugs

Treatment of patients with advanced colorectal cancer (colon and rectum): in combination with 5-fluorouracil and folinic acid in patients who have not received prior advanced chemotherapy; as monotherapy after failure of a treatment regimen containing 5-fluorouracil.

1 vial 2 ml (5 ml, 15 ml, 25 ml) contains 40 mg (100 mg, 300 mg, 500 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.

It is used after considering the benefit in terms of risk: in patients at risk, especially in WHO status 2, and in the few cases where it is impossible to adapt to the recommendations for observation and treatment of adverse reactions (immediate implementation and prolonged anti-diarrheal treatment, combined with intensive fluid replacement in the event 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 people with previous radiotherapy of the abdominal / pelvic area, patients with initial severe 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 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) immediate treatment with broad-spectrum antibiotics administered intravenously in the hospital is necessary. 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, 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.

monotherapy. Very common: diarrhea, abdominal pain, severe nausea, severe vomiting; neutropenia, anemia; fever; infection; dehydration; dyspnoea; alopecia. Common: mucositis, constipation; neutropenia with fever, thrombocytopenia; acute cholinergic syndrome, severe asthenia; lack of appetite; increased activity of aminotransferases, alkaline phosphatase, bilirubin and serum creatinine. Uncommon: pseudomembranous colitis, intestinal blockage, intestinal obstruction, gastrointestinal haemorrhage; renal failure; reactions at the infusion site, hypotension, cardiovascular failure; interstitial lung disease; skin reactions; allergic reactions. Rare: colitis, intestinal perforation; hypertension; anaphylactic reactions; hypokalemia, hyponatremia. Very rare: increased activity of amylase and / or lipase; transient speech disorders.Combination therapy. Very common: diarrhea, abdominal pain, mucositis; neutropenia, anemia, thrombocytopenia; dehydration, lack of appetite; alopecia; increased activity of aminotransferases (grades 1 and 2), alkaline phosphatase (grades 1 and 2), serum bilirubin (grades 1 and 2). Common: severe nausea, severe vomiting, constipation; neutropenia with fever; acute cholinergic syndrome, severe asthenia, fever; infection; dyspnoea; increased serum bilirubin (Grade 3). Uncommon: pseudomembranous colitis, intestinal blockage, intestinal obstruction, gastrointestinal haemorrhage; reactions at the infusion site; hypotension, failure of the circulatory system; renal failure; interstitial lung disease; skin reactions; allergic reactions. Rare: colitis, intestinal perforation; hypertension; anaphylactic reactions; hypokalemia, hyponatremia. Very rare: autoimmune thrombocytopenia; increased amylase and / or lipase activity; transient speech disorders. In addition, paresthesia, cramps or muscle spasms have been observed.

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.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. At the beginning of the next infusion cycle, the dose of irinotecan and, if appropriate, 5-fluorouracil should be reduced depending on the severity of the side effects. Treatment can 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.