Index of drugs

Treatment of advanced colorectal cancer: in combination with 5-fluorouracil and folinic acid in patients who have not received advanced cancer chemotherapy, as monotherapy in patients who have failed treatment with 5-fluorouracil. In combination with cetuximab, irinotecan is indicated for the treatment of patients with metastatic colorectal cancer (EGRF) expressing epithelium, with a wild-type KRAS gene not previously receiving treatment for metastasis or after failure with irinotecan-containing cytotoxic therapy. In combination with 5- Fluorouracil, folinic acid and bevacizumab, irinotecan is indicated as the first line treatment in patients with metastatic colorectal cancer. In combination with capecitabine and with or without bevacizumab, irinotecan is indicated as the first line treatment in patients with metastatic carcinoma of the colon and rectum.

1 vial contains 40 mg or 100 mg irinotecan hydrochloride trihydrate. The preparation contains sorbitol.

An anti-cancer drug, selectively inhibiting the activity of topoisomerase I DNA, a semi-synthetic derivative of camptothecin. In most tissues, it is metabolized to SN-38, a compound with greater activity than irinotecan relative to purified topoisomerase I and showing more potent cytotoxic activity against numerous mouse and human tumor cell lines. Inhibition of topoisomerase I DNA activity by irinotecan or SN-38 results in the formation of single-stranded DNA segments blocking the replication fork of DNA and responsible for the cytotoxic properties of the drug. The cytotoxic effect is time-dependent and specific to the S phase. In addition to the anti-cancer effect, the drug inhibits acetylcholinesterase. Irinotecan and SN-38 bind to plasma proteins at 65% and 95%, respectively. Two metabolic pathways have been characterized, each of which affects at least 12% of the administered drug dose: hydrolysis with carboxyl esterase to the active metabolite SN-38; oxidation processes involving cytochrome P450 3A enzymes. Over 50% of the dose is excreted unchanged, of which 33% in the faeces through bile and 22% in the urine. Medium T_0,5 in blood in the first phase of the three-phase model is 12 minutes, in the second phase - 2.5 hours and the final phase of elimination is 14.2 hours.

Severe hypersensitivity to irinotecan or to any of the excipients. Chronic inflammatory bowel disease and / or intestinal obstruction. Concentration of bilirubin over 3 times higher than ULN. Severe bone marrow dysfunction. General condition according to the WHO classification> 2. Concomitant use of St. John's wort. Pregnancy and breastfeeding. Additional contraindications for the use of cetuximab, bevacizumab or capecitabine can be found in the information materials of these preparations.

The drug should only be administered in departments specialized in the use of cytotoxic chemotherapy and under the supervision of a physician qualified in the use of anti-cancer chemotherapy. Due to the nature and frequency of adverse reactions, irinotecan should only be prescribed in the following cases, after an assessment of the expected benefits to a possible risk: in risk patients, in particular those in a WHO grade 2 WHO status; in rare cases, when patients are unable to adhere to the recommendations for the treatment of side effects (the need for immediate and long-term anti-diarrheal treatment combined with drinking large amounts of fluid after the onset of delayed diarrhea). In such cases, it is recommended that patients be placed in the hospital and subject to strict observation. Irinotecan monotherapy is usually used once daily for 3 weeks, however, in patients who require more accurate monitoring or are particularly at risk for severe neutropenia, a once weekly schedule may be considered. Patients should be informed about the possibility of diarrhea, which may occur more than 24 hours after administration of the drug or at any time before the start of the Next course of therapy.Patients should promptly inform the attending physician about the occurrence of diarrhea and start appropriate treatment immediately. Patients with an increased risk of diarrhea include: people with previous radiotherapy of the abdominal or pelvic region, patients with increased leukocytosis before treatment, patients in the WHO status of ≥2 and women. Immediately after the onset of diarrhea patients should start drinking large amounts of electrolyte-containing drinks and use anti-diarrheal therapy (high doses of loperamide: first 4 mg dose, then 2 mg every 2 hours), which should be continued for 12 hours after the last liquid stool. Do not modify the dose. Anti-diarrheal therapy should in no case be used for more than 48 hours due to the risk of paralytic ileus and shorter than 12 hours. Do not administer Loperamide prophylactically, even in those patients whose delayed diarrhea occurred during previous courses of treatment with irinotecan. In cases of diarrhea and severe neutropenia (neutrophil count <500 / mm)³), in addition to anti-diarrheal treatment, prophylactically antibiotics with a broad spectrum of activity are used. The patient should undergo a hospital treatment in the following cases: diarrhea with accompanying fever, severe diarrhea (intravenous hydration is necessary), diarrhea within 48 hours of starting therapy with high doses of loperamide. In patients who develop severe diarrhea, it is recommended to reduce the dose of irinotecan in subsequent courses of treatment. During treatment with irinotecan a weekly full blood test is recommended. Patients should be informed about the risk of neutropenia and the importance of fever. Febrile neutropenia (temperature> 38st.C and neutrophil count ≤1000 / mm³) should be treated immediately in a hospital setting, with intravenous antibiotics with a wide range of action. In patients with severe haematological adverse reactions, a dose reduction is recommended in subsequent treatment courses. In patients with severe diarrhea, there is an increased risk of hematologic infection and toxicity, in these patients a complete blood count should be performed. Testing of liver function parameters should be performed before starting treatment and before each subsequent course of therapy. In patients with bilirubin 1.5-3 times more than GGN, a full blood count should be performed weekly, because the clearance of irinotecan in these patients is reduced (risk of hematopoietic damage). Before each administration of irinotecan, a preventive administration of an antiemetic and anti-nausea medicine is recommended. Patients who experience vomiting and delayed diarrhea should be hospitalized immediately. In cases of acute cholinergic syndrome, atropine sulphate (0.25 mg subcutaneously) should be administered unless there are contraindications. Use with caution in patients with asthma. In patients with 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 (use of lung toxic drugs, radiotherapy and colony stimulating factors) should be closely monitored for their respiratory symptoms before and during treatment with irinotecan. Due to the higher prevalence of biological dysfunction in elderly patients, especially liver function, caution should be used when selecting the dose of the drug. Patients with intestinal obstruction must not be treated with irinotecan before the occlusion has subsided. No studies have been performed in patients with impaired renal function. SN-38 is detoxified to SN-38 glucuronide via the UGT1A1 gene. In people with congenital low expression of UGT1A1 (Crigler Najjara type I and type II syndrome and in persons homozygous for the UGT1A1 * 28 allele [Gilbert's syndrome]), the risk of irinotecan toxicity is increased - in these patients a reduction of the initial dose is recommended. Due to the sorbitol content, the preparation should not be used for congenital fructose intolerance. The concomitant use of irinotecan with potent inhibitors or inducers of CYP3A4 should be avoided. Irinotecan should not be used in children.

The preparation is contraindicated in pregnancy and breast-feeding. Women of childbearing age and men must use methods of contraception during treatment and for at least 3 months after its completion.

Very common: severe delayed diarrhea, severe nausea and vomiting (as monotherapy) and, neutropenia (reversible and non-invasive), anemia, thrombocytopenia (during combination therapy), infection (during monotherapy), transient alopecia, fever without infection and no severe neutropenia (as monotherapy), in combination therapy - transient increase in transaminases, alkaline phosphatase or bilirubin without progressive liver metastases. Common: severe nausea and vomiting (in combination therapy), dehydration (usually associated with diarrhea and / or vomiting), constipation associated with irinotecan and / or Loperamide, febrile neutropenia, infection (during combination therapy), severe infection neutropenia (in 3 cases ended with death), thrombocytopenia (during monotherapy), fever without infection and without severe neutropenia (in combination therapy), severe transient cholinergic syndrome, weakness, as monotherapy - transient elevation of transaminases, alkaline phosphatase or bilirubin without metastases to the liver, in combination therapy - transient increase in grade 3 bilirubin, transient, mild or moderate increase in serum creatinine. Uncommon: pseudomembranous colitis, renal failure, hypotension or cardiovascular failure due to dehydration, intestinal obstruction, gastrointestinal bleeding, mild skin reactions, reactions around the site of administration, interstitial pneumonitis manifesting as pulmonary infiltrates, shortness of breath, mild reactions allergic, in patients with sepsis - renal insufficiency, hypotension or cardiovascular failure. Rare: colitis (including inflammation of the caecum and ischemic or ulcerative colitis), perforation of the intestine, lack of appetite, abdominal pain, gastritis, symptomatic or asymptomatic pancreatitis, hypokalaemia, hyponatremia, anaphylactic / anaphylactoid reactions, hypertension during or after infusion, muscle spasms, paresthesia. Very rare: case of peripheral thrombocytopenia with antiplatelet antibodies, amylase and / or lipase elevations, transient speech disorders, tumor decay syndrome.
The most common adverse reactions limiting the dose of Irinotecan: delayed diarrhea (occurring more than 24 hours after administration) and blood disorders such as neutropenia, anemia or thrombocytopenia. A severe, transient, acute cholinergic syndrome was often observed. The main symptoms were defined as early diarrhea and a set of symptoms such as: abdominal pain, conjunctivitis, hay fever, hypotension, vasodilatation, sweating, chills, poor general well-being, dizziness, blurred eyesight, miosis, watery eyes and excessive salivation that appear within 24 hours of the first infusion of irinotecan. In the case of combined treatment with cetuximab, additional side effects associated with this drug have been reported (eg acne rash at 88%). Adverse reactions occurring in patients treated with capecitabine in combination with irinotecan, in addition to those observed during monotherapy with capecitabine (or reported more frequently than with capecitabine alone) are: very often - thrombosis / embolism; often - hypersensitivity reaction, myocardial ischemia / myocardial infarction, febrile neutropenia. Grade 3 and 4 adverse reactions reported in patients treated with capecitabine in combination with irinotecan and bevacizumab, in addition to bevacizumab monotherapy or reported more frequently than monotherapy with capecitabine, include: neutropenia, thrombosis / embolism, hypertension and myocardial ischemia / infarction myocardium.

Only in adults. The dilution solution should be infused into a peripheral or central vein.monotherapy (in previously treated patients): the recommended dose is 350 mg / m² pc. once every 3 weeks, by intravenous infusion lasting 30-90 min.Multidrug therapy (in previously untreated patients): irinotecan with 5 FU / FA in the regimen every 2 weeks - 180 mg / m² pc.irinotecan once every 2 weeks as an intravenous infusion lasting 30-90 min, followed by an infusion of FA and 5FU. Dosage and method of administration of concomitant cetuximab is found in the Summary of Product Characteristics (SmPC). Typically, the same dose of irinotecan is used as in the last cycles of an earlier treatment regimen containing irinotecan. Irinotecan can not be administered earlier than 1 hour after completing the cytuximab infusion. Dosage and method of administration of co-administered bevacizumab is included in the SPC. The dosage and method of administration of concomitant capecitabine are given below and the SmPC. Data from a randomized, controlled phase III trial confirms the appropriateness of using capecitabine at an initial dose of 1000 mg / m² pc. the first line of patients with metastatic colorectal cancer. Data from the transient analysis of a multicentre, randomized, controlled phase II study supports the use of capecitabine at a starting dose of 800 mg / m² pc. for 2 weeks in cycles every 3 weeks, in combination with irinotecan and bevacizumab, for the first-line treatment of patients with metastatic colorectal cancer.Dosage modifications. The preparation can be administered after the reduction of adverse reactions to grade 0 or 1 according to the NCI-CTC toxicity scale and complete resolution of diarrhea associated with the treatment. At the beginning of the next course of treatment, the dose of irinotecan and, if appropriate, 5FU should be reduced, depending on the most serious side effects that occurred during the previous treatment cycle. The dose of irinotecan and / or 5FU should be reduced by 15-20% in the presence of haematological toxicity (grade 4 neutropenia, febrile neutropenia / grade 3-4 and grade 2-4 fever, thrombocytopenia and leukopenia grade 4) or non-haematological toxicity - grade 3-4. The dose recommendations for cetuximab given in combination with irinotecan and bevacizumab given in combination with irinotecan / 5FU / FA in the SPC should be followed. If combination therapy with capecitabine is used in patients ≥65 years, it is recommended to reduce the starting dose of capecitabine to 800 mg / m² pc, administered twice a day. Treatment with irinotecan should be continued until objective progression of the disease or intolerable toxicity.Special groups of patients. In patients in the ≤2 functional state, the parameter determining the starting dose of irinotecan should be the concentration of bilirubin in the blood (up to 3 times higher than ULN). In such patients with hyperbilirubinaemia and prothrombin time> 50%, the clearance of irinotecan is reduced and therefore the risk of hematologic toxicity is increased. Therefore, in these patients, complete blood counts should be performed once a week. In patients with a bilirubin concentration 1.5 times greater than ULN, the recommended dose of irinotecan is 350 mg / m² pc .; in patients whose bilirubin levels are 1.5 to 3 times higher than GGN, the recommended dose of irinotecan is 200 mg / m² pc. Irinotecan should not be used in patients with a concomitant bilirubin> 3-fold GGN. There are no data in patients with hepatic impairment treated with irinotecan in combination chemotherapy. The use of irinotecan in patients with impaired renal function is not recommended due to lack of testing. Elderly patients should be carefully titrated and subjected to particularly careful monitoring.