Index of drugs

Treatment of patients with advanced stage of colorectal cancer: as monotherapy, in patients after failure of 5-fluorouracil therapy; in combination therapy with 5-fluorouracil and folinic acid, in patients not previously treated with advanced chemotherapy. Irinotecan in combination with cetuximab is used to treat patients with a disseminated form of colorectal cancer whose cells express the epidermal growth factor receptor (EGFR) after failure of cytotoxic therapy with irinotecan. Irinotecan in combination with 5- Fluorouracil, folinic acid and bevacizumab is used for the first-line treatment of patients with disseminated colon or rectal cancer.

1 vial contains 40 mg, 100 mg or 300 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 enteritis and / or bowel obstruction. Bilirubin concentration greater than 3-fold GGN. Severe bone marrow failure. WHO efficiency status> 2. Concomitant use of St. John's wort. Pregnancy and breastfeeding. Additional contraindications for cetuximab or bevacizumab 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 the possible risk: in patients at risk of complications whose WHO status is 2; 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, close hospital supervision is recommended. 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 those who have had previous radiotherapy to the abdominal or pelvic area, patients with increased leukocytosis, patients in the WHO> 2 functional state and women. Immediately after the onset of diarrhea, patients should start drinking large amounts of mineral-containing drinks and use anti-diarrheal therapy (high doses of loperamide: the 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 addition to anti-diarrheal treatment, antibiotics with a wide range of effects should be used prophylactically, especially when diarrhea is accompanied by severe neutropenia (neutrophil count <500 / mm³). In addition to the use of antibiotics, hospitalization is recommended for the treatment of diarrhea 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. In patients who develop severe diarrhea, a dose reduction is recommended in subsequent treatment cycles. 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 prophylactic administration of an antiemetic 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 pneumonia (use of lung toxic drugs, radiotherapy and colony stimulating factors) should be closely monitored for their respiratory symptoms prior to therapy and irinotecan. Due to the higher prevalence of organ dysfunction in elderly patients, especially liver function, care should be taken 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.

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 (monotherapy) and, neutropenia (reversible and non-invasive with dose), anemia, thrombocytopenia (in combination therapy), infections (monotherapy), transient alopecia, fever without infection, and without associated severe neutropenia (monotherapy), in combination therapy - transient increase in transaminases, alkaline phosphatase or bilirubin without liver metastases.Common: severe nausea and vomiting (in combination therapy), dehydration (usually associated with diarrhea and / or vomiting), constipation associated with the administration of irinotecan and / or Loperamide, febrile neutropenia, infections (during combination therapy), infections due to severe neutropenia (in 3 cases ended with death), thrombocytopenia (on monotherapy), fever without infection and without associated severe neutropenia (in combination therapy), severe transient cholinergic syndrome, weakness, as monotherapy - transient elevation of transaminases, alkaline phosphatase or bilirubin without hepatic metastases, in combination therapy - transient elevation of grade 3 bilirubin, transient, mild or moderate increase in serum creatinine. Uncommon: pseudomembranous colitis, renal failure, hypotension or cardiovascular failure due to dehydration caused by diarrhea and / or vomiting, intestinal obstruction, gastrointestinal and / or intestinal bleeding, mild skin reactions, reactions around the site of administration, interstitial inflammation pulmonary infiltrates, dyspnea, mild allergic reactions, patients with sepsis - renal failure, 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, hypokalemia, 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.
In the case of combined treatment with cetuximab, additional side effects associated with this drug have been reported (eg acne rash at 88%). 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.

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.Combination 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.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 5FU should be reduced and adjusted to the degree of adverse reactions that occurred during the previous treatment cycle. Treatment should be delayed by 1-2 weeks in order to cure side effects associated with treatment. The dose of irinotecan and / or 5-FU should be reduced by 15-20% in the event of: haematological toxicity (grade 4 neutropenia, febrile neutropenia / grade 3-4 and grade 2-4 fever, thrombocytopenia and leukopenia grade 4) or toxicity non-haematological - 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. Treatment with irinotecan should be continued until disease progression or unacceptable toxicity.Special groups of patients. The initial dose of irinotecan should be adjusted to bilirubin in the blood (up to 3-fold ULN) in patients in the general state WHO ≤2. In patients with hyperbilirubinemia and prothrombin time> 50%, the clearance of irinotecan is reduced and hence the risk of hematologic toxicity is increased. Therefore, in these patients once a week, complete blood counts should be performed. In patients with bilirubin 1.5-fold 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 particularly carefully titrated and subjected to particularly careful monitoring.