Vizirin
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIZIRIN (VISIRIN)
Composition:
Active substance: irinotecan;
1 ml of solution contains irinotecan hydrochloride trihydrate 20 mg;
Excipients: sorbitol (E 420), lactic acid, water for injections.
Pharmaceutical form. Solution for injection.
Main physicochemical properties: clear solution ranging from colorless to slightly yellowish.
Pharmacotherapeutic group.
Antineoplastic agents. Irinotecan. ATC code: L01XX19.
Pharmacological Properties
Pharmacodynamics. Irinotecan is an antineoplastic agent, a semisynthetic derivative of camptothecin—an alkaloid from Camptotheca acuminata—and a specific inhibitor of topoisomerase I.
Irinotecan and its active metabolite SN-38 bind to the "topoisomerase I–DNA" complex and prevent replication of these single-stranded DNA sequences. According to recent studies, the cytotoxicity of irinotecan is associated with double-stranded DNA damage during DNA synthesis, when the replication enzyme interacts with the quaternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38.
Irinotecan is a water-soluble prodrug of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan via a carbamate linkage between camptothecin and a dipiperidine side chain. As an inhibitor of topoisomerase I isolated from human and rodent tumor cell lines, SN-38 is approximately 1,000 times more potent than irinotecan. In vitro cytotoxicity analyses indicate that the potency of SN-38 relative to irinotecan varies from 2 to 2,000-fold. However, the area under the plasma concentration-time curve (AUC) of SN-38 accounts for only 2–8% of that of irinotecan. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxyl anion form. A pH-dependent equilibrium exists between these two forms: acidic pH favors formation of the lactone, while alkaline pH favors the hydroxyl anion form.
Pharmacokinetics. After intravenous infusion in humans, plasma concentrations of irinotecan decline in a multi-exponential manner, with a mean elimination half-life of approximately 6 hours. The mean elimination half-life of SN-38 is about 10 hours. The mean elimination half-lives of the lactone and hydroxyl anion forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, respectively, due to equilibrium between the forms.
Within the dose range of 50–350 mg/m², the area under the concentration-time curve (AUC) of irinotecan increases linearly and dose-dependently; the AUC of SN-38 increases at a slower rate than the dose increase. Maximum SN-38 concentration is reached 1 hour after completion of a 90-minute irinotecan infusion.
Irinotecan is moderately bound to plasma proteins (30–68%). SN-38 is extensively bound to plasma proteins (approximately 95%). Both irinotecan and SN-38 bind primarily to albumin.
Metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and occurs primarily in the liver. Subsequently, SN-38 undergoes glucuronidation to form an inactive metabolite, SN-38 glucuronide. The cytotoxic activity of SN-38 glucuronide is 1/50 to 1/100 that of SN-38, as determined in in vitro assays using two cell lines. The distribution of irinotecan in humans has not been fully characterized. Renal excretion of irinotecan accounts for 11–20% of the administered dose, SN-38 less than 1%, and SN-38 glucuronide about 3%. Cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) within 48 hours after administration ranges from 25% (at 100 mg/m²) to 50% (at 300 mg/m²).
Pharmacokinetics in Specific Populations
Elderly Patients. Studies have not revealed significant differences in the pharmacokinetics of irinotecan, SN-38, or SN-38 glucuronide between elderly individuals and those under 65 years of age. The terminal half-life of irinotecan was 5.5 hours in patients under 65 years and 6 hours in those over 65 years. The AUC0–24 of SN-38 in patients over 65 years was 11% higher than in younger patients; however, this difference was not statistically significant.
Gender. The pharmacokinetics of irinotecan are not influenced by gender.
Race. The pharmacokinetic characteristics of irinotecan in patients of different racial backgrounds have not been studied.
Hepatic Impairment. The clearance of irinotecan is reduced in patients with impaired liver function, resulting in increased SN-38 concentrations. The extent of this effect depends on the degree of hepatic dysfunction, as assessed by serum levels of total bilirubin and transaminases.
Renal Impairment. The effect of renal impairment on the pharmacokinetics of irinotecan has not been studied.
Clinical characteristics.
Indications.
Treatment of patients with advanced colorectal cancer:
- in combination with 5-fluorouracil (5-FU) and folinic acid (FA) – for patients who have not received prior chemotherapy for the treatment of advanced disease;
- monotherapy – for patients in whom treatment with 5-fluorouracil has been ineffective.
Irinotecan in combination with cetuximab is indicated for the treatment of patients with metastatic colorectal cancer with wild-type KRAS gene and overexpressed epidermal growth factor receptor (EGFR), who have not previously received chemotherapy, or following ineffective cytotoxic therapy including irinotecan.
Irinotecan in combination with 5-fluorouracil, folinic acid, and bevacizumab is indicated for the treatment of metastatic colorectal cancer as first-line therapy.
In combination with capecitabine (with or without bevacizumab), irinotecan is used as first-line therapy in patients with metastatic colorectal cancer.
Contraindications.
- Chronic inflammatory bowel diseases and/or bowel obstruction (see section "Special precautions");
- hypersensitivity to irinotecan hydrochloride or to any other components of the medicinal product;
- pregnancy or breastfeeding;
- hyperbilirubinemia (serum bilirubin level exceeding the upper limit of normal by 3 times);
- severe bone marrow suppression;
- patient's general condition > 2 (according to WHO classification);
- severe neutropenia (less than 1.5 × 10⁹/L);
- concomitant use of St. John’s wort (Hypericum perforatum) preparations;
- administration of live attenuated vaccines;
When used in combination with cetuximab, bevacizumab, or capecitabine – additional contraindications listed in the instructions for medical use of the respective medicinal products apply.
Special safety measures.
Care should be taken during the preparation and administration of irinotecan, and protective eyewear, mask, and gloves should be used. If the concentrate or prepared infusion solution comes into contact with the skin, it should be immediately and thoroughly washed off with soap and water. If the concentrate or prepared infusion solution comes into contact with mucous membranes, they should be immediately rinsed with water.
Disposal
All materials used for dilution and administration of the medicinal product should be destroyed according to standard procedures for cytotoxic agents.
Interaction with other medicinal products and other types of interactions.
The following medicinal products are contraindicated for concomitant use with Visirin (see section "Contraindications").
Live attenuated vaccines (e.g., yellow fever vaccine): Risk of generalized vaccine reaction, potentially fatal. Concomitant use of irinotecan is contraindicated during treatment and for 6 months after discontinuation of chemotherapy. Inactivated or killed vaccines may be administered; however, the immune response to such vaccines may be reduced.
St. John’s wort (Hypericum perforatum): Decreased plasma levels of the active metabolite of irinotecan, SN-38. In a small pharmacokinetic study (n = 5), co-administration of irinotecan 350 mg/m² with St. John’s wort 900 mg resulted in a 42% reduction in plasma concentration of SN-38. Therefore, St. John’s wort must not be used concomitantly with irinotecan.
Concomitant use of the following medicinal products with Visirin is not recommended.
Concomitant administration of irinotecan with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter irinotecan metabolism and should be avoided (see section "Special precautions"):
Medicinal products that are strong inducers of CYP3A4 or UGT1A1 (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide):
Caution should be exercised when treating patients who are concurrently taking inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin, carbamazepine, phenobarbital, or phenytoin) of drug metabolism via cytochrome P450 3A4.
Results of several studies have demonstrated that concomitant use of anticonvulsant drugs that are CYP3A inducers (e.g., carbamazepine, phenobarbital, or phenytoin) reduces exposure to irinotecan, SN-38, and SN-38-glucuronide, leading to diminished pharmacodynamic effect. These anticonvulsants reduced the AUC of SN-38 and SN-38-glucuronide by 50% or more. In addition to CYP3A induction, reduced exposure to irinotecan and its metabolites may also be due to enhanced glucuronidation and increased biliary excretion.
Anticonvulsants that do not induce enzymes should be prescribed cautiously, at least one week prior to initiation of irinotecan therapy.
Irinotecan clearance is significantly reduced in patients receiving combined therapy with ketoconazole, resulting in increased SN-38 concentration. Ketoconazole should be discontinued at least one week before starting irinotecan therapy and should not be administered during irinotecan treatment.
Phenytoin – possible exacerbation of seizures due to decreased gastrointestinal absorption of phenytoin under the influence of cytotoxic agents or increased toxicity due to enhanced metabolic conversion under the influence of phenytoin.
Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin).
A study showed that concomitant administration of ketoconazole resulted in an 87% reduction in AUC of metabolite APC and a 109% reduction in AUC of metabolite SN-38 compared to irinotecan monotherapy.
UGT1A1 inhibitors (e.g., atazanavir, ketoconazole, regorafenib).
Concomitant use of atazanavir sulfate, an inhibitor of CYP3A4 and UGT1A1, may increase systemic concentrations of SN-38, the active metabolite of irinotecan. Physicians should consider this when co-prescribing this agent.
Other CYP3A4 inhibitors (e.g., crizotinib, idelalisib).
Risk of increased irinotecan toxicity due to reduced metabolism when used concomitantly with crizotinib or idelalisib.
The following medicinal products should be used concomitantly with Visirin with caution.
Due to increased risk of thrombosis, anticoagulants are frequently prescribed to cancer patients. When vitamin K antagonists are indicated, INR (international normalized ratio) should be monitored more frequently than usual. This is due to the narrow therapeutic range of these agents, high individual variability in coagulation parameters, and potential interactions between oral anticoagulants and anticancer chemotherapeutic agents.
Immunosuppressants (e.g., cyclosporine, tacrolimus) – due to the risk of excessive immune system suppression and development of lymphocyte proliferation.
Neuromuscular blockers: interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, prolonged neuromuscular blockade may occur with succinylcholine, and antagonistic interaction regarding neuromuscular transmission may occur when used concomitantly with non-depolarizing muscle relaxants.
Other combinations.
Adverse effects of irinotecan such as myelosuppression and diarrhea may be exacerbated by other anticancer agents (including fluorocytosine as a prodrug of 5-fluorouracil) that have a similar adverse effect profile.
Use of dexamethasone as an antiemetic increases the likelihood of lymphopenia; however, significant opportunistic infections or specific complications typical of lymphopenia have not been observed.
Hyperglycemia has been reported in patients with diabetes mellitus or impaired glucose tolerance receiving irinotecan. Hyperglycemia may develop in some patients due to the use of dexamethasone as an antiemetic.
Laxatives used during irinotecan therapy may worsen tolerability or increase the severity of diarrhea.
Irinotecan may cause secondary dehydration due to vomiting or diarrhea, which may necessitate discontinuation of diuretics during irinotecan treatment or in cases of severe vomiting or diarrhea.
Interactions common to all cytotoxic agents.
There is no information on the effect of cetuximab on the safety profile of irinotecan or vice versa.
Bevacizumab. Results of a specific drug interaction study did not demonstrate a significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude the possibility of increased toxicity due to their pharmacological properties.
5-Fluorouracil/folinic acid. Concomitant administration of 5-FU/FA as part of combination therapy does not alter the pharmacokinetics of irinotecan.
Special precautions for use
Irinotecan hydrochloride infusion should be administered only in specialized centers where cytotoxic chemotherapy is performed and only under the supervision of a physician experienced in the use of chemotherapy in oncology.
Considering the nature and frequency of adverse effects, irinotecan hydrochloride should be prescribed only when the expected benefit outweighs the potential risk:
- for treatment of patients with risk factors, particularly those with a performance status of 2 (according to WHO scale);
- in individual cases when patients do not comply with recommendations for prevention of adverse effects (especially the need for immediate and prolonged antidiarrheal therapy along with increased fluid intake). Such patients require careful clinical monitoring.
Delayed diarrhea
Patients should be informed about the risk of delayed diarrhea, which may occur more than 24 hours after administration of irinotecan and at any time before the next cycle. When used as monotherapy, the median time to the first episode of loose stools was 5 days after drug administration. Patients must immediately inform their physician about the frequency of such episodes and initiate appropriate treatment.
Patients at increased risk of developing diarrhea include: those previously treated with radiotherapy to the abdominal and pelvic regions; patients with prior hyperleukocytosis; patients with poor general condition (performance status > 2 according to WHO classification); and female patients. If diarrhea is not properly treated, it may become life-threatening, especially when associated with neutropenia.
Upon the first episode of loose stools, patients should be advised to drink fluids containing electrolytes frequently and to immediately initiate appropriate antidiarrheal therapy. Recommended antidiarrheal treatment includes high-dose loperamide (4 mg initially, then 2 mg every 2 hours). This therapy should be continued for an additional 12 hours after the last episode of diarrhea, but not longer than 48 hours—due to the risk of paralytic ileus. The treatment regimen must not be modified. After hospital discharge, patients should be provided with prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should inform their treating physician or the department where they received Vizirin about the occurrence of diarrhea. In cases of diarrhea associated with neutropenia (neutrophil count < 0.5 × 10⁹/L), broad-spectrum antibiotics should be administered prophylactically in addition to antidiarrheal agents.
Hospitalization is required for diarrhea management in the following situations, apart from cases requiring antibiotic therapy: diarrhea accompanied by fever; severe diarrhea (requiring intravenous hydration); diarrhea persisting for more than 48 hours despite high-dose loperamide therapy.
Loperamide should not be prescribed prophylactically, even in patients who experienced late diarrhea in previous treatment cycles. In patients who experienced severe diarrhea, dose reduction of irinotecan is recommended in subsequent treatment cycles. The recommended dose of the drug is 125 mg/m² administered as an intravenous infusion over 90 minutes once weekly for 4 weeks, followed by a 2-week break.
Patients with severe diarrhea are at increased risk of infectious diseases and hematotoxic effects. In such patients, regular complete blood counts are recommended.
Hematological disorders
In clinical studies, the incidence of grade 3–4 neutropenia according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was significantly higher in patients previously irradiated in the pelvic/abdominal region compared to those who did not receive such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or higher also had a significantly higher probability of developing grade 3–4 neutropenia during the first treatment cycle compared to patients with bilirubin levels below 1.0 mg/dL.
Complete blood counts should be performed weekly during irinotecan treatment. Neutropenia accompanied by fever (temperature > 38 °C and neutrophil count < 1 × 10⁹/L) must be urgently treated in a medical facility with intravenous broad-spectrum antibiotics.
Patients who experienced severe hematological adverse reactions should have their irinotecan dose reduced in subsequent administrations (see section "Dosage and administration"). Patients with severe diarrhea are at increased risk of infections and hematological toxicity manifestations. Complete blood count monitoring is required in such patients.
Hepatic impairment
Liver function tests should be performed before initiating therapy and prior to each subsequent cycle. In patients with serum total bilirubin concentrations 1.5 to 3 times above the upper normal limit, complete blood counts should be performed weekly due to reduced irinotecan clearance (see section "Pharmacokinetics") and, consequently, increased risk of hematotoxicity. The drug must not be administered to patients with bilirubin levels exceeding the upper normal limit by more than 3 times (see section "Contraindications").
Nausea and vomiting
Prophylactic antiemetic treatment is recommended before each irinotecan administration. Nausea and vomiting are frequently reported during irinotecan therapy. Patients experiencing vomiting in combination with delayed diarrhea should be urgently hospitalized for appropriate treatment.
Acute cholinergic syndrome
In the absence of clinical contraindications (see section "Adverse reactions"), atropine sulfate 0.25 mg should be administered subcutaneously in case of acute cholinergic syndrome (early diarrhea in combination with other symptoms such as increased sweating, abdominal cramps, miosis, and increased salivation).
These symptoms, which may occur during or immediately after irinotecan infusion, are associated with the anticholinesterase activity of the parent compound irinotecan. It is expected that the frequency of these symptoms increases with higher doses of irinotecan.
Caution should be exercised in patients with bronchial asthma. Patients who experienced acute and severe cholinergic syndrome are recommended to receive prophylactic atropine sulfate prior to subsequent irinotecan infusions.
Respiratory system disorders
Rare cases of interstitial lung disease, manifesting as pulmonary infiltrates, may occur during irinotecan treatment. Interstitial lung disease may lead to fatal outcomes. Risk factors for pulmonary infiltrates include use of pneumotoxic agents, radiotherapy, and colony-stimulating factors. Continuous monitoring of respiratory symptoms before and during irinotecan therapy is required when these risk factors are present.
Extravasation
Although irinotecan is not considered a vesicant, it should be administered with caution, and the infusion site should be monitored for signs of inflammation. In case of extravasation, the infusion site should be flushed and ice applied.
Elderly patients
Due to reduced biological functions, particularly liver function, caution should be exercised when selecting the irinotecan dose for elderly patients (see section "Dosage and administration").
Chronic inflammatory bowel disease and/or bowel obstruction
Irinotecan should not be administered to patients until bowel obstruction has resolved (see section "Contraindications").
Patients with renal impairment
Elevated serum creatinine or blood urea nitrogen levels have been observed. Cases of acute renal failure have occurred. These events were usually associated with complications of infection or dehydration due to nausea, vomiting, or diarrhea. Additionally, isolated cases of renal impairment due to tumor lysis syndrome have been reported.
Cardiac disorders
Myocardial ischemia has been observed after irinotecan treatment, primarily in patients with pre-existing heart disease, other cardiovascular risk factors, or prior cytotoxic chemotherapy (see section "Adverse reactions").
Therefore, patients with risk factors require close monitoring. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia).
Vascular disorders
In patients with multiple risk factors in addition to the primary malignancy, irinotecan use has rarely been associated with thromboembolic complications (pulmonary embolism, venous thrombosis, and arterial thromboembolism).
Immunosuppressants and increased susceptibility to infections
Administration of live or live attenuated vaccines to patients with chemotherapy-induced immunosuppression (including from irinotecan) may lead to severe infections, even with fatal outcomes. Live vaccines should be avoided in patients receiving irinotecan. Inactivated or killed vaccines may be used, but the immune response to such vaccines may be diminished.
Radiation therapy
Patients previously treated with pelvic or abdominal irradiation are at increased risk of myelosuppression during irinotecan therapy. Physicians should use this drug cautiously in patients who previously received extensive radiotherapy (e.g., irradiation of > 25% of bone marrow within 6 weeks before starting irinotecan treatment). This patient group may require dose adjustment of the drug (see section "Dosage and administration").
Others
The product contains sorbitol. If a patient has known intolerance to certain sugars, medical advice should be sought before using the medicinal product. The product must not be administered to patients with hereditary fructose intolerance.
Isolated cases of renal failure, arterial hypotension, or circulatory failure have been observed in patients who experienced diarrhea, vomiting, or sepsis leading to dehydration.
During treatment and for at least 3 months after completion of therapy, patients should use effective contraception methods.
Concomitant administration of irinotecan with a strong inhibitor (e.g., ketoconazole) or inducer (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort, apalutamide) of CYP3A4 may alter irinotecan metabolism (see section "Interaction with other medicinal products and other forms of interaction").
Use during pregnancy or breastfeeding
The medicinal product is contraindicated during pregnancy or breastfeeding due to its high toxicity.
Women of childbearing potential should use effective contraception during treatment and for 1 month after treatment. Men should use effective contraception during treatment and for 3 months after completion of therapy.
Ability to affect reaction rate when driving or operating machinery
Patients should be warned about the possible occurrence of dizziness and visual disturbances during irinotecan treatment, which may develop within 24 hours, and advised to refrain from driving or operating potentially hazardous machinery if use of the drug is necessary.
Administration and Dosage.
The medication is intended for treatment of adults only. The infusion solution must be administered into a peripheral or central vein.
Preparation of the solution for intravenous administration.
As with other injectable medications, the drug solution should be prepared under aseptic conditions. If visible precipitate is present in the vial or after reconstitution, the product should be discarded following standard procedures for disposal of cytotoxic agents.
Under aseptic conditions, withdraw the required amount of drug solution from the vial using a calibrated syringe and transfer the dose into a 250 mL bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. Mix the solution thoroughly by manually inverting the container.
Recommended dosages of the drug.
As monotherapy, the drug is typically administered once every 3 weeks. However, for patients who may require closer monitoring or who are at increased risk of developing severe neutropenia, a weekly administration schedule may be considered (see section "Pharmacological properties").
Monotherapy (for previously treated patients): the recommended dose of the drug is 350 mg/m² body surface area administered as an intravenous infusion over 30–90 minutes every 3 weeks (see section "Special instructions").
Combination therapy (for treatment-naïve patients): in combination with 5-fluorouracil (5-FU) and folinic acid (FA), the drug should be administered according to the following dosing schedule (see section "Pharmacodynamics") – Vezirin and 5-FU/FA every 2 weeks. The recommended dose of Vezirin is 180 mg/m² body surface area administered as an intravenous infusion over 30–90 minutes once every 2 weeks, followed by infusion of folinic acid or 5-fluorouracil. The same dose of irinotecan as used in the last cycles of prior irinotecan-containing therapy should generally be applied. Irinotecan should be administered no earlier than 1 hour after completion of cetuximab infusion.
Dose adjustment.
Vezirin should be administered only after all adverse reactions have adequately resolved to grade 0 or 1 according to the NCI-CTC scale (National Cancer Institute Common Toxicity Criteria) and after complete resolution of treatment-related diarrhea.
At the beginning of each subsequent infusion, the dose of the drug and 5-FU (if used) should be reduced based on the most severe adverse reaction observed during the previous infusion.
Treatment initiation should be delayed by 1–2 weeks to allow resolution of treatment-related adverse reactions.
The dose of the drug and/or 5-FU should be reduced by 15–20% in the event of the following adverse reactions:
- Hematotoxicity (grade IV neutropenia, febrile neutropenia (grade III–IV neutropenia accompanied by fever of grade II–IV), thrombocytopenia, and leukopenia (grade IV));
- Non-hematological toxicity (grade III–IV).
For patients aged 65 years and older receiving irinotecan and capecitabine, the capecitabine dose should be reduced to 800 mg/m² body surface area twice daily.
Duration of treatment.
Treatment with the drug should continue until objective disease progression or development of signs of unacceptable toxicity.
Patients with hepatic impairment.
Monotherapy.
For patients with a performance status index ≤ 2, the initial dose of the drug should be determined based on serum bilirubin levels (when bilirubin levels are elevated up to 3 times the upper limit of normal). In such patients with hyperbilirubinemia and prothrombin time exceeding normal by more than 50%, irinotecan clearance is reduced (see section "Pharmacokinetics"), resulting in an increased risk of hematotoxicity. Therefore, weekly monitoring of complete blood count is recommended in these patients.
- For patients with bilirubin levels up to 1.5 times the upper limit of normal, the recommended dose is 350 mg/m² body surface area.
- For patients with bilirubin levels between 1.5 and 3 times the upper limit of normal, the recommended dose is 200 mg/m² body surface area.
- The drug should not be administered to patients with bilirubin levels exceeding 3 times the upper limit of normal (see sections "Contraindications" and "Special instructions").
There is no information available on the use of the drug in combination with other agents in patients with hepatic impairment.
Patients with renal impairment.
The use of the drug in patients with renal impairment is not recommended, as studies in this patient population have not been conducted (see sections "Special instructions" and "Pharmacokinetics").
Elderly patients.
No specific pharmacokinetic studies have been conducted in elderly patients. However, dose selection in this patient group should be cautious due to the higher likelihood of decreased physiological functions. These patients require more intensive monitoring (see section "Special instructions").
As with other antineoplastic agents, Vezirin should be prepared and administered with caution. The use of protective eyewear, mask, and gloves is mandatory.
In case of contact of concentrate or infusion solution with the skin, the area should be immediately flushed and thoroughly washed with soap and water; in case of contact with mucous membranes, the area should be immediately rinsed with water.
Disposal.
All materials used for reconstitution and administration of the drug must be disposed of in accordance with the healthcare institution's standard procedures for cytotoxic agents.
Children.
Irinotecan is not used for the treatment of children.
Overdose.
Overdose has been associated with an intensification of adverse effects. An overdose twice the recommended therapeutic dose may be fatal. The most significant adverse effects in overdose were severe neutropenia and diarrhea. There is no specific antidote for irinotecan. Intensive supportive therapy should be initiated immediately to prevent dehydration due to diarrhea and to treat infectious complications. Treatment is symptomatic.
Adverse reactions.
Clinical studies.
Data on adverse reactions were carefully collected during studies in metastatic colorectal cancer; the frequency of their occurrence is presented below. When the medicinal product is used for indications other than colorectal cancer, similar adverse reactions are expected to occur.
The most common (≥ 1/10) dose-limiting adverse reactions of irinotecan are delayed diarrhea (occurring more than 24 hours after drug administration) and hematological disorders, including neutropenia, anemia, and thrombocytopenia.
Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; during monotherapy or combination therapy, the median time to reach the minimum neutrophil level was 8 days.
A transient acute cholinergic syndrome of severe degree was very frequently observed. Its main symptoms were early diarrhea and various other symptoms such as abdominal pain, sweating, miosis, and increased salivation, occurring during or within the first 24 hours after irinotecan infusion. These symptoms resolved after administration of atropine (see section "Dosage and administration").
Monotherapy.
The adverse reactions listed below, possibly or probably related to irinotecan administration, were observed in 765 patients receiving the recommended dose of 350 mg/m² as monotherapy. The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Adverse reactions reported during monotherapy with irinotecan (schedule 350 mg/m² every 3 weeks):
Infections and infestations.
Common: infections.
Blood and lymphatic system disorders.
Very common: neutropenia, anemia.
Common: thrombocytopenia, febrile neutropenia.
Metabolism and nutrition disorders.
Very common: decreased appetite.
Nervous system disorders.
Very common: cholinergic syndrome.
Gastrointestinal disorders.
Very common: diarrhea, vomiting, nausea, abdominal pain.
Common: constipation.
Skin and subcutaneous tissue disorders.
Very common: alopecia (reversible).
General disorders and administration site conditions.
Very common: mucositis, fever, asthenia.
Investigations.
Common: increased blood creatinine, increased transaminases (alanine aminotransferase and aspartate aminotransferase), increased bilirubin, increased alkaline phosphatase in blood.
Description of selected adverse reactions (during monotherapy).
Severe diarrhea was observed in 20% of patients who followed diarrhea management recommendations. In evaluable treatment cycles, severe diarrhea occurred in 14%. The median time to onset of loose stools after irinotecan infusion was 5 days.
Nausea and vomiting were severe in approximately 10% of patients receiving antiemetic prophylaxis.
Constipation occurred in less than 10% of patients.
Neutropenia was observed in 78.7% of patients, of whom severe grade (neutrophil count < 500 cells/mm³) occurred in 22.6%. In evaluable treatment cycles, neutrophil count was below 1,000 cells/mm³ in 18%, including 7.6% with neutrophil count < 500 cells/mm³.
Complete recovery usually took up to 22 days.
Fever with severe neutropenia was observed in 6.2% of patients and in 1.7% of all treatment cycles.
Infectious episodes occurred in approximately 10.3% of patients (2.5% of all treatment cycles) and were associated with severe neutropenia in about 5.3% of patients (1.1% of all treatment cycles); in 2 cases, this complication led to a fatal outcome.
Anemia was reported in approximately 58.7% of patients (8% with hemoglobin < 8 g/dL and 0.9% with hemoglobin < 6.5 g/dL).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4% of patients (1.8% of all treatment cycles), of whom 0.9% of patients (0.2% of treatment cycles) had platelet counts ≤ 50,000 cells/mm³.
In nearly all patients, recovery took up to 22 days.
Acute cholinergic syndrome.
Transient acute cholinergic syndrome of severe degree was observed in 9% of patients receiving monotherapy.
Asthenia was severe in less than 10% of patients receiving monotherapy. The causal relationship between this event and irinotecan administration was not clearly established. Fever in the absence of infection or concomitant severe neutropenia occurred in 12% of patients receiving monotherapy.
Laboratory tests.
Mild or moderate transient increases in serum transaminases, alkaline phosphatase, or bilirubin were observed in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases.
Mild or moderate transient increase in serum creatinine was observed in 7.3% of patients.
Combination therapy.
The adverse reactions described in this section relate to irinotecan.
There is no evidence that cetuximab affects the safety profile of irinotecan or vice versa. During combination therapy with cetuximab, additional adverse reactions expected with cetuximab use were reported (e.g., acneiform rash in 88% of cases). Information on adverse reactions with combined use of irinotecan and cetuximab is also provided in the cetuximab prescribing information.
The following adverse reactions were observed in patients receiving capecitabine in combination with irinotecan, in addition to those observed during capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy. Very common, all grades of adverse reactions: thrombosis/embolism.
Common, all grades of adverse reactions: hypersensitivity reactions, ischemia/myocardial infarction.
Common, adverse reactions of grade 3 and 4: febrile neutropenia.
Complete information on capecitabine adverse reactions is provided in the prescribing information for this medicinal product.
The following adverse reactions of grade 3 and 4 severity were observed in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those observed during capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy.
Common, adverse reactions of grade 3 and 4: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction.
Arterial hypertension of grade 3 was the main significant risk factor associated with adding bevacizumab to the treatment regimen of bolus irinotecan/fluorouracil (5-FU)/folinic acid (FA). Also, with this regimen, the frequency of grade III–IV diarrhea and leukopenia was slightly increased compared to patients receiving bolus irinotecan/5-FU/FA without bevacizumab.
Additional information on adverse reactions with combination therapy including bevacizumab is provided in the prescribing information for this medicinal product.
Studies evaluating the use of irinotecan in combination with 5-FU and FA for the treatment of metastatic colorectal cancer have been conducted.
Safety data from clinical trials show that adverse reactions of grade 3 or 4 according to the National Cancer Institute scale, possibly or probably related to therapy, are very commonly observed in the following MedDRA organ system classes: blood and lymphatic system disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders.
The following adverse reactions, possibly or probably related to irinotecan and observed in 145 patients receiving irinotecan at the recommended dose of 180 mg/m² in combination with 5-FU/FA every 2 weeks, are listed below.
Adverse reactions reported during combination therapy with irinotecan (schedule 180 mg/m² every 2 weeks):
Infections and infestations.
Common: infections.
Blood and lymphatic system disorders.
Very common: thrombocytopenia, neutropenia, anemia.
Common: febrile neutropenia.
Metabolism and nutrition disorders.
Very common: decreased appetite.
Nervous system disorders.
Very common: cholinergic syndrome.
Gastrointestinal disorders.
Very common: diarrhea, vomiting, nausea.
Common: abdominal pain, constipation.
Skin and subcutaneous tissue disorders.
Very common: alopecia (reversible).
General disorders and administration site conditions.
Very common: mucositis, asthenia.
Common: fever.
Investigations.
Very common: increased transaminases (ALT and AST), increased bilirubin, increased alkaline phosphatase in blood.
Description of selected adverse reactions (during combination therapy).
Severe diarrhea was observed in 13.1% of patients who followed diarrhea management recommendations. In evaluable treatment cycles, severe diarrhea occurred in 3.9%.
Severe nausea and vomiting occurred less frequently (in 2.1% and 2.8% of patients, respectively).
Constipation due to irinotecan and/or loperamide occurred in 3.4% of patients. Neutropenia was observed in 82.5% of patients, of whom severe grade (neutrophil count < 500 cells/mm³) occurred in 9.8%. In evaluable treatment cycles, neutrophil count was below 1,000 cells/mm³ in 67.3%, including 2.7% with neutrophil count < 500 cells/mm³. Complete recovery usually took 7–8 days.
Fever with severe neutropenia was observed in 3.4% of patients and in 0.9% of all treatment cycles.
Infectious episodes occurred in approximately 2% of patients (0.5% of all treatment cycles) and were associated with severe neutropenia in about 2.1% of patients (0.5% of all treatment cycles); in one case, this complication led to a fatal outcome.
Anemia was observed in 97.2% of patients (2.1% with hemoglobin < 8 g/dL).
Thrombocytopenia (< 100,000 cells/mm³) was observed in 32.6% of patients and in 21.8% of all treatment cycles. No cases of severe thrombocytopenia (< 50,000 cells/mm³) were observed.
Acute cholinergic syndrome.
Transient acute cholinergic syndrome of severe degree was observed in 1.4% of patients receiving combination therapy.
Asthenia was severe in 6.2% of patients receiving combination therapy. The causal relationship between this event and irinotecan administration was not clearly established.
Fever in the absence of infection or concomitant severe neutropenia occurred in 6.2% of patients receiving combination therapy.
Laboratory tests.
Transient increases (grades 1 and 2) in serum AST, ALT, alkaline phosphatase, or bilirubin were observed in 15%, 11%, 11%, and 10% of patients, respectively, in the absence of progressive liver metastases. Transient grade 3 increases in these parameters were observed in 0%, 0%, 0%, and 1% of patients, respectively. No grade 4 increases were observed.
Very rare reports of increased amylase and/or lipase levels were received. Rare cases of hypokalemia and hyponatremia were reported, primarily associated with diarrhea and vomiting.
Other adverse reactions reported in clinical trials of weekly irinotecan regimen.
Additional adverse reactions associated with the use of the drug were identified in clinical trials using a weekly schedule: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin symptoms, gait disturbance, confusion, headache, syncope, hot flashes, bradycardia, urinary tract infections, chest pain, increased gamma-glutamyl transferase, hemorrhage, tumor lysis syndrome, cardiovascular disorders (angina, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders, vascular disorders), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebrovascular accident, deep vein thrombophlebitis, lower limb venous embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Dosage and administration").
Post-marketing surveillance.
The frequency of adverse reactions during post-marketing surveillance is unknown (cannot be estimated from available data).
Infections and infestations: pseudomembranous colitis, one case of which was confirmed bacteriologically (Clostridium difficile), sepsis, fungal infection*, viral infection**.
Blood and lymphatic system disorders: peripheral thrombocytopenia with formation of anti-platelet antibodies.
Metabolism and nutrition disorders: dehydration (due to diarrhea and vomiting), hypovolemia.
Immune system disorders: hypersensitivity reactions, anaphylactic reaction.
Nervous system disorders: speech disorders, mostly reversible and in some cases associated with cholinergic syndrome observed during or immediately after irinotecan infusion, paresthesia, involuntary muscle contractions.
Cardiac disorders: arterial hypertension (during or after infusion), cardiac failure***.
Vascular disorders: hypotension***.
Respiratory, thoracic and mediastinal disorders: interstitial lung disease, manifesting as pulmonary infiltrates, infrequently observed during irinotecan treatment [cases of early effects such as dyspnea have been reported (see section "Dosage and administration")]; hiccups.
Gastrointestinal disorders: intestinal obstruction, ileus (including cases of ileus without preceding colitis), megacolon, gastrointestinal hemorrhage, colitis, in some cases colitis complicated by ulcers, bleeding, ileus, or infection, typhlitis, ischemic colitis, ulcerative colitis, gastrointestinal bleeding, symptomatic or asymptomatic elevation of pancreatic enzymes, intestinal perforation.
Hepatobiliary disorders: steatohepatitis, hepatic steatosis.
Skin and subcutaneous tissue disorders: skin reactions.
General disorders and administration site conditions: infusion site reactions.
Investigations: increased blood amylase, increased lipase, hypokalemia, hyponatremia, primarily associated with diarrhea and vomiting, very rare reports of increased serum transaminases (AST and ALT) in the absence of progressive liver metastases.
Musculoskeletal and connective tissue disorders: muscle contractions or cramps.
Renal and urinary disorders: renal function impairment and acute renal failure (usually observed in patients with infection and/or hypovolemia developed due to severe gastrointestinal toxicity***), renal failure***.
*e.g., Pneumocystis pneumonia, bronchopulmonary aspergillosis, systemic candidiasis. **Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.
***Rare cases of renal failure, hypotension, or cardiac failure were observed in patients who experienced dehydration due to diarrhea and/or vomiting or sepsis.
Shelf life. 2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of the reach of children. Do not freeze.
Incompatibilities.
The medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution or 5% glucose solution.
Packaging. 5 ml in a vial, 1 vial in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Venus Remedies Limited.
Manufacturer's address and place of business. Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.