Irinotecan medac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN MEDAC (IRINOTECAN MEDAC)

Composition:

Active substance: irinotecan;

1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate (equivalent to 17.33 mg of irinotecan);

Excipients: lactic acid, sorbitol (E 420), sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear yellow-colored solution.

Pharmacotherapeutic group.

Antineoplastic agents. Topoisomerase I inhibitors.

ATC code L01CE02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Irinotecan is a semisynthetic derivative of camptothecin. It is an antineoplastic agent that acts as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase in most tissues, the drug is metabolized to SN-38, a compound that is more active against purified topoisomerase I and more cytotoxic than irinotecan against several human and murine tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 causes single-strand DNA breaks, which block the replication fork and lead to cytotoxic effects. This cytotoxic effect has been shown to be time-dependent and specific to the S-phase of the cell cycle.

In vitro, irinotecan and SN-38 were not significantly recognized by P-glycoprotein, a multidrug resistance protein, and demonstrated cytotoxic activity against cell lines resistant to doxorubicin and vinblastine.

Moreover, irinotecan exhibits a broad spectrum of antitumor activity in vivo against murine tumor models (pancreatic duct adenocarcinoma P03, mammary adenocarcinoma MA16/C, colon adenocarcinomas C38 and C51) and human tumor xenografts (colon adenocarcinoma Co-4, mammary adenocarcinoma Mx-1, gastric adenocarcinomas ST-15 and ST-16). Irinotecan is also effective against tumors expressing P-glycoprotein, a multidrug resistance protein (vincristine- and doxorubicin-resistant leukemia P388).

In addition to the antitumor activity of Irinotecan medac, the most significant pharmacological effect of irinotecan is inhibition of acetylcholinesterase activity.

Clinical study data

First-line combination therapy for metastatic colorectal carcinoma

In combination with folinic acid and 5-fluorouracil.

A phase III study was conducted in 385 patients with metastatic colorectal cancer who had not previously received treatment for this disease. Treatment was administered according to either a "once every 2 weeks" regimen or a "once weekly" regimen (see section "Administration and dosage"). In the "once every 2 weeks" regimen, on day 1, irinotecan was administered at a dose of 180 mg/m² body surface area (once every 2 weeks), followed by infusions of folinic acid (FA) (200 mg/m² body surface area intravenously over 2 hours) and 5-fluorouracil (5-FU) (400 mg/m² body surface area intravenous bolus, followed by 600 mg/m² body surface area intravenously over 22 hours as a continuous infusion). On day 2, FA and 5-FU were administered at the same doses and according to the same schedule. In the "once weekly" regimen, for 6 weeks, after administration of irinotecan at a dose of 80 mg/m² body surface area, infusions of FA (500 mg/m² body surface area intravenously over 2 hours) and 5-FU (2300 mg/m² body surface area intravenously over 24 hours as a continuous infusion) were given. In the combination therapy study using the two regimens described above, the efficacy of irinotecan was evaluated in 198 patients.

5-FU: 5-fluorouracil

FA: folic acid

NS – not significant;

* according to the analysis performed in the per-protocol treatment group.

With the "once weekly" regimen, the incidence of severe diarrhea was 44.4% in patients receiving irinotecan in combination with 5-FU/FA and 25.6% in patients receiving 5-FU/FA alone. The incidence of severe neutropenia (neutrophil count less than 500 cells/mm³) was 5.8% in patients receiving irinotecan in combination with 5-FU/FA and 2.4% in patients receiving 5-FU/FA alone. In addition, the median time to definitive deterioration in health status was significantly longer in the combination therapy group receiving irinotecan compared to the group receiving 5-FU/FA alone (p=0.046).

Quality of life in this phase III study was assessed using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration was consistently longer in the irinotecan treatment group. Gradual changes in the Global Health Status/Quality of Life score in the combination therapy group with irinotecan were slightly better (although not significant), suggesting that effective treatment with irinotecan as part of combination therapy does not compromise quality of life.

In combination therapy with bevacizumab

The evaluation of bevacizumab in combination with irinotecan/5-FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum was conducted in a randomized, double-blind, active-controlled phase III clinical trial (study AVF2107g). The addition of bevacizumab to the combination of irinotecan/5-FU/FA resulted in a statistically significant improvement in overall survival. The clinical benefit, assessed by overall survival, was evident across all predefined patient subgroups, including those defined by age, sex, performance status, primary tumor location, number of affected organs, and duration of metastatic disease (see also the prescribing information for bevacizumab). The efficacy results from study AVF2107g are presented in the table below.

a 5 mg/kg every 2 weeks;
b compared with the control group;
CI – confidence interval.

In combination with cetuximab

The randomized EMR 62202-013 study involving 599 patients with metastatic colorectal cancer who had not previously received treatment was conducted to compare the combination of cetuximab and irinotecan with or without the addition of 5-FU/FA infusions (599 patients). In the patient group evaluated for KRAS gene status, patients with tumors characterized by wild-type KRAS accounted for 64%. The efficacy results obtained in this study are presented in the table below.

In combination therapy with capecitabine

Results of a phase III randomized controlled trial (CAIRO) confirm the use of capecitabine at an initial dose of 1000 mg/m² body surface area (for 2 weeks out of every 3) in combination with irinotecan as first-line therapy for the treatment of patients with metastatic colorectal cancer. A total of 820 patients were randomized into sequential treatment (n=410) or combination therapy (n=410). Sequential treatment consisted of first-line therapy (capecitabine 1250 mg/m² body surface area twice daily for 14 days), second-line therapy (irinotecan 350 mg/m² body surface area on day 1), and third-line combination therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days and oxaliplatin 130 mg/m² body surface area on day 1). Combination therapy consisted of first-line therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days) in combination with irinotecan (250 mg/m² body surface area on day 1) (XELIRI) and second-line therapy (capecitabine 1000 mg/m² body surface area twice daily for 14 days and oxaliplatin 130 mg/m² body surface area on day 1). All treatment cycles were administered every 3 weeks. During first-line treatment, median progression-free survival in the intent-to-treat population was 5.8 months (95% CI: 5.1–6.2 months) for capecitabine monotherapy and 7.8 months (95% CI: 7.0–8.3 months) for XELIRI (p=0.0002).

Results of an interim analysis of a multicenter randomized controlled phase II trial (AIO KRK 0604) support the feasibility of using capecitabine at an initial dose of 800 mg/m² body surface area (for 2 weeks out of every 3) in combination with irinotecan and bevacizumab as first-line therapy for patients with metastatic colorectal cancer. A total of 115 patients were randomized to receive combination therapy with capecitabine and irinotecan (XELIRI) plus bevacizumab: capecitabine (800 mg/m² body surface area twice daily for 2 weeks followed by a 7-day break), irinotecan (200 mg/m² body surface area as a 30-minute infusion on day 1 of each 3-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each 3-week cycle); overall, 118 patients were randomized to the treatment group receiving capecitabine in combination with oxaliplatin and bevacizumab: capecitabine (1000 mg/m² body surface area twice daily for 2 weeks followed by a 7-day break), oxaliplatin (130 mg/m² body surface area as a 2-hour infusion on day 1 of each 3-week cycle), and bevacizumab (7.5 mg/kg as a 30–90 minute infusion on day 1 of each 3-week cycle). Progression-free survival at 6 months in the intent-to-treat population was 80% in the XELIRI plus bevacizumab group and 74% in the XELOX plus bevacizumab group. Overall response rate (complete and partial response) was 45% (XELOX and bevacizumab) versus 47% (XELIRI and bevacizumab).

Monotherapy as second-line treatment of metastatic colorectal carcinoma

Phase II/III clinical trials using a 3-weekly dosing schedule have been conducted in over 980 patients with metastatic colorectal cancer who had failed prior 5-FU-based therapy. The efficacy of irinotecan was evaluated in 765 patients who had documented disease progression on 5-FU at study entry.

NC – not calculated;

* - statistically significant difference.

In phase II studies involving 455 patients using a dosing regimen of once every 3 weeks, progression-free survival at 6 months was 30%, and median survival was 9 months. Median time to progression was 18 weeks. Additional non-comparative phase II studies were conducted in 304 patients who received irinotecan at a dose of 125 mg/m² body surface area as 90-minute intravenous infusions weekly for 4 weeks followed by a 2-week rest period. In these studies, median time to progression was 17 weeks, and median survival was 10 months. The safety profile observed in 193 patients treated with the weekly regimen at an initial dose of 125 mg/m² body surface area was similar to that observed in studies using the every-3-weeks irinotecan administration schedule. The median time to first episode of diarrhea was 11 days.

In combination therapy with cetuximab after failure of cytotoxic therapy with irinotecan

The efficacy of the combination of cetuximab and irinotecan was evaluated in two clinical trials. Overall, 356 patients with metastatic colorectal cancer expressing epidermal growth factor receptors received combination therapy; these were patients for whom cytotoxic therapy with irinotecan had failed. The minimum Karnofsky performance status score was 60, but in most patients it was ≥ 80. In the randomized trial EMR 62 202-007, combination therapy with cetuximab and irinotecan (218 patients) was compared to monotherapy with cetuximab (111 patients). In the open-label single-treatment-arm study IMCL CP02-9923, combination therapy was evaluated in 138 patients. Efficacy results from these studies are presented in the table below.

CI – confidence interval;

ORR – objective response rate (patients with complete or partial response);

DCR – disease control rate (patients with complete response, partial response, or stable disease for at least 6 weeks);

PFS – progression-free survival;

OS – overall survival.

With regard to objective response rate, disease control rate, and progression-free survival, the combination of cetuximab and irinotecan is more effective than cetuximab monotherapy. In the randomized trial, no impact on overall survival was demonstrated (hazard ratio 0.91, p-value = 0.48).

Pharmacokinetics.

Absorption

At the end of infusion, following administration of the recommended dose of 350 mg/m² body surface area, mean peak plasma concentrations were 7.7 µg/mL for irinotecan and 56 ng/mL for SN-38, with mean values of the area under the pharmacokinetic curve (AUC) being 34 µg×h/mL and 451 ng×h/mL, respectively. SN-38 typically exhibits marked inter-individual variability in pharmacokinetic characteristics.

Distribution

In a phase I study involving 60 patients who received irinotecan at doses ranging from 100 to 750 mg/m² body surface area as a 30-minute intravenous infusion every three weeks, the steady-state volume of distribution (Vss) was 157 L/m² body surface area.

Plasma protein binding of irinotecan and SN-38 in vitro was approximately 65% and 95%, respectively.

Metabolism

Mass balance and metabolism studies using 14C-labeled irinotecan demonstrated that more than 50% of the intravenously administered dose of irinotecan is excreted unchanged, with 33% of the dose eliminated in feces (primarily via bile) and 22% in urine.

Each of the two following metabolic pathways accounts for the conversion of at least 12% of the dose:

• hydrolysis by carboxylesterase to form the active metabolite SN-38, which is eliminated primarily through glucuronidation, followed by excretion of the glucuronide conjugate via liver and kidneys (less than 0.5% of the irinotecan dose); SN-38-glucuronide is believed to undergo further hydrolysis in the gastrointestinal tract;
• oxidation by cytochrome P450 3A enzymes, leading to cleavage of the outer piperidine ring, resulting in the formation of an aminopentanoic acid derivative and a primary amine derivative (see section "Interaction with other medicinal products and other forms of interaction").

Unchanged irinotecan constitutes the main fraction of the drug in plasma. Other components, in descending order of their relative abundance, are the aminopentanoic acid derivative, SN-38-glucuronide, and SN-38. Only SN-38 exerts significant cytotoxic activity.

Elimination

In a phase I study involving 60 patients who received irinotecan at doses from 100 to 750 mg/m² as a 30-minute intravenous infusion every 3 weeks, plasma elimination of irinotecan followed a biphasic or triphasic pattern. Mean plasma clearance of irinotecan was 15 L/h/m², and the volume of distribution at steady state (Vss) was 157 L/m². The mean elimination half-life in plasma was 12 minutes during the first phase, 2.5 hours during the second phase, and 14.2 hours during the third phase of the triphasic model. Plasma elimination of SN-38 was biphasic, with a mean terminal half-life of 13.8 hours.

Clearance of irinotecan is reduced by approximately 40% in patients with hyperbilirubinemia, in whom bilirubin levels exceed the upper limit of normal (ULN) by 1.5 to 3 times. In such patients, an irinotecan dose of 200 mg/m² results in drug exposure in plasma comparable to that achieved with a dose of 350 mg/m² in cancer patients with normal hepatic function.

Linearity/Non-linearity

Population pharmacokinetic analysis of irinotecan was performed in a cohort of 148 patients with metastatic colorectal cancer. These patients received irinotecan at various doses and dosing regimens in phase II studies. Pharmacokinetic parameters derived using a three-compartment model were similar to those obtained in phase I studies. Results from all studies indicate that exposure to irinotecan (CPT-11) and SN-38 increases proportionally with the dose of CPT-11. The pharmacokinetics of these compounds are independent of the number of prior treatment cycles and dosing schedule.

Pharmacokinetic/Pharmacodynamic interactions

The severity of the main toxicities observed with the drug (e.g., leukopenia and diarrhea) correlates with the AUC levels of the active substance and its metabolite SN-38. A significant correlation has been established between the severity of hematological toxicity (minimum leukocyte and neutrophil counts) or diarrhea and AUC values for irinotecan and its metabolite SN-38 during monotherapy.

Patients with reduced UGT1A1 activity

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is involved in the conversion of SN-38, the active metabolite of irinotecan, into the inactive glucuronide SN-38 (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in various metabolic activity variants. The most extensively studied genetic variants of UGT1A1 are UGT1A1*28 and UGT1A1*6. These variants, as well as other inherited defects in UGT1A1 expression (such as Gilbert’s syndrome and Crigler-Najjar syndrome), are associated with reduced enzyme activity.

Patients who are poor metabolizers of UGT1A1 (e.g., homozygous for UGT1A1*28 or *6 variants) have an increased risk of severe adverse reactions, such as neutropenia and diarrhea, following irinotecan administration, due to accumulation of SN-38. According to data from several meta-analyses, this risk is higher in patients receiving irinotecan doses >180 mg/m² (see section "Special precautions for use").

UGT1A1 genotyping may be used to identify patients at increased risk of developing severe neutropenia and diarrhea. The homozygous UGT1A1*28 variant occurs with a frequency of 8–20% in European, African, Middle Eastern, and Latin American populations. The *6 variant is nearly absent in these populations. In East Asian populations, the *28/*28 variant is found in approximately 1–4%, the *6/*28 variant in 3–8%, and the *6/*6 variant in 2–6%. In Central and South Asian populations, the *28/*28 variant occurs in about 17%, the *6/*28 variant in 4%, and the *6/*6 variant in 0.2%.

Preclinical safety data

Irinotecan and SN-38 have been shown to exhibit mutagenic activity in vitro in CHO cells in the chromosomal aberration test, as well as in vivo in mice in the micronucleus test.

However, in the Ames test, they were shown to lack any mutagenic potential.

In rats treated once weekly for 13 weeks at the maximum dose of 150 mg/m² (less than half the recommended human dose), no treatment-related tumors were reported 91 weeks after the end of treatment.

Toxicity studies following single and repeated doses of irinotecan were conducted in mice, rats, and dogs. The main toxic effects were observed in the hematopoietic and lymphatic systems. In dogs, delayed-onset diarrhea was reported, associated with atrophy and focal necrosis of the intestinal mucosa. Alopecia was also observed. The severity of these effects was dose-dependent and reversible.

Reproduction

Irinotecan showed teratogenic effects in rats and rabbits at doses lower than the human therapeutic dose. In rats with external abnormalities born to irinotecan-treated rats, reduced fertility was observed. This was not observed in morphologically normal offspring. In pregnant rats treated with irinotecan, reduced placental weight was observed, and in their offspring, reduced fetal viability and increased incidence of behavioral disturbances were noted.

Clinical characteristics.

Indications.

For the treatment of advanced colorectal cancer:

• in combination with 5-fluorouracil and folinic acid in patients who have not received prior chemotherapy for advanced disease;
• as monotherapy in patients for whom a treatment regimen containing 5-fluorouracil has proven ineffective.

In combination with cetuximab, Irinotecan medac is indicated for the treatment of metastatic colorectal cancer with wild-type KRAS gene, expressing epidermal growth factor receptors, in patients who have not previously received treatment for metastatic disease or for whom cytotoxic therapy with irinotecan has proven ineffective (see section "Pharmacodynamics").

In combination with 5-fluorouracil, folinic acid, and bevacizumab, Irinotecan medac is indicated as first-line therapy in patients with metastatic carcinoma of the colon or rectum.

In combination with capecitabine (with or without bevacizumab), Irinotecan medac is indicated as first-line therapy in patients with metastatic colorectal cancer.

Contraindications.

• Chronic inflammatory bowel diseases and/or intestinal obstruction (see section "Special precautions");
• hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• breastfeeding period (see sections "Special precautions" and "Use during pregnancy or breastfeeding");
• serum bilirubin level exceeding three times the upper limit of normal (see section "Special precautions");
• severe bone marrow insufficiency;
• patient's general condition > 2 (according to WHO classification);
• concomitant use of St. John's wort (see section "Interaction with other medicinal products and other types of interactions");
• live attenuated vaccines (see section "Interaction with other medicinal products and other types of interactions").

For combination therapy with cetuximab or bevacizumab, refer to additional contraindications listed in the instructions for medical use of the respective medicinal products.

Special safety measures.

As with other antineoplastic agents, precautions should be taken regarding safe handling of Irinotecan medac during dilution and administration. Protective goggles, mask, and gloves should be used when handling this medicinal product.

If concentrate or the resulting infusion solution accidentally comes into contact with the skin, it should be immediately and thoroughly washed with soap and water. If the concentrate or the resulting infusion solution contacts mucous membranes, they should be immediately rinsed with water.

Preparation of solution for intravenous administration.

The Irinotecan medac infusion solution should be prepared under aseptic conditions (see section "Shelf life").

If any precipitate is observed after dilution of the concentrate in vials, the product should be destroyed according to standard procedures for cytotoxic agents.

Under aseptic conditions, the required amount of concentrate should be withdrawn from the vial using a calibrated syringe and transferred into an infusion bag with a capacity of 250 ml or into a vial containing either 0.9% sodium chloride solution or 5% glucose solution. The infusion solution should be thoroughly mixed by gently rotating the vial manually.

Disposal

Any unused medicinal product or waste material must be destroyed in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Concomitant use of medicinal products contraindicated (see section "Contraindications")

St. John's wort

Reduced plasma levels of the active metabolite of irinotecan, SN-38. In a small pharmacokinetic study (n=5), where irinotecan at a dose of 350 mg/m² body surface area was administered in combination with St. John's wort (Hypericum perforatum) at a dose of 900 mg, a 42% reduction in plasma concentration of SN-38, the active metabolite of irinotecan, was observed. Therefore, St. John's wort should not be used concomitantly with irinotecan.

Live attenuated vaccines (e.g., yellow fever vaccine)

Risk of developing systemic diseases with potentially fatal outcome. Concomitant administration of live attenuated vaccines is contraindicated during treatment with irinotecan and for 6 months after completion of chemotherapy. Inactivated vaccines may be used, but the immune response to such vaccines may be reduced.

Concomitant use not recommended (see section "Special precautions")

Concomitant administration of irinotecan with strong inducers/inhibitors of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should therefore be avoided (see section "Special precautions").

Strong inducers of CYP3A4 and/or UGT1A1 (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide)

Risk of reduced efficacy of irinotecan, SN-38, SN-38 glucuronide, and reduced pharmacodynamic effect. Several studies have shown that concomitant use of antiepileptic drugs that are inducers of CYP3A reduces the efficacy of irinotecan, SN-38, and SN-38 glucuronide, leading to a reduced pharmacodynamic effect. These antiepileptic drugs caused a reduction in AUC for SN-38 and SN-38 glucuronide by 50% or more. In addition to induction of CYP3A4 enzymes, reduced efficacy of irinotecan and its metabolites may also be due to enhanced glucuronidation and more intensive biliary excretion. Additionally, with phenytoin: risk of seizure exacerbation due to reduced absorption of phenytoin caused by cytostatic agents.

Strong inhibitors of CYP3A4 (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 the metabolite APC and a 109% reduction in AUC of the metabolite SN-38 compared to irinotecan monotherapy.

UGT1A1 inhibitors (e.g., atazanavir, ketoconazole, regorafenib)

Risk of increased systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should consider this when co-prescribing these two drugs.

Other CYP3A4 inhibitors (e.g., crizotinib, idelalisib)

Risk of increased irinotecan toxicity due to reduced metabolism when administered concomitantly with crizotinib or idelalisib.

Use with caution

Vitamin K antagonists

Increased risk of hemorrhage and thrombotic events in cancer patients. If vitamin K antagonists are indicated, increased frequency of monitoring of the International Normalized Ratio (INR) is required.

Concomitant use requires attention

Immunosuppressants (e.g., cyclosporine, tacrolimus)

Excessive immunosuppression with risk of lymphocyte proliferation.

Neuromuscular blocking agents

Interaction between irinotecan and neuromuscular blockers cannot be excluded. Since irinotecan has anticholinesterase activity, drugs with anticholinesterase effects may prolong the neuromuscular blocking effect of succinylcholine and the neuromuscular blockade of non-depolarizing agents.

Other combinations

5-Fluorouracil/Folinic acid

Concomitant administration of 5-FU/FA as part of combination therapy does not alter the pharmacokinetics of irinotecan.

Bevacizumab

Results from specific drug interaction studies did not demonstrate a significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude any increased toxicity due to their pharmacological properties.

Cetuximab

Information on the effect of cetuximab on the safety profile of irinotecan or vice versa is lacking.

Antineoplastic agents (including flucytosine as a prodrug of 5-fluorouracil)

Adverse effects of irinotecan, such as myelosuppression, may be intensified by other antineoplastic drugs with a similar adverse effect profile.

Special precautions for use.

Irinotecan medac should be used exclusively in a department specialized in cytotoxic chemotherapy. This medicinal product should be administered only under the supervision of a physician experienced in anticancer chemotherapy.

Due to the nature and frequency of adverse reactions, irinotecan medac should be used only after careful assessment of the benefit-risk ratio in the following cases:

• for treatment of patients with risk factors, particularly patients with a WHO performance status of 2;
• in rare individual cases where patients are unlikely to comply with recommendations for managing adverse reactions (the need for immediate and prolonged treatment of diarrhea combined with high fluid intake at the onset of delayed diarrhea). Such patients should be closely monitored in a hospital setting.

When irinotecan hydrochloride is used as monotherapy, the dosing schedule is once every 3 weeks. However, a weekly dosing schedule (see section "Pharmacological properties") may be considered for patients requiring closer monitoring or at risk of severe neutropenia.

Delayed diarrhea

Patients should be informed about the possible risk of delayed diarrhea, which occurs more than 24 hours after administration of irinotecan medac and may occur at any time before the start of the next treatment cycle. With monotherapy, the median time to first episode of loose stools was 5 days after administration of irinotecan medac. Patients should promptly notify their physician about the onset of diarrhea and immediately initiate appropriate therapy.

Patients at increased risk of diarrhea include those previously treated with abdominal or pelvic radiotherapy, patients with baseline hyperleukocytosis, patients with a performance status ≥ 2, and women. Without adequate treatment, diarrhea may be life-threatening, particularly if associated with neutropenia.

After the first episode of loose stools, patients should immediately start drinking large amounts of electrolyte-containing fluids and begin appropriate anti-diarrheal therapy. Anti-diarrheal treatment should be initiated at the department where irinotecan medac was administered. After hospital discharge, patients should receive prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should notify the physician at the department where irinotecan medac was administered about the occurrence of diarrhea.

Current recommended anti-diarrheal treatment consists of high-dose loperamide (4 mg initially, followed by 2 mg every 2 hours). Treatment should continue for 12 hours after the last episode of loose stools. The treatment regimen should not be modified. Loperamide at these doses should never be used for longer than 48 hours due to the risk of paralytic ileus; however, treatment should not last less than 12 hours.

If diarrhea is accompanied by severe neutropenia (neutrophil count less than 500 cells/mm³), broad-spectrum antibiotics should be administered prophylactically in addition to anti-diarrheal treatment.

Hospitalization of patients is recommended in addition to antibiotic treatment if:

• diarrhea is accompanied by fever;
• diarrhea is severe (requiring intravenous rehydration);
• diarrhea persists for 48 hours after initiation of high-dose loperamide treatment.

Loperamide should not be used prophylactically in patients who experienced delayed diarrhea in previous treatment cycles.

Patients with severe diarrhea should have their dose reduced in subsequent treatment cycles (see section "Dosage and administration").

Hematological effects

In clinical studies, the incidence of grade III–IV neutropenia according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was significantly higher in patients previously treated with pelvic/abdominal irradiation compared to those who did not receive such irradiation. Patients with baseline total serum bilirubin levels of 1.0 mg/dL or higher also had a significantly higher probability of developing grade III–IV 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. Patients with febrile neutropenia (body temperature > 38°C and neutrophil count ≤ 1000 cells/mm³) require immediate intravenous administration of broad-spectrum antibiotics in a hospital setting.

Patients with a history of severe hematological toxicity should have their dose reduced upon subsequent administration of this medicinal product (see section "Dosage and administration").

There is an increased risk of infections and hematological toxicity in patients with severe diarrhea. Such patients require blood count monitoring.

Hepatic impairment

Liver function tests should be performed during treatment and before the start of each cycle.

Complete blood counts should be performed weekly in patients with bilirubin levels 1.5–3 times above the upper limit of normal (ULN), due to decreased irinotecan clearance (see section "Pharmacokinetics") and increased risk of hematotoxicity. For patients with bilirubin levels exceeding ULN by 3 times, see section "Contraindications".

Nausea and vomiting

Prophylactic antiemetic treatment is recommended before initiation of irinotecan therapy. Patients with delayed diarrhea accompanied by vomiting should be urgently hospitalized for comprehensive treatment.

Acute cholinergic syndrome

In case of acute cholinergic syndrome (early diarrhea in combination with other symptoms such as increased sweating, abdominal cramps, miosis, and increased salivation), atropine sulfate (0.25 mg subcutaneously) should be administered in the absence of clinical contraindications (see section "Adverse reactions").

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 when administering the medicinal product to patients with bronchial asthma. Prophylactic administration of atropine sulfate followed by irinotecan infusion is recommended for patients with a history of severe acute cholinergic syndrome.

Respiratory disorders

Interstitial lung disease, manifested as pulmonary infiltrates, is not common with irinotecan treatment. However, interstitial lung disease may lead to fatal outcomes. Risk factors possibly associated with the development of interstitial lung disease include the use of pneumotoxic medicinal products, radiotherapy, and colony-stimulating factors. Patients with risk factors should be carefully monitored for symptoms of respiratory disorders before and during irinotecan treatment.

Extravasation

Although irinotecan is not considered a vesicant, extravasation should be avoided, and the infusion site should be monitored for signs of inflammation. In case of extravasation, the infusion site should be irrigated and ice applied.

Elderly patients

Due to the higher frequency of decreased physiological functions, particularly hepatic 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 been resolved (see section "Contraindications").

Renal impairment

Increased 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.

No additional studies have been conducted in this patient group.

Radiotherapy

Patients who have previously received pelvic or abdominal irradiation are at increased risk of developing myelosuppression after irinotecan treatment. Physicians should use this medicinal product with caution in patients who have previously received extensive radiotherapy (e.g., irradiation of > 25% of bone marrow within 6 weeks before initiation of irinotecan treatment). This group of patients may require dose adjustment (see section "Dosage and administration").

Cardiac disorders

Cases of myocardial ischemia have been observed after irinotecan treatment, primarily in patients with a history of cardiovascular disorders, risk factors for heart disease, or after cytotoxic chemotherapy (see section "Adverse reactions").

Therefore, patients with known risk factors should be carefully monitored, and all modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia) should be minimized.

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).

Other factors

Concomitant administration of irinotecan with a strong inhibitor (e.g., ketoconazole) or inducer (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin) of CYP3A4 may alter irinotecan metabolism and should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Isolated cases of renal failure, arterial hypotension, or circulatory failure due to dehydration associated with diarrhea and/or vomiting, or in cases of sepsis, have been observed.

Patients with reduced UGT1A1 activity

Patients with poor UGT1A1 metabolism, such as patients with Gilbert's syndrome (e.g., homozygous for UGT1A1*28 or *6 variants), have an increased risk of severe neutropenia and diarrhea after irinotecan treatment. This risk increases with higher doses of irinotecan.

Although the exact initial dose has not been established, consideration should be given to reducing the initial dose of irinotecan for patients with poor UGT1A1 metabolism, particularly patients receiving doses > 180 mg/m², or for frail patients. Clinical recommendations for dosing in this patient group should be taken into account. Subsequent doses may be increased depending on individual treatment tolerance.

UGT1A1 genotyping may be used to identify patients at increased risk of severe neutropenia and diarrhea; however, the clinical benefit of genotyping prior to treatment is uncertain, as UGT1A1 polymorphism does not account for all toxicity observed with irinotecan therapy (see section "Pharmacological properties").

Contraception in men and women

Due to the potential for genotoxicity, female patients of reproductive potential should be advised to use highly effective contraceptive methods during treatment and for 6 months after the last dose of irinotecan.

Due to the potential for genotoxicity, male patients with female partners of reproductive potential should be advised to use effective contraceptive methods during treatment and for 3 months after the last dose of irinotecan. See section "Pregnancy and breastfeeding".

Breastfeeding

Due to the potential for adverse reactions in infants, breastfeeding should be discontinued during treatment with this medicinal product (see sections "Contraindications" and "Pregnancy and breastfeeding").

This medicinal product contains sorbitol (see section "Composition"), which is a source of fructose. This medicinal product should not be administered to patients with hereditary fructose intolerance (HFI) unless absolutely necessary. HFI may not yet be diagnosed in infants and children under 2 years of age. Medicinal products containing fructose administered intravenously may have life-threatening effects in individuals with HFI and should not be administered to this patient group unless there is a high clinical necessity or no alternative.

Before administering this medicinal product to each patient, a history of symptoms of HFI should be obtained.

This medicinal product contains 45 mg of sorbitol per 1 ml.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Contraception

Due to the potential for genotoxicity, female patients of reproductive potential should be advised to use highly effective contraceptive methods during treatment and for 6 months after the last dose of irinotecan (see section "Special precautions for use").

Due to the potential for genotoxicity, male patients with female partners of reproductive potential should be advised to use effective contraceptive methods during treatment and for 3 months after the last dose of irinotecan (see section "Special precautions for use").

Pregnancy

Data on the use of irinotecan in pregnant women are limited. Animal studies have demonstrated embryotoxic and teratogenic effects of irinotecan (see section "Non-clinical safety data"). Therefore, considering animal study results and the mechanism of action of irinotecan, irinotecan should not be used during pregnancy except in cases of extreme necessity. Women of childbearing potential should not receive irinotecan unless pregnancy has been excluded. Pregnancy should be avoided if either partner is receiving irinotecan.

Breastfeeding

Available data are limited but suggest that irinotecan and its metabolites are excreted in breast milk. Therefore, due to the potential for adverse reactions in infants, breastfeeding should be discontinued during treatment with this medicinal product (see sections "Contraindications" and "Special precautions for use").

Fertility

Animal studies have documented effects of irinotecan on fertility and offspring (see section "Non-clinical safety data").

Prior to initiating treatment, patients should be offered counseling regarding fertility preservation.

Ability to drive and use machines.

Patients should be warned about the possible occurrence of dizziness or visual disturbances within 24 hours after irinotecan administration. Therefore, during irinotecan therapy, special caution should be exercised when driving or operating machinery if these symptoms occur.

Administration and Dosage

The medicinal product is intended for treatment of adults only. After dilution, the irinotecan solution for infusion is administered via peripheral or central vein.

Monotherapy (for patients previously treated).

The recommended dose of irinotecan is 350 mg/m² administered as an intravenous infusion over 30–90 minutes every 3 weeks (see sections "Special Warnings and Precautions" and "Special Precautions").

Combination therapy (for patients previously untreated).

The efficacy and safety of the medicinal product in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were evaluated according to the following dosage schedule (see section "Pharmacodynamics").

Irinotecan/5-FU/FA every 2 weeks.

The recommended dose of irinotecan is 180 mg/m² every 2 weeks as an intravenous infusion over 30–90 minutes, followed by administration of folinic acid and 5-fluorouracil.

Information on dosing and administration of cetuximab in combination therapy can be found in the product information for that medicinal product. The same dose of irinotecan as used in previous treatment cycles containing irinotecan should generally be applied. Irinotecan should be administered no earlier than 1 hour after the end of cetuximab infusion.

Information on dosing and administration of bevacizumab can be found in the product information for that medicinal product.

Dose adjustment.

Irinotecan should be administered only after all adverse effects have completely resolved to NCI-CTC (National Cancer Institute Common Toxicity Criteria) grade 0 or 1, and when treatment-related diarrhea has completely resolved.

At the beginning of the next infusion cycle, the doses of irinotecan and 5-FU (if administered) should be reduced according to the highest toxicity level observed during the previous infusion. Treatment should be delayed by 1–2 weeks until adverse effects related to the medicinal product have resolved.

The dose of irinotecan and/or 5-FU (if administered) should be reduced by 15–20% in the event of any of the following adverse effects:

• Hematological toxicity symptoms (grade 4 neutropenia, neutropenia with fever (grade 3–4 neutropenia and grade 2–4 fever), thrombocytopenia and leukopenia (grade 4));
• Non-hematological toxicity symptoms (grade 3–4).

Dose adjustment recommendations for cetuximab when used in combination with irinotecan should be followed as described in the product information for cetuximab.

Information on dose modification of bevacizumab when used in combination therapy with irinotecan/5-FU/FA can be found in the product information for bevacizumab.

For patients aged 65 years and older receiving irinotecan in combination with capecitabine, a reduced dose of capecitabine to 800 mg/m² body surface area twice daily is recommended according to the capecitabine product information. See also dose modification recommendations for the combination regimen provided in the capecitabine product information.

Duration of treatment.

Treatment with irinotecan medac should be continued until objective disease progression or unacceptable toxicity occurs.

Special patient groups.

Patients with impaired liver function

Monotherapy

For patients with a performance status index ≤ 2, the initial dose of irinotecan medac should be determined based on serum bilirubin levels (when bilirubin levels exceed the upper limit of normal [ULN] by no more than 3 times). In such patients with hyperbilirubinemia and prothrombin time greater than 50%, irinotecan clearance is reduced (see section "Pharmacokinetics"), thereby increasing the risk of hematotoxicity. Therefore, these patients require weekly complete blood counts.

• For patients with bilirubin levels exceeding ULN by ≤ 1.5 times, the recommended dose of irinotecan is 350 mg/m².
• For patients with bilirubin levels exceeding ULN by 1.5–3 times, the recommended dose of irinotecan is 200 mg/m².
• Irinotecan should not be administered to patients with bilirubin levels exceeding ULN by > 3 times (see sections "Contraindications" and "Special Warnings and Precautions").

Combination therapy

Data on patients with hepatic impairment receiving irinotecan as part of combination therapy are not available.

Patients with impaired renal function

Irinotecan is not recommended for patients with impaired renal function, as studies in this patient group have not been conducted (see sections "Special Warnings and Precautions" and "Pharmacokinetics").

Elderly patients

Specific pharmacokinetic studies in elderly patients have not been conducted. Dose selection should be cautious in individual cases due to the natural decline in biological functions. This patient group requires closer monitoring (see section "Special Warnings and Precautions").

Administration method

Instructions for dilution of the medicinal product prior to administration are provided in the section "Special Precautions".

Children.

There are no published data on the safety and efficacy of irinotecan in children.

Overdose.

Cases of overdose, which may be fatal, have been reported following administration of doses approximately twice the recommended therapeutic dose. The most significant adverse reactions were severe neutropenia and severe diarrhea. There is no known antidote for irinotecan medac. Intensive supportive treatment should be administered to prevent dehydration due to diarrhea and to treat possible infectious complications.

Adverse Reactions

Clinical Studies

Data on adverse reactions were thoroughly collected during studies of metastatic colorectal cancer; the frequency of their occurrence is presented below. When the drug is used for indications other than colorectal cancer, similar adverse reactions are expected.

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 the dose-limiting toxic effect. Neutropenia was reversible and not cumulative; during monotherapy or combination therapy, the median time to reach the lowest neutrophil count was 8 days.

A transient acute cholinergic syndrome of severe degree was very frequently observed.

Its main symptoms included early diarrhea and various other symptoms such as abdominal pain, increased 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 "Special Instructions").

Monotherapy

The following adverse reactions, possibly or probably related to irinotecan administration, were reported 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 (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), and very rare (<1/10,000).

Adverse reactions reported during irinotecan monotherapy (regimen: 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, pyrexia, asthenia.

Investigations

Common: increased blood creatinine levels, increased transaminase levels (ALT and AST), increased bilirubin levels, increased alkaline phosphatase levels in blood.

Description of selected adverse reactions (during monotherapy)

Severe diarrhea occurred in 20% of patients who followed recommendations for diarrhea control. 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 therapy.

Constipation occurred in less than 10% of patients.

Neutropenia occurred 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 1000 cells/mm³ in 18%, including 7.6% with neutrophil count <500 cells/mm³.

Complete recovery of counts usually took up to 22 days.

Febrile neutropenia occurred in 6.2% of patients and in 1.7% of all treatment cycles.

Infections occurred in approximately 10.3% of patients (2.5% of all treatment cycles) and were associated with severe neutropenia in approximately 5.3% of patients (1.1% of all treatment cycles); in two cases, this complication led to a fatal outcome.

Anemia was observed 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) occurred 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 almost all patients, recovery of counts took up to 22 days.

Acute cholinergic syndrome: transient severe acute cholinergic syndrome occurred in 9% of patients receiving monotherapy.

Asthenia was severe in less than 10% of patients receiving monotherapy. A 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 findings: slight or moderate transient increases in serum transaminase, alkaline phosphatase, or bilirubin levels were observed in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases.

Slight or moderate transient increases in serum creatinine levels were 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 (e.g., acneiform rash in 88% of cases) were reported. Information on adverse reactions with the combination of irinotecan and cetuximab is also provided in the respective product information leaflets.

The following adverse reactions were reported in patients receiving capecitabine in combination with irinotecan, in addition to those observed during capecitabine monotherapy or occurring at a 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 – Grade III and IV adverse reactions: febrile neutropenia. Full information on capecitabine adverse reactions is provided in the product information leaflet for this medicinal product.

The following Grade III and IV adverse reactions were reported in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those observed during capecitabine monotherapy or occurring at a higher frequency compared to capecitabine monotherapy:

Common – Grade III and IV adverse reactions: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction. Full information on adverse reactions of capecitabine and bevacizumab is provided in the product information leaflets for these medicinal products.

The development of Grade III arterial hypertension was the main significant risk associated with adding bevacizumab to the bolus regimen of irinotecan/5-FU/leucovorin. Additionally, with this treatment regimen, there was a slight increase in the frequency of Grade III/IV chemotherapy-related adverse reactions—diarrhea and leukopenia—compared to patients receiving only the bolus regimen of irinotecan/5-FU/leucovorin. Additional information on adverse reactions with combination therapy including bevacizumab is provided in the product information leaflet for this medicinal product.

Studies have been conducted on the use of irinotecan in combination with 5-FU and leucovorin for the treatment of metastatic colorectal cancer.

Safety data on adverse reactions obtained during clinical trials show that adverse reactions of Grade III or IV according to the National Cancer Institute scale, possibly or probably related to therapy, were very commonly observed in the following MedDRA organ system classes: blood and lymphatic system, gastrointestinal tract, skin and subcutaneous tissue.

The following adverse reactions, possibly or probably related to irinotecan use, were reported in 145 patients receiving irinotecan at the recommended dose of 180 mg/m² in combination with 5-FU/leucovorin every 2 weeks.

Adverse reactions reported during combination therapy with irinotecan (regimen: 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: pyrexia.

Investigations

Very common: increased transaminase levels (ALT and AST), increased bilirubin levels, increased alkaline phosphatase levels in blood.

Description of selected adverse reactions (during combination therapy)

Severe diarrhea occurred in 13.1% of patients who followed recommendations for diarrhea control. In evaluable treatment cycles, severe diarrhea occurred in 3.9%.

Severe nausea and vomiting occurred at a lower frequency (in 2.1% and 2.8% of patients, respectively).

Constipation due to irinotecan and/or loperamide occurred in 3.4% of patients.

Neutropenia occurred 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 1000 cells/mm³ in 67.3%, including 2.7% with neutrophil count <500 cells/mm³. Complete recovery of counts usually took 7–8 days.

Febrile neutropenia occurred in 3.4% of patients (0.9% of all treatment cycles).

Infections occurred in approximately 2% of patients (0.5% of all treatment cycles) and were associated with severe neutropenia in approximately 2.1% of patients (0.5% of all treatment cycles); in one case, this complication led to a fatal outcome.

Anemia occurred in 97.2% of patients (2.1% with hemoglobin <8 g/dL).

Thrombocytopenia (<100,000 cells/mm³) occurred in 32.6% of patients (21.8% of all treatment cycles). No cases of severe thrombocytopenia (<50,000 cells/mm³) were observed.

Acute cholinergic syndrome: transient severe acute cholinergic syndrome occurred in 1.4% of patients receiving combination therapy.

Asthenia was severe in 6.2% of patients receiving combination therapy. A causal relationship between this event and irinotecan administration was not clearly established.

Pyrexia in the absence of infection or concomitant severe neutropenia occurred in 6.2% of patients receiving combination therapy.

Laboratory findings: transient increases (Grade I and II) in serum AST, ALT, alkaline phosphatase, or bilirubin levels were observed in 15%, 11%, 11%, and 10% of patients, respectively, in the absence of progressive liver metastases. Transient increases in these parameters to Grade III were observed in 0%, 0%, 0%, and 1% of patients, respectively. No Grade IV cases of this adverse reaction 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 studies of weekly irinotecan regimens

In clinical studies of irinotecan, the following additional adverse reactions related to drug administration were reported: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin reactions, gait disturbances, confusion, headache, syncope, flushing, 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 vessel embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special Instructions").

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 blood thrombocytopenia with formation of antiplatelet 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 diseases, manifesting as pulmonary infiltrates, are uncommon during irinotecan treatment (cases of early effects such as dyspnea have been reported; see section "Special Instructions"); dyspnea (see section "Special Instructions"), hiccups.

Gastrointestinal disorders: intestinal obstruction, ileus, including cases of ileus without prior colitis; megacolon, gastrointestinal hemorrhage, colitis, in some cases 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.

Musculoskeletal and connective tissue disorders: muscle contractions or cramps.

Renal and urinary disorders: renal dysfunction and acute renal failure usually occurred in patients with infection and/or hypovolemia resulting from severe gastrointestinal toxicity***, renal failure***.

General disorders and administration site conditions: infusion site reactions.

Investigations: increased blood amylase levels, increased lipase levels, hypokalemia, hyponatremia, primarily associated with diarrhea and vomiting; very rare reports of increased serum transaminase levels (AST and ALT) in the absence of progressive liver metastases.

* 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. 3 years.

Diluted medicinal product (infusion solution)

After dilution with 0.9% sodium chloride solution or 5% glucose solution, chemical and physical stability has been demonstrated for 6 hours when stored at room temperature (approximately 25°C) under normal lighting conditions, or for 48 hours when stored refrigerated (approximately 2–8°C).

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user; typically, the solution should be stored for no longer than 6 hours at room temperature or 24 hours at 2–8°C, unless dilution is performed under controlled and validated aseptic conditions.

Storage conditions.

Store out of reach of children, in the original packaging to protect from light.

Do not freeze.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution or 5% glucose solution.

Packaging.

2 ml, 5 ml, or 15 ml in Type I glass vial; 1 vial per carton.

A protective film may be applied to the vial.

Prescription status.

Prescription only.

Manufacturer.

Medac Gesellschaft für klinische Spezialpräparate mbH / Medac Gesellschaft fur klinische Spezialpraparate m.b.H.

Manufacturer's address and place of business.

Theaterstrasse, 6, 22880 Wedel, Germany.