Irinocidan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Irinosindan (Irinosindan)

Composition:

Active substance: irinotecan;

1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Antineoplastic agents. Topoisomerase I inhibitors. ATC code L01CE02.

Pharmacological Properties.

Pharmacodynamics.

Irinotecan is a semisynthetic derivative of camptothecin. It is an antineoplastic agent acting 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 leads to single-strand DNA damage, which blocks the replication fork and results in cytotoxic effects. This cytotoxic effect has been shown to be time-dependent and specific to the S-phase of the cell cycle.

It has been established that irinotecan and SN-38 are not significantly recognized in vitro by P-glycoprotein (multidrug resistance protein) and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine. Moreover, irinotecan demonstrates broad-spectrum antitumor activity in vivo against murine tumor models (pancreatic ductal 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 multidrug resistance protein (vincristine- and doxorubicin-resistant leukemias P388). In addition to the antitumor activity of Irinosindan, the most significant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase activity.

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, while mean values of the area under the pharmacokinetic curve (AUC) were 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 3 weeks, the volume of distribution at steady state (Vss) was 157 L/m².

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

Biological Transformation (Metabolism)

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

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

• Hydrolysis by carboxylesterase, forming 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 intestinal 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.

Unchanged irinotecan is the major component of the drug in plasma. The remaining components, in decreasing order of concentration, are the aminopentanoic acid derivative, SN-38-glucuronide, and SN-38. Only SN-38 exhibits 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, the elimination profile of irinotecan was shown to be biphasic or triphasic. Mean plasma clearance was 15 L/h/m². The mean elimination half-life in the first phase of the triphasic model was 12 minutes, in the second phase 2.5 hours, and the terminal half-life was 14.2 hours. SN-38 elimination follows a biphasic pattern, with a mean terminal half-life of 13.8 hours.

In patients with bilirubin levels 1.5 to 3 times above the upper limit of normal, irinotecan clearance is reduced by 40%. In patients of this group, administration of a 200 mg/m² dose of irinotecan results in the same plasma exposure as a 350 mg/m² dose 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 schedules in phase II studies. Pharmacokinetic parameters determined 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 CPT-11 dose. The pharmacokinetics of these compounds are independent of the number of prior treatment cycles and dosing regimen.

Pharmacokinetic/Pharmacodynamic Relationship

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

Patients with Reduced UGT1A1 Activity. UDP-glucuronosyltransferase 1A1 (UGT1A1) is involved in the metabolic inactivation of SN-38, the active metabolite of irinotecan, forming the inactive SN-38-glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, leading to variable metabolic rates among patients. The most extensively studied genetic variants of UGT1A1 are UGT1A1*28 and UGT1A1*6. These variants, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Crigler-Najjar syndrome), are associated with reduced enzyme activity. Patients who are slow metabolizers of UGT1A1 (e.g., homozygotes for UGT1A1*28 or *6) 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 at doses >180 mg/m² (see section "Special Warnings and Precautions for Use"). Genotyping for UGT1A1 may be used to identify patients at increased risk of severe neutropenia and diarrhea. Homozygotes for UGT1A1*28 occur at 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 frequency of *28/*28 is approximately 1–4%, 3–8% for *6/*28, and 2–6% for *6/*6. In Central and South Asian populations, the frequency of *28/*28 is approximately 17%, 4% for *6/*28, and 0.2% for *6/*6.

Clinical characteristics.

Indications.

Treatment of patients with advanced colorectal cancer:

• in combination with 5-fluorouracil (5-FU) and folinic acid (FA) in patients who have not previously received chemotherapy;
• as monotherapy in 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 RAS wild-type status and with overexpression of epidermal growth factor receptor (EGFR), who have not previously received chemotherapy or after 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.

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

Contraindications.

• Chronic inflammatory bowel diseases and/or intestinal obstruction (see section "Special precautions");
• hypersensitivity to irinotecan hydrochloride or to any other component of the medicinal product;
• breastfeeding (see section "Use during pregnancy or breastfeeding");
• serum bilirubin level exceeding the upper normal limit by more than 3 times (see section "Special precautions");
• severe bone marrow insufficiency;
• performance status >2 (by WHO classification);
• concomitant use with St. John's wort (see section "Interaction with other medicinal products and other forms of interaction");
• live attenuated vaccines (see section "Interaction with other medicinal products and other forms of interaction").

When used in combination with cetuximab, bevacizumab, or capecitabine – additional contraindications are listed in the instructions for medical use of these medicinal products.

Special safety precautions.

As with other antineoplastic agents, caution is required when handling and preparing the medicinal product Irinosidan. Protective goggles, mask, and gloves must be used.

If concentrate or infusion solution comes into contact with the skin, immediately and thoroughly wash the area with soap and water. If concentrate or infusion solution comes into contact with mucous membranes, immediately rinse with water.

Preparation of solution for intravenous administration

As with other injectable medicinal products, the Irinosidan solution must be prepared under aseptic conditions.

If any precipitate is observed in the vial or after reconstitution, the product must be disposed of according to standard procedures for disposal of cytotoxic agents.

Under aseptic conditions, withdraw the required volume of concentrated Irinosidan solution using a calibrated syringe from the vial and transfer the dose into a 250 mL bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. Mix thoroughly by gentle manual rotation of the container.

Chemical and physical stability of the medicinal product has been demonstrated for 24 hours at 30°C and for 48 hours at 2–8°C after dilution in the recommended infusion solutions. From a microbiological standpoint, the product should be used immediately after dilution. If not used immediately, responsibility for storage duration and conditions lies with the user. Generally, storage time should not exceed 24 hours at 2–8°C, except when dilution is performed under validated controlled aseptic conditions.

Disposal

Any unused medicinal product and all materials used for dilution and administration must be disposed of according to standard institutional procedures.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated (see section "Contraindications")

St. John's wort – reduced plasma concentration 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 generalized vaccine reaction with potentially fatal outcome. Concomitant use is contraindicated during irinotecan treatment and for 6 months after discontinuation of chemotherapy. Inactivated or killed vaccines may be administered, but the immune response to such vaccines may be reduced.

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

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

Strong inducers of CYP3A4 and/or UGT1A1 (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, apalutamide) – risk of reduced exposure to irinotecan, SN-38, and SN-38-glucuronide, and diminished pharmacodynamic effects. Results from several studies have shown that concomitant use of CYP3A4-inducing antiepileptic drugs leads to reduced exposure to irinotecan, SN-38, and SN-38-glucuronide, and decreased pharmacodynamic effects. These antiepileptic drugs reduced AUC for SN-38 and SN-38-glucuronide by 50% or more. In addition to CYP3A4 induction, reduced exposure to irinotecan and its metabolites may also result from enhanced glucuronidation and increased biliary excretion. Additionally, for phenytoin – risk of seizure exacerbation due to reduced absorption of phenytoin in the gastrointestinal tract caused by cytotoxic agents.

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% decrease in AUC of the metabolite APC and a 109% increase in AUC of 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 such combination cannot be avoided.

Other CYP3A4 inhibitors (e.g., crizotinib, idelalisib) – risk of increased irinotecan toxicity due to reduced metabolism of irinotecan by crizotinib or idelalisib.

Use with caution

Vitamin K antagonists – increased risk of bleeding and thrombosis in cancer patients. If vitamin K antagonists are indicated, International Normalized Ratio (INR) should be monitored more frequently.

Monitor during concomitant use

Immunosuppressants (e.g., cyclosporine, tacrolimus) – excessive immunosuppression with risk of lymphoproliferative disorders.

Neuromuscular blocking agents – interaction between irinotecan and agents affecting neuromuscular transmission cannot be excluded. Irinotecan has anticholinesterase activity; medicinal products with anticholinesterase activity may prolong the neuromuscular blockade induced by succinylcholine and antagonistically affect the neuromuscular blockade induced by non-depolarizing agents.

Other combinations

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

Bevacizumab – results from a dedicated drug interaction study demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude increased toxicity due to their pharmacological properties.

Cetuximab – there is no evidence that cetuximab affects the safety profile of irinotecan or that irinotecan affects the profile of cetuximab.

Antineoplastic agents (including fluorocytosine as a prodrug of 5-fluorouracil) – adverse effects of irinotecan, such as myelosuppression, may be enhanced by other antineoplastic agents with a similar adverse effect profile.

Special precautions for use.

Irinotecan should be administered only in specialized institutions where cytotoxic chemotherapy is performed and only under the supervision of a physician experienced in the use of chemotherapy in oncology.

Due to the nature and frequency of adverse reactions, irinotecan should be used only after assessing the benefit-risk ratio in the following situations:

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

When irinotecan is used as monotherapy, it is typically administered on a schedule with administration every 3 weeks. However, a weekly administration schedule may be considered for patients who may require closer monitoring or who are at particular risk of developing severe neutropenia.

Delayed diarrhea

Patients should be informed about the risk of delayed diarrhea, which may occur more than 24 hours after administration of Irinosindan and at any time before the next cycle. In monotherapy regimens, the median time to the first episode of loose stools is 5 days after drug administration. Patients must promptly inform their physician of any onset of diarrhea and immediately initiate appropriate therapy.

Patients at increased risk of developing diarrhea include those who have previously received abdominal or pelvic radiotherapy; patients with baseline hyperleukocytosis; patients with a performance status ≥2; and female patients. Without adequate treatment, diarrhea may be life-threatening, especially if accompanied by neutropenia.

After the first episode of loose stools, patients should be instructed to consume large amounts of electrolyte-containing fluids and to immediately initiate appropriate anti-diarrheal therapy at the facility where Irinosindan infusion was administered. After hospital discharge, patients should be provided with prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, the patient must inform the physician at the department where Irinosindan was administered about the occurrence of diarrhea.

The currently recommended anti-diarrheal therapy consists of high-dose loperamide (4 mg as the first dose, then 2 mg every 2 hours). This regimen should be continued for an additional 12 hours after the last episode of loose stools. The treatment schedule must not be modified. Loperamide at such doses should never be used for longer than 48 hours due to the risk of paralytic ileus, while treatment should not last less than 12 hours.

In cases where 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.

In addition to antibiotic use for diarrhea treatment, hospitalization of patients is recommended in the following cases:

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

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

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

Hematology

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 who had previously undergone pelvic/abdominal irradiation compared to those who had not. Patients with a baseline total serum bilirubin level 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 monitored weekly during Irinosindan treatment. Patients should be warned about the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature >38 °C and neutrophil count ≤1000 cells/mm³) must be treated urgently in an inpatient setting with intravenous broad-spectrum antibiotics.

Patients experiencing severe hematological adverse reactions should have their Irinosindan dose reduced in subsequent administrations (see section "Dosage and administration").

Patients with severe diarrhea have an increased risk of infections and hematological toxicity. Complete blood counts should be performed in patients with severe diarrhea.

Liver function

Liver function tests should be performed before starting therapy and before each subsequent cycle. Patients with plasma total bilirubin levels 1.5 to 3 times above the upper limit of normal should have complete blood counts performed weekly due to decreased irinotecan clearance and, consequently, increased risk of hematotoxicity in this patient group. The drug must not be administered to patients with bilirubin levels exceeding the upper limit of normal by more than 3 times (see section "Contraindications").

Nausea and vomiting

Prophylactic antiemetic treatment is recommended before each Irinosindan administration. Nausea and vomiting are frequently reported with the use of this drug. Patients experiencing vomiting accompanied by delayed diarrhea should be urgently hospitalized.

Acute cholinergic syndrome

In the absence of clinical contraindications, at the onset of acute cholinergic syndrome (early diarrhea in combination with various other signs and symptoms such as increased sweating, abdominal cramps, miosis, and increased salivation), 0.25 mg of subcutaneous sulfate atropine should be administered.

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 will increase with higher doses of irinotecan.

Caution should be exercised in patients with bronchial asthma. Patients who have experienced acute and severe cholinergic syndrome should be given prophylactic sulfate atropine prior to subsequent Irinosindan infusions.

Respiratory disorders

Rare cases of interstitial lung disease, manifesting as lung infiltrates, may occur during irinotecan treatment. Interstitial lung disease may be fatal. Risk factors possibly associated with the development of interstitial lung disease include the use of lung-toxic drugs, radiotherapy, and colony-stimulating factors. Patients with existing risk factors should be closely monitored for respiratory symptoms before and during irinotecan treatment.

Extravasation

Although irinotecan is not considered a vesicant-forming agent, 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 irrigated and ice applied.

Elderly patients

Due to decreased biological functions, particularly liver function, caution should be exercised when selecting the Irinosindan dose for elderly patients (see section "Dosage and administration").

Chronic inflammatory bowel disease and/or bowel obstruction

Irinosindan should not be administered to patients until bowel obstruction has resolved (see section "Contraindications").

Kidney function

Elevations in serum creatinine or blood urea nitrogen 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 dysfunction due to tumor lysis syndrome have been reported.

Radiation therapy

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

Cardiac disorders

Myocardial ischemia has been observed after irinotecan treatment, predominantly in patients with pre-existing heart disease, other known risk factors for cardiac disease, and in patients who have previously received cytotoxic chemotherapy (see section "Adverse reactions").

Therefore, patients with known risk factors require close monitoring. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, arterial hypertension, and 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).

Patients with reduced UGT1A1 activity

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

Although the exact extent of initial dose reduction has not been established, consideration should be given to reducing the initial irinotecan dose in patients who are slow UGT1A1 metabolizers, particularly in patients receiving doses >180 mg/m² or in frail patients. Relevant clinical guidelines for dosing in this patient group should be considered. 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, but the clinical benefit of genotyping prior to treatment is uncertain, as UGT1A1 polymorphism does not explain all the toxicity observed during irinotecan therapy.

Others

Concomitant use of irinotecan with strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, apalutamide) of CYP3A4 should be avoided, as such combinations may alter irinotecan metabolism (see section "Interaction with other medicinal products and other forms of interaction").

Rare cases of renal failure, arterial hypotension, or circulatory failure have occurred in patients with dehydration due to diarrhea and/or vomiting, as well as in patients with sepsis.

This medicinal product contains 45 mg of sorbitol per mL of concentrate. Sorbitol is a source of fructose. This product must not be administered to patients with hereditary fructose intolerance (HFI), except in cases of extreme necessity. HFI may not yet be diagnosed in infants and young children (under 2 years of age). Medicinal products containing fructose administered intravenously may be life-threatening to patients with HFI and must not be prescribed to this patient group, except in cases of acute clinical necessity and absence of alternatives. A detailed history of HFI symptoms should be obtained from each patient before prescribing this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Contraception

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

Due to the potential genotoxicity of the medicinal product, male patients with female partners of childbearing potential should use highly effective contraceptive methods during treatment and for 3 months after the last dose of irinotecan.

Pregnancy

Data on the use of irinotecan in pregnant women are limited. Animal studies have demonstrated that irinotecan has embryotoxic and teratogenic effects. Therefore, considering the results of animal studies 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 metabolite pass into human breast milk. Therefore, due to the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with Irinosindan (see section "Contraindications").

Fertility

Information regarding the effect of irinotecan on human reproductive function is lacking. Adverse effects of irinotecan on reproductive function in animal offspring have been documented in animal studies. Patients should be offered the possibility of gamete preservation before starting irinotecan treatment.

Ability to affect reaction speed when driving or operating machinery.

Irinotecan has a moderate influence on the ability to drive or operate machinery. Patients should be warned about the possible development of dizziness or visual disturbances within 24 hours after irinotecan administration and advised not to drive or operate machinery if these symptoms occur.

Administration and Dosage

The medicinal product is intended for the treatment of adult patients. After dilution, the irinotecan solution for infusion should be administered into a peripheral or central vein.

Recommended Doses

Monotherapy (for previously treated patients)

The recommended dose of the medicinal product is 350 mg/m² body surface area, to be administered by intravenous infusion over 30–90 minutes every 3 weeks (see sections "Safety Precautions" and "Special Warnings and Precautions for Use").

Combination Therapy (for previously untreated patients)

The efficacy and safety of irinotecan in combination with 5-FU and FA were evaluated according to the dosing schedule described below.

• Irinotecan hydrochloride + 5-FU/FA every 2 weeks

The recommended dose of irinotecan is 180 mg/m² once every 2 weeks, administered as a 30–90 minute intravenous infusion, followed by infusion of folinic acid or 5-fluorouracil.

Information on the dosage and administration of cetuximab when used concomitantly can be found in the cetuximab product information.

Irinotecan is generally administered at the same doses as in the last cycles of the prior irinotecan-containing regimen. Irinotecan should not be administered earlier than 1 hour after completion of cetuximab infusion.

Information on the dosage and administration of bevacizumab can be found in the bevacizumab product information.

Information on the dosage and use of irinotecan in combination with capecitabine is provided in the relevant sections of the capecitabine product information.

Dose Adjustment

Irinotecan should be administered only after adequate resolution of all adverse effects to a toxicity level of 0 or 1 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), and only after treatment-related diarrhea has been completely resolved.

At the start of the next infusion, the doses of irinotecan hydrochloride and 5-FU must be reduced based on the most severe adverse reactions observed during the previous infusion. If necessary, treatment should be delayed by 1–2 weeks until treatment-related adverse effects have resolved.

The dose of irinotecan hydrochloride and 5-FU should be reduced by 15–20% in the event of the following adverse effects:

• Hematological toxicity [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).

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

For patients aged 65 years and older receiving irinotecan and capecitabine, a reduced starting dose of capecitabine to 800 mg/m² body surface area twice daily is recommended, according to the capecitabine product information. Information on dose adjustments during combination therapy is also provided in the capecitabine product information.

Treatment Duration

Treatment with Irinotecan should be continued until objective disease progression or until signs of unacceptable toxicity develop.

Special Patient Populations

Patients with Hepatic Impairment

Monotherapy

For patients with a performance status ≤2, the initial dose of irinotecan 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 greater than 50%, irinotecan clearance is reduced, thereby increasing the risk of hematotoxicity. Therefore, weekly monitoring of complete blood counts is required in this population.

• For patients with plasma bilirubin levels up to 1.5 times the upper limit of normal, the recommended dose of irinotecan is 350 mg/m².
• For patients with plasma bilirubin levels 1.5 to 3 times the upper limit of normal, the recommended dose of irinotecan is 200 mg/m².
• Irinotecan is contraindicated in patients with plasma bilirubin levels exceeding 3 times the upper limit of normal (see sections "Contraindications" and "Special Warnings and Precautions for Use").

There is no available information on the use of irinotecan in combination with other agents in patients with hepatic impairment.

Patients with Renal Impairment

Irinotecan is not recommended for use in patients with renal impairment, as studies in this patient group have not been conducted (see section "Special Warnings and Precautions for Use").

Elderly Patients

Specific pharmacokinetic studies in elderly patients have not been conducted. However, dose selection for patients in this group should be cautious, as they are more likely to have decreased physiological function. These patients require more intensive monitoring (see section "Special Warnings and Precautions for Use").

Administration Method

Precautions During Medicinal Product Administration

Instructions for dilution of the medicinal product are provided in the section "Safety Precautions".

Children

The safety and efficacy of irinotecan in children have not been established. Data are lacking.

The medicinal product is indicated for use in adults only.

Overdose

Symptoms. Cases of overdose have been reported with doses approximately twice the recommended therapeutic dose; such overdose may be fatal. The most significant adverse reactions were severe neutropenia and severe diarrhea.

Treatment. There is no known antidote for irinotecan. Intensive supportive treatment should be administered to prevent dehydration due to diarrhea, and infectious complications should be treated appropriately.

Adverse reactions

Clinical studies

Data on adverse reactions were carefully collected during studies in metastatic colorectal cancer; the frequencies of their occurrence are listed 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 level was 8 days.

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

Its main symptoms were 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 "Dosage and administration").

Monotherapy

The adverse reactions listed below, considered possibly or probably related to irinotecan use, were reported in 765 patients who received the recommended dose of 350 mg/m² as monotherapy. Within each frequency category, adverse reactions are listed in order of decreasing severity. 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 (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Description of individual adverse reactions (with monotherapy)

Severe diarrhea was observed in 20% of patients who followed recommendations for diarrhea management. 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 medications.

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 counts were below 1000 cells/mm³ in 18%, including 7.6% with neutrophil counts <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 reported in approximately 58.7% of patients (8% with hemoglobin levels <8 g/dL and 0.9% with hemoglobin levels <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 acute cholinergic syndrome of severe grade was observed 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 has not been 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 elevations 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. Slight or moderate transient elevation in serum creatinine levels was observed in 7.3% of patients.

Combination therapy

The adverse reactions described in this section pertain to irinotecan. Information on the effect of cetuximab on the safety profile of irinotecan or on the effect of irinotecan on the safety profile of cetuximab is lacking. Additional adverse reactions observed during concomitant administration of irinotecan with cetuximab corresponded to adverse reactions expected with cetuximab (e.g., acneiform rash in 88% of cases). Information on adverse reactions to irinotecan when administered concomitantly with cetuximab can also be found in the instructions for medical use of the respective medicinal products.

The following adverse reactions were reported in patients receiving capecitabine in combination with irinotecan, in addition to those observed with 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, grade III and IV adverse reactions: febrile neutropenia.

Complete information on capecitabine adverse reactions is provided in the capecitabine instructions for medical use.

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 with capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy:

common, grade III and IV adverse reactions: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction.

Complete information on adverse reactions of capecitabine and bevacizumab is provided in the instructions for medical use of capecitabine and bevacizumab.

The development of grade III arterial hypertension was the main significant risk associated with adding bevacizumab to the bolus regimen of irinotecan/5-FU/FA. In addition, with this treatment regimen, a slight increase in the frequency of grade III/IV chemotherapy-related adverse reactions—diarrhea and leukopenia—was observed compared to patients receiving only the bolus regimen of irinotecan/5-FU/FA. Additional information on adverse reactions with combination therapy including bevacizumab is provided in the bevacizumab instructions for medical use.

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

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

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

Description of individual adverse reactions (with 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% of patients.

Severe nausea and vomiting occurred less frequently (in 2.1% and 2.8% of patients, respectively).

Constipation due to administration of irinotecan and/or loperamide was observed in 3.4% of patients.

Neutropenia occurred in 82.5% of patients, of whom 9.8% experienced severe neutropenia (neutrophil count <500 cells/mm³). In evaluable treatment cycles, 67.3% of patients had neutrophil counts below 1000 cells/mm³, including 2.7% with counts <500 cells/mm³. Complete recovery typically took up to 7–8 days.

Febrile neutropenia occurred in 3.4% of patients and in 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 was observed in 97.2% of patients (2.1% with hemoglobin levels <8 g/dL).

Thrombocytopenia (<100,000 cells/mm³) occurred 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 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 has not been clearly established.

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

Laboratory parameters. Transient elevations (Grade 1 and 2) in serum levels of 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 elevations in these parameters were observed in 0%, 0%, 0%, and 1% of patients, respectively. No Grade 4 adverse reactions of this type were observed.

Very rare cases of increased amylase and/or lipase levels have been reported.

Rare cases of hypokalemia and hyponatremia have been reported, primarily associated with diarrhea and vomiting.

Other adverse reactions reported in clinical trials of weekly irinotecan regimens

In clinical trials of irinotecan administration, the following additional adverse reactions related to drug use were reported: pain, sepsis, anorectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin reactions, gait disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain, increased gamma-glutamyl transferase, extravasation, tumor lysis syndrome, cardiovascular disorders (angina pectoris, cardiac arrest, myocardial infarction, myocardial ischemia, peripheral vascular disorders, vascular disorders), and thromboembolic events (arterial thrombosis, ischemic stroke, cerebral ischemia, deep vein thrombosis, peripheral vascular embolism, pulmonary embolism, thrombophlebitis, thrombosis, sudden death).

Post-marketing surveillance

The frequency of adverse reactions during the post-marketing surveillance period is unknown (cannot be estimated based on available data).

*For example, Pneumocystis pneumonia, bronchopulmonary aspergillosis, systemic candidiasis.

**Herpes zoster, influenza, reactivation of hepatitis B, cytomegalovirus colitis.

***Rare cases of renal failure, hypotension, or cardiovascular failure have been observed in patients who experienced dehydration due to diarrhea and/or vomiting or sepsis.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light and in a place inaccessible to children.

Do not freeze.

Incompatibility. Do not mix with other medicinal products except those indicated in the section "Special precautions for handling".

Packaging.

2 ml, 5 ml, 15 ml, or 25 ml in a vial, 1 vial in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sindan Pharma S.R.L.

Actavis Italia S.p.A.

Manufacturer's address and address of its place of business.

Bd. Ion Mihalache, 11, Sector 1, 011171, Bucharest, Romania.

Via Pasteur, 10, 20014 Nerviano (Milan), Italy.