Iritero

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

Composition:

Active substance: irinotecan;

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

1 vial of concentrate for preparation of infusion solution contains 40 mg or 100 mg of irinotecan hydrochloride trihydrate;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: light yellow aqueous solution without visible particles.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01CE02.

Pharmacological properties.

Pharmacodynamics.

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, it is metabolized to SN-38, a compound that is more active against purified topoisomerase I and more cytotoxic than irinotecan against a number of human and murine tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 leads to single-strand DNA damage, which in turn blocks DNA replication and exerts 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 demonstrated that irinotecan and SN-38 are not significantly recognized in vitro by the multidrug resistance P-glycoprotein and exert cytotoxic effects on cell lines resistant to doxorubicin and vinblastine.

In addition, irinotecan exhibits a broad spectrum of antitumor activity in vivo against tumor models in mice (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 the multidrug resistance P-glycoprotein (vincristine- and doxorubicin-resistant P388 leukemias).

Besides antitumor activity, the most significant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.

Patients with reduced UGT1A1 activity

Uridine diphosphate 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, resulting in various metabolic intensities within the population. One specific variant of the UGT1A1 gene contains a polymorphic region in the promoter area, known as UGT1A1*28. This variant, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Crigler-Najjar syndrome), are associated with reduced enzyme activity. Meta-analysis data indicate that patients with Crigler-Najjar syndrome (types 1 and 2) or homozygous for the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk of developing hematological toxicity (grades 3 and 4) following administration of moderate or high doses of irinotecan (>150 mg/m²). No association has been established between the UGT1A1 genotype and the occurrence of irinotecan-induced diarrhea.

Patients known to be homozygous for the UGT1A1*28 allele should receive the standard initial dose of irinotecan. However, these patients should be closely monitored for signs of hematological toxicity. For patients who have previously experienced hematological toxicity during prior treatment cycles, consideration should be given to reducing the initial dose of irinotecan. The exact extent of dose reduction for this patient group has not been established. Any further dosage adjustments should be based on the patient's tolerance to treatment (see sections "Special precautions for use" and "Method of administration and dosage").

Currently, there are insufficient clinical data to conclude on the usefulness of UGT1A1 allele genotyping in patients.

Pharmacokinetics.

Absorption

At the end of infusion with the recommended dose of 350 mg/m², the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 µg/mL and 56 ng/mL, respectively, and the mean values of the area under the concentration-time curve (AUC) were 34 µg•h/mL and 451 ng•h/mL, respectively. High inter-individual variability in pharmacokinetic parameters is generally observed for SN-38.

Distribution

In a study with dosing regimens ranging from 100 mg/m² to 750 mg/m² administered as a 30-minute intravenous infusion every 3 weeks, the steady-state volume of distribution (Vss) was found to be 157 L/m².

In vitro, plasma protein binding is approximately 65% for irinotecan and 95% for the metabolite SN-38.

Biological transformation

Mass balance and metabolism studies of the ¹⁴C-labeled drug showed that more than 50% of the intravenously administered dose of irinotecan is excreted unchanged: 33% 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, leading to the formation of the active metabolite SN-38, which is primarily eliminated via glucuronidation followed by excretion of the glucuronide conjugate through the liver and kidneys (<0.5% of the administered irinotecan dose); SN-38 glucuronide is likely subsequently hydrolyzed in the intestine;
• Oxidation by cytochrome P450 3A, resulting in cleavage of the outer piperidine ring and formation of an aminopentanoic acid derivative (APC) 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. In descending order of quantity, the next components are the APC derivative, SN-38 glucuronide, and SN-38. Only SN-38 exerts significant cytotoxic activity.

Elimination

Following administration of irinotecan at doses of 100–750 mg/m² as a 30-minute intravenous infusion every 3 weeks, a biphasic or triphasic plasma elimination of irinotecan is observed. The mean plasma clearance was 15 L/h/m². The mean elimination half-life of the first phase in the triphasic model was 12 minutes, of the second phase was 2.5 hours, and the terminal half-life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal half-life of 13.8 hours.

Irinotecan clearance is reduced by almost 40% in patients with bilirubinemia (serum total bilirubin concentration 1.5 to 3 times above the upper limit of normal (ULN)). In these patients, a dose of irinotecan of 200 mg/m² results in plasma drug exposure comparable to that achieved with a dose of 350 mg/m² in cancer patients with normal liver function.

Linearity/Non-linearity

Population pharmacokinetic analysis of irinotecan was performed in 148 patients with metastatic colorectal cancer who received treatment under various regimens and doses in phase II studies. Pharmacokinetic parameters estimated using a three-compartment model were similar to those observed in phase I studies. All studies showed that exposure to irinotecan (CPT-11) and SN-38 increases proportionally with the administered CPT-11 dose; their pharmacokinetics are independent of the number of prior cycles and dosing schedule.

Pharmacokinetic/Pharmacodynamic relationships

The severity of the most prominent toxic effects of irinotecan (e.g., leukoneutropenia and diarrhea) is related to exposure (AUC) to unchanged irinotecan and its metabolite SN-38. Significant correlations were observed between hematological toxicity (nadir decrease in leukocyte and neutrophil counts) or the intensity of diarrhea and the AUC values of irinotecan and its metabolite SN-38 during monotherapy.

Clinical characteristics.

Indications.

Treatment of advanced colorectal cancer:

• in combination with 5-fluorouracil (5-FU) and folinic acid (FA) in patients who have not received prior chemotherapy for the treatment of advanced disease;
• as monotherapy if the standard treatment regimen with 5-FU has proven ineffective.

In combination with cetuximab, the medicinal product Iritero 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.

In combination with 5-FU, FA, and bevacizumab, the medicinal product Iritero is indicated as first-line therapy in patients with metastatic carcinoma of the colon or rectum.

In combination with capecitabine (with or without addition of bevacizumab), the medicinal product Iritero 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");
• history of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to any of the excipients of Iritero;
• serum bilirubin level exceeding the upper limit of normal by 3 times or more;
• severe bone marrow suppression;
• patient's general condition > 2 (according to WHO classification);
• breastfeeding period;
• concomitant use with St. John’s wort preparations;
• live attenuated vaccines (see section "Interaction with other medicinal products and other forms of interaction").

When used in combination with cetuximab, bevacizumab, or capecitabine, see additionally the contraindications listed in the instructions for medical use of the respective medicinal products.

Safety precautions.

Extreme caution should be exercised when preparing and administering Iritero, and protective eyewear, mask, and gloves should be used. If the concentrate or prepared infusion solution comes into contact with the skin, it should be immediately and thoroughly washed off with soap and water. If the concentrate or prepared infusion solution comes into contact with mucous membranes, they should be immediately rinsed with water.

Preparation of infusion solution

PREPARATION OF THE INFUSION SOLUTION MUST BE PERFORMED UNDER ASEPTIC CONDITIONS.

The concentrate for infusion solution should be used immediately after opening.

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

If any precipitate is observed after reconstitution in the vials, the product should be discarded according to standard procedures for cytotoxic agents.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to administration lies with the user; however, storage should not exceed 24 hours at 2–8 °C.

Disposal

All materials used for dilution and administration of the drug must be disposed of according to standard procedures applicable to cytotoxic agents.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated (see section "Contraindications")

St. John’s wort (Hypericum perforatum). Decreased plasma levels of the active metabolite of irinotecan, SN-38. In a small pharmacokinetic study (n = 5), where irinotecan 350 mg/m² was administered concomitantly with St. John’s wort (Hypericum perforatum) 900 mg, a 42% reduction in plasma levels of the active metabolite SN-38 was observed. Therefore, St. John’s wort must not be used concomitantly with irinotecan.

Live attenuated vaccines (e.g., yellow fever vaccine). Risk of generalized vaccine reaction, potentially fatal. Concomitant use is contraindicated during treatment with irinotecan and for 6 months following discontinuation of chemotherapy. Inactivated or killed vaccines may be administered, although the immune response to such vaccines may be reduced.

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

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

Medicinal products that are strong inducers of CYP3A4 and/or UGT1A1 (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide). Risk of reduced exposure to irinotecan, SN-38, and SN-38 glucuronide, resulting in decreased pharmacodynamic effects. Several studies have shown that concomitant use of anticonvulsant drugs inducing CYP3A4 leads to reduced exposure to irinotecan, SN-38 glucuronide, and SN-38, and diminished pharmacodynamic effects. These anticonvulsant drugs were associated with a reduction in AUC of SN-38 and SN-38G by 50% or more. In addition to CYP3A4 induction, enhanced glucuronidation and increased biliary excretion may contribute to reduced exposure to irinotecan and its metabolites. Additionally, when phenytoin is used: risk of seizure exacerbation due to reduced gastrointestinal absorption of phenytoin caused by cytotoxic agents.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin). Concomitant use of ketoconazole has been shown to reduce AUC of the APC metabolite by 87% and increase AUC of the SN-38 metabolite by 109% compared to irinotecan monotherapy.

UGT1A1 inhibitors (e.g., atazanavir, ketoconazole, regorafenib). There is a risk of increased systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should consider this risk if the 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 thrombotic events in cancer patients. If a vitamin K antagonist is indicated, increased monitoring frequency of the international normalized ratio (INR) is required.

Concomitant use should be considered

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

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

Other combinations

5-FU/FA. Concomitant administration of 5-FU/FA in a combination regimen 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 or its active metabolite SN-38. However, this does not exclude any potential increase in toxicity due to their pharmacological properties.

Cetuximab. There is no evidence that cetuximab affects the safety profile of irinotecan or vice versa.

Anticancer agents (including flucytosine as a prodrug of 5-FU). Adverse reactions of irinotecan, such as myelosuppression, may be intensified by other anticancer agents with a similar adverse reaction profile.

Special precautions for use.

Considering the nature and frequency of adverse reactions, the medicinal product Iritero should be administered only when the expected benefit outweighs the potential risk in the following cases:

• patients with risk factors, particularly with a performance status of 2 (according to the WHO scale);
• in rare individual cases where 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 a hospital setting.

When irinotecan is used as monotherapy, it is usually administered on a 3-week dosing schedule. However, a weekly dosing regimen may be used for patients who may require closer monitoring or who are at particular risk of neutropenia.

Delayed diarrhea

Patients should be informed about the risk of delayed diarrhea, which may occur more than 24 hours after administration of Iritero and at any time before the next cycle. With monotherapy, the median time to first episode of loose stools was 5 days after drug administration. Patients should immediately inform their physician about the frequency of such episodes and initiate appropriate treatment.

Patients at increased risk of developing diarrhea include those who have previously received radiotherapy to the abdominal and pelvic areas, patients with prior hyperleukocytosis, those with poor general condition (performance status ≥ 2 according to WHO classification), and female patients. If diarrhea is not adequately treated, it may become life-threatening, especially when associated with concomitant neutropenia.

At the first episode of loose stools, patients should receive frequent oral fluids containing electrolytes and immediate appropriate anti-diarrheal therapy. Anti-diarrheal treatment should be initiated in the department where the patient received Iritero. After hospital discharge, patients should be provided with prescribed medications to allow immediate initiation of diarrhea treatment upon its onset. Additionally, patients should inform their physician at the department where they received Iritero about the occurrence of diarrhea.

The currently recommended anti-diarrheal therapy includes 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 these doses should not be used for longer than 48 hours due to the risk of paralytic ileus; however, treatment should not last less than 12 hours.

In cases of diarrhea associated with severe neutropenia (neutrophil count < 500 cells/mm³), broad-spectrum antibiotics should be administered prophylactically in addition to anti-diarrheal agents.

Hospitalization is required for diarrhea treatment in the following situations, in addition to antibiotic therapy:

• diarrhea associated with fever;
• severe diarrhea (requiring intravenous rehydration);
• diarrhea lasting more than 48 hours despite high-dose loperamide therapy.

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

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

Hematology

In clinical studies, the incidence of grade 3–4 neutropenia according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was significantly higher in patients who had previously received pelvic/abdominal irradiation compared to those who had not. Patients with a baseline total serum bilirubin level of 1 mg/dL or higher also had a significantly higher probability of developing grade III–IV neutropenia compared to patients with bilirubin levels below 1 mg/dL.

Complete blood counts should be performed weekly during Iritero treatment. Patients should be warned about the risk of neutropenia and the significance of fever. Neutropenia associated with fever (temperature > 38°C and neutrophil count ≤1000 cells/mm³) should be urgently treated in a hospital setting with intravenous broad-spectrum antibiotics.

Patients who experienced severe hematological adverse reactions should have their Iritero dose reduced upon subsequent administration. Patients with severe diarrhea are at increased risk of infections and hematological toxicity. Complete blood counts should be performed in such patients.

Hepatic impairment

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

Nausea and vomiting

Prophylactic antiemetic treatment is recommended before each Iritero administration. Nausea and vomiting are frequently reported with the use of this drug. Patients with vomiting in combination with delayed diarrhea should be urgently hospitalized for appropriate treatment.

Acute cholinergic syndrome

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

These symptoms, which may occur during or immediately after irinotecan infusion, are associated with the anticholinesterase activity of the parent compound irinotecan. It is expected that the frequency of these symptoms will increase with higher doses of irinotecan.

Caution should be exercised in patients with bronchial asthma. Patients who experienced acute and severe cholinergic syndrome are recommended to receive prophylactic atropine sulfate prior to subsequent Iritero administration.

Respiratory disorders

Rare cases of interstitial lung disease, manifested by pulmonary infiltrates, may occur during irinotecan treatment. Interstitial lung disease may lead to fatal outcomes. 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, it should be administered with caution, and the infusion site should be monitored for signs of inflammation. In case of extravasation, the infusion site should be flushed and ice applied.

Elderly patients

Due to decreased biological functions, particularly liver function, caution should be exercised when selecting the Iritero dose for elderly patients.

Chronic inflammatory bowel diseases and/or bowel obstruction

Patients should not be treated with Iritero until complete resolution of bowel obstruction.

Patients with renal impairment

Elevations in serum creatinine or blood urea nitrogen have been observed. Cases of acute renal failure have been reported. 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 previously received pelvic/abdominal irradiation have an increased risk of myelosuppression after irinotecan administration. Physicians should be cautious when treating patients with extensive prior irradiation (e.g., > 25% bone marrow irradiation and within 6 weeks before starting irinotecan therapy). Dose adjustments may be applied for this patient group (see section "Dosage and administration").

Cardiac disorders

Cases of myocardial ischemia have been observed after irinotecan administration, primarily in patients with pre-existing heart disease, other known risk factors for heart disease, and in patients who 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 (smoking, arterial hypertension, and hyperlipidemia).

Vascular disorders

In patients with multiple risk factors in addition to the primary malignancy, irinotecan use has been rarely associated with thromboembolic complications (pulmonary embolism, venous thrombosis, and arterial thromboembolism).

Other factors

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").

Isolated cases of renal failure, arterial hypotension, or circulatory failure have been observed in patients who experienced diarrhea, vomiting, or sepsis leading to dehydration.

Contraception in women of childbearing potential/men

Due to the potential for genotoxicity, women of childbearing potential are advised to use highly effective contraception 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 contraception during treatment and for 3 months after the last dose of irinotecan (see section "Use during pregnancy or breastfeeding").

Breastfeeding

Due to the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with Iritero (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Since the drug contains sorbitol, a source of fructose, it should not be administered to patients with hereditary fructose intolerance (HFI), unless there is an acute clinical need.

In infants and young children (under 2 years of age), HFI may not yet have been diagnosed. Intravenous fructose-containing drugs may have life-threatening effects in patients with HFI and should not be administered to such patients unless there is a compelling clinical need and no alternative.

A detailed medical history regarding symptoms of HFI should be obtained from each patient before administration of this medicinal product.

Use during pregnancy or breastfeeding.

Contraception

Due to the potential for genotoxicity, women of childbearing potential should be advised to use highly effective contraception 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 should be advised to use effective contraception 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. Given the results of animal studies and the mechanism of action of irinotecan, the medicinal product Iritero should not be used during pregnancy, except in cases of urgent need.

Women of childbearing potential should not start irinotecan treatment until 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 Iritero (see sections "Contraindications" and "Special precautions for use").

Effect on fertility

There is no information on the effect of irinotecan on human fertility. Animal studies have documented negative effects of irinotecan on fertility in offspring. Patients should be counseled regarding gamete preservation before starting Iritero treatment.

Ability to drive and use machines.

The medicinal product has a moderate influence on the ability to drive and use machines. Patients should be warned about the possible occurrence of dizziness or visual disturbances within 24 hours after administration of Iritero and advised not to drive or operate machinery if these symptoms occur.

Administration and Dosage.

The medicinal product is intended for treatment of adult patients only. The infusion solution 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 administered by intravenous infusion over 30–90 minutes every 3 weeks (see section "Special Warnings and Precautions for Use").

Combination therapy (for previously untreated patients): the efficacy and safety of the medicinal product in combination with 5-FU and LV were evaluated according to the following dosing schedule:

• irinotecan and 5-FU/LV every 2 weeks.

The recommended dose of irinotecan is 180 mg/m² body surface area administered by intravenous infusion over 30–90 minutes once every 2 weeks, followed by infusion of LV or 5-FU.

For information on dosing and administration of concomitant cetuximab, refer to the prescribing information for that medicinal product.

The same dose of irinotecan as used in the last cycles of irinotecan-containing treatment should generally be applied. Irinotecan should be administered no earlier than 1 hour after the end of cetuximab infusion.

For information on dosing and administration of bevacizumab, see the prescribing information for bevacizumab.

For information on dosing and administration of irinotecan in combination with capecitabine, see the relevant sections of the prescribing information for capecitabine.

Dosage Adjustment

Iriritero should be administered after complete resolution of all adverse reactions to grade 0 or 1 according to the NCI-CTC (National Cancer Institute Common Toxicity Criteria) and after complete cessation of treatment-related diarrhea.

At the beginning of the next infusion, the dose of Iriritero and 5-FU (if used) should be reduced depending on the most severe adverse reaction observed during the previous infusion. Treatment initiation should be delayed by 1–2 weeks to allow resolution of treatment-related adverse reactions.

The dose of Iriritero and/or 5-FU (if used) should be reduced by 15–20% in case of the following adverse reactions:

− hematological toxicity (grade 4 neutropenia, febrile neutropenia (grade 3–4 neutropenia accompanied by fever grade 2–4), grade 4 thrombocytopenia, and grade 4 leukopenia);

− non-hematological toxicity grade 3–4.

Dosage modification recommendations for cetuximab when used in combination with irinotecan should be followed according to the product information for that medicinal product.

For patients aged 65 years and older receiving irinotecan and capecitabine, the dose of capecitabine should be reduced to 800 mg/m² body surface area twice daily. For information on dose adjustment in combination therapy, refer to the prescribing information for capecitabine.

Treatment Duration

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

Patients with Hepatic Impairment

Monotherapy

• For patients with performance status ≤ 2, the initial dose of Iriritero should be determined based on serum bilirubin levels (if bilirubin levels are elevated up to 3 times above ULN). In such patients with hyperbilirubinemia and prothrombin time increased by more than 50%, irinotecan clearance is reduced, resulting in an increased risk of hematological toxicity. Therefore, complete blood count should be monitored weekly in these patients.
• For patients with bilirubin levels up to 1.5 times above ULN, the recommended dose of Iriritero is 350 mg/m² body surface area.
• For patients with bilirubin levels between 1.5 and 3 times above ULN, the recommended dose of Iriritero is 200 mg/m² body surface area.
• Iriritero is not recommended for patients with bilirubin levels exceeding ULN by more than 3 times (see sections "Contraindications" and "Special Warnings and Precautions for Use").

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

Patients with Renal Impairment

The use of Iriritero in patients with renal impairment is not recommended, as studies in this patient population have not been conducted (see sections "Special Warnings and Precautions for Use").

Elderly Patients

Specific pharmacokinetic studies in elderly patients have not been conducted. However, dose selection should be cautious in this population due to the higher likelihood of decreased physiological functions. Patients in this age group require more intensive monitoring (see section "Special Warnings and Precautions for Use").

Children

The medicinal product is intended for treatment of adult patients only.

Overdose

Cases of overdose, potentially fatal, have been reported with doses approximately twice the recommended therapeutic dose. The most significant adverse reactions include severe neutropenia and severe diarrhea. There is no known antidote for irinotecan overdose. Intensive supportive treatment should be initiated to prevent dehydration due to diarrhea and to manage infectious complications.

Adverse reactions.

Clinical studies

Data on adverse reactions were carefully collected during studies of metastatic colorectal cancer, and the frequencies are presented below. When the drug is used for other indications besides 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, severe acute cholinergic syndrome was very commonly 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 "Dosage and administration").

Monotherapy

The adverse reactions listed below, considered possibly or probably related to irinotecan administration, were observed 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 agents.

Constipation occurred in less than 10% of patients.

Neutropenia was observed in 78.7% of patients, of whom severe grade (neutrophil count <500 cells/mm³) occurred in 22.6%. In evaluable treatment cycles, neutrophil count was below 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 was observed in 6.2% of patients (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 level <8 g/dL and 0.9% with hemoglobin level <6.5 g/dL).

Thrombocytopenia (<100,000 cells/mm³) was observed in 7.4% of patients (1.8% of all treatment cycles), of whom 0.9% (0.2% of treatment cycles) had platelet counts ≤50,000 cells/mm³. In nearly all patients, recovery of counts took up to 22 days.

Acute cholinergic syndrome. Transient severe acute cholinergic syndrome was observed in 9% of patients receiving irinotecan as monotherapy.

Asthenia was severe in less than 10% of patients receiving irinotecan as 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 irinotecan as monotherapy.

Laboratory parameters

Mild or moderate transient elevations in serum levels of transaminases, alkaline phosphatase, or bilirubin were recorded in 9.2%, 8.1%, and 1.8% of patients, respectively, in the absence of progressive liver metastases. Mild or moderate transient elevations in serum creatinine levels were observed in 7.3% of patients.

Combination therapy

The adverse reactions described in this section are attributed to irinotecan. Information on the effect of cetuximab on the safety profile of irinotecan or vice versa is lacking. Additional adverse reactions observed with concomitant administration of irinotecan and cetuximab corresponded to those adverse reactions expected with cetuximab (e.g., acneiform rash 88%). Information on adverse reactions with combined use of irinotecan and cetuximab is also provided in the respective product information leaflets.

Below are the adverse reactions reported in patients receiving capecitabine in combination with irinotecan, in addition to those reactions observed with capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy.

Very common, all grades of severity: thrombosis/embolism.

Common, all grades of severity: hypersensitivity reactions, ischemia/myocardial infarction.

Common, grade 3 and 4 adverse reactions: febrile neutropenia.

Complete information on capecitabine adverse reactions is provided in the product information leaflet for this medicinal product.

Below are the grade 3 and 4 adverse reactions reported in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those reactions observed with capecitabine monotherapy or occurring with higher frequency compared to capecitabine monotherapy.

Common, grade 3 and 4 adverse reactions: neutropenia, thrombosis/embolism, arterial hypertension, ischemia/myocardial infarction. Complete information on adverse reactions of capecitabine and bevacizumab is provided in the product information leaflets for these medicinal products.

Grade 3 arterial hypertension was the main significant risk factor associated with the addition of bevacizumab to the treatment regimen of bolus irinotecan/5-FU/FA. Additionally, with this regimen, there was a slightly increased frequency of grade 3/4 diarrhea and leukopenia compared to patients receiving bolus irinotecan/5-FU/FA alone without bevacizumab. Other 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 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 3 or 4 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.

Below are the adverse reactions that were possibly or probably related to irinotecan administration and were observed in 145 patients receiving 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 the recommended diarrhea management guidelines. In evaluable treatment cycles, severe diarrhea occurred in 3.9%.

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

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

Neutropenia was observed 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 neutrophil counts <500 cells/mm³. Full recovery typically took up to 7–8 days.

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

Thrombocytopenia (<100,000 cells/mm³) was observed 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 acute cholinergic syndrome of severe intensity was observed 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 the use of irinotecan 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 increases (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 increases in these parameters were observed in 0%, 0%, 0%, and 1% of patients, respectively. No cases of grade 4 adverse reactions 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, the following adverse reactions related to the drug have been reported: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin reactions, gait disturbances, confusion, headache, syncope, hot flashes, bradycardia, urinary tract infections, chest pain, increased gamma-glutamyl transferase, hemorrhage, 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, cerebrovascular disorders, deep vein thrombophlebitis, lower extremity venous embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special precautions").

Post-marketing surveillance

The frequency of adverse reactions during post-marketing surveillance 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, arterial hypotension, or cardiovascular failure were observed in patients who experienced dehydration due to diarrhea and/or vomiting or sepsis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine.

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from light at a temperature not exceeding 25 °C, in a place inaccessible to children. Do not freeze.

Incompatibilities.

The drug must not be mixed with other medicinal products, except those listed in the section "Special precautions for safety".

Packaging.

2 ml (40 mg) or 5 ml (100 mg) in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. HETERO LABS LIMITED.

Manufacturer's address and location of its business operation.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.