Irinotecan amaksa: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IRINOTECAN AMAXA IRINOTECAN AMAXA

Composition:

Active substance: irinotecan;

1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate, corresponding to 17.33 mg of irinotecan;

Excipients: D-sorbitol, lactic acid, sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear yellow-colored solution.

Pharmacotherapeutic group. Antineoplastic agents. Cytostatic topoisomerase I inhibitors. ATC code L01CB02.

Pharmacological Properties

Pharmacodynamics

Irinotecan Amaksa is a semisynthetic compound derived from camptothecin. It is an antineoplastic agent that acts as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase, the drug is metabolized in most tissues to SN-38, a compound that is significantly more active than irinotecan against purified topoisomerase I and more cytotoxic against a range of 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 DNA 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.

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

Patients with Reduced UGT1A1 Activity

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is involved in the metabolic inactivation of SN-38, the active metabolite of irinotecan, by forming the inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic activity among individuals. One specific genetic variant, UGT1A1*28, contains a polymorphic region in the promoter region. This variant, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Crigler-Najjar syndrome), is 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 III–IV) following administration of medium or high doses of irinotecan (>150 mg/m²). No association has been established between UGT1A1 genotype and 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 experienced hematological toxicity during previous treatment cycles, a reduction in the initial dose of irinotecan should be considered. The exact magnitude 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 Warnings and Precautions for Use" and "Dosage and Administration"). Currently, there are insufficient clinical data to conclude on the utility of UGT1A1 genotyping in patients.

Pharmacokinetics

Following administration of irinotecan at doses of 100–750 mg/m² via 30-minute intravenous infusion every 3 weeks, a biphasic or triphasic plasma elimination of irinotecan is observed. The mean plasma clearance is 15 L/h/m², and the volume of distribution at steady state (Vss) is 157 L/m² of body surface area. The mean plasma half-life during the first phase of the triphasic model was 12 minutes, during the second phase – 2.5 hours, and during the third phase – 14.2 hours. Plasma elimination of SN-38 was biphasic, with a mean terminal half-life of 13.8 hours.

Plasma protein binding, as determined in vitro, is approximately 65% for irinotecan and 95% for the metabolite SN-38.

More than 50% of the intravenously administered dose of irinotecan is excreted unchanged, with 33% excreted in feces, primarily via bile, and 22% in urine.

Irinotecan clearance is reduced by nearly 40% in patients with hyperbilirubinemia (serum total bilirubin concentration 1.5–3 times the upper limit of normal). In these patients, a dose of irinotecan 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.

The severity of the most prominent toxic effects of irinotecan (e.g., leukopenia and diarrhea) is related to the exposure (area under the concentration-time curve [AUC]) of unchanged irinotecan and its metabolite SN-38. A significant correlation has been observed between hematological toxicity (nadir counts of leukocytes and neutrophils) or the severity of diarrhea and the AUC of irinotecan and its metabolite SN-38 during monotherapy.

Clinical characteristics.

Indications.

Treatment of patients with advanced colorectal cancer:

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

Irinotecan Amaksa in combination with cetuximab is indicated for the treatment of patients with metastatic colorectal cancer with wild-type KRAS gene and overexpression of epidermal growth factor receptor (EGFR), who have not previously received chemotherapy, or following ineffective cytotoxic therapy that included irinotecan.

In combination with 5-FU, FA, and bevacizumab, Irinotecan Amaksa is used as first-line therapy for patients with metastatic carcinoma of the colon or rectum.

In combination with capecitabine (with or without bevacizumab), Irinotecan Amaksa is used as first-line therapy for patients with metastatic colorectal cancer.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.
Chronic inflammatory bowel diseases and/or bowel obstruction (see section "Special precautions").
Breastfeeding period (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
Bilirubin levels exceeding the upper limit of normal by more than 3 times (see section "Special precautions").
Severe bone marrow insufficiency.
Performance status > 2 according to WHO scale.
Concomitant treatment with St. John's wort (see section "Interaction with other medicinal products and other forms of interaction").
Live attenuated vaccines.

Complete information on contraindications for cetuximab, bevacizumab, or capecitabine is provided in the respective instructions for medical use of these medicinal products.

Interaction with other medicinal products and other forms of interaction.

Medicinal products contraindicated for concomitant use with Irinotecan Amaksa (see section "Contraindications"):

St. John's wort – in a small pharmacokinetic study, 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 infections with potentially fatal outcomes. This risk is increased in patients with already suppressed immune systems due to their underlying disease. Concomitant administration of live attenuated vaccines is contraindicated during treatment with irinotecan and for six months after completion of chemotherapy. Inactivated vaccines should be used if available (e.g., polio vaccine), although the response to such vaccines may be reduced.

Medicinal products not recommended for concomitant use with Irinotecan Amaksa (see section "Special precautions"):

Concomitant use of irinotecan with strong inducers/inhibitors of cytochrome P450 3A4 (CYP3A4) should be avoided, as this may lead to changes in irinotecan metabolism (see section "Special precautions").

Strong CYP3A4 and/or UGT1A1 inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, or apalutamide) – results of several studies have demonstrated that concomitant use of anticonvulsants, which are CYP3A4 inducers (carbamazepine, phenobarbital, or phenytoin), leads to reduced efficacy of irinotecan, SN-38, and SN-38-glucuronide, resulting in decreased pharmacodynamic effect. These anticonvulsants caused a reduction in 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 be due to enhanced glucuronidation and more intensive biliary excretion.

Phenytoin – risk of seizure exacerbation due to reduced absorption of phenytoin in the gastrointestinal tract under the influence of cytotoxic agents.

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin) – a study showed that concomitant use 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 the active metabolite of irinotecan, SN-38. Physicians should consider this possibility when prescribing these two drugs concomitantly.

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

Medicinal products that should be used with caution in combination with Irinotecan Amaksa:

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

Immunosuppressants (e.g., cyclosporine, tacrolimus) – risk of excessive immune system suppression with potential for lymphocyte proliferation.

Neuromuscular blockers – interaction between irinotecan and neuromuscular blockers cannot be excluded. Since irinotecan has anticholinesterase activity, drugs with similar anticholinesterase effects may prolong the neuromuscular blockade of succinylcholine and antagonize the neuromuscular blockade of non-depolarizing agents.

Other combinations.

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

Bevacizumab – results of 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 enhanced by other anticancer agents with a similar adverse effect profile.

Special precautions for use.

Irinotecan Amaksa should be administered exclusively in a department specializing in cytotoxic chemotherapy. The drug must be used only under the supervision of a qualified physician experienced in anticancer chemotherapy.

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

for treatment of patients with risk factors, particularly those with a WHO performance status score of 2;
in rare individual cases where patients are unlikely to comply with recommendations for managing adverse reactions (e.g., 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 is used as monotherapy, it is typically administered on a 3-week dosing schedule. However, a weekly dosing regimen may be considered 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 occurs more than 24 hours after administration of Irinotecan Amaksa and at any time before the next treatment cycle. During monotherapy, the median time to the first episode of loose stools was 5 days after administration of Irinotecan Amaksa. Patients must promptly notify their physician if diarrhea develops and immediately initiate appropriate therapy.

Patients at increased risk of diarrhea include those previously treated with abdominal or pelvic radiation, patients with baseline hyperleukocytosis, patients with a WHO performance status ≥ 2, and women. Without proper treatment, diarrhea can be life-threatening, especially when associated with neutropenia.

After the first episode of loose stools, patients should immediately begin drinking large amounts of fluids containing electrolytes and initiate appropriate antidiarrheal therapy. Antidiarrheal treatment should be initiated in the department where Irinotecan Amaksa was administered. After hospital discharge, patients should receive prescribed medications to allow immediate treatment of diarrhea upon onset. Additionally, patients must inform their physician or the department where Irinotecan Amaksa was administered about the occurrence of diarrhea.

Current recommended antidiarrheal treatment involves high-dose loperamide (4 mg initially, then 2 mg every 2 hours). Treatment should continue for 12 hours after the last episode of loose stools. This regimen must not be modified. Loperamide at these doses must not 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 below 500 cells/mm³), broad-spectrum antibiotics should be administered prophylactically in addition to antidiarrheal therapy.

Hospitalization of patients is additionally recommended in the following cases:

diarrhea associated with fever;
severe diarrhea (requiring intravenous rehydration);
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").

Effects on the blood system.

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 irradiated in the pelvic/abdominal region compared to those not irradiated. 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 compared to patients with bilirubin levels below 1.0 mg/dL.

Complete blood counts should be monitored weekly during treatment with Irinotecan Amaksa. 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 immediately in a hospital setting with intravenous broad-spectrum antibiotics. Patients experiencing severe hematological complications should have their dose reduced in subsequent treatment cycles (see section "Dosage and administration"). Patients with severe diarrhea are at increased risk of infections and hematological toxicity. Such patients require complete blood count monitoring.

Patients with reduced UGT1A1 activity.

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

Although a specific reduction in initial dose has not been established, consideration should be given to reducing the initial dose of irinotecan in patients with poor UGT1A1 metabolism, especially those receiving doses > 180 mg/m² or frail patients. Appropriate clinical guidelines regarding dosing recommendations for such patients should be consulted. Subsequent doses may be increased based 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 observed toxicity during irinotecan therapy (see section "Pharmacokinetics").

Hepatic impairment.

Liver function tests should be performed at baseline and before each cycle.

Patients with bilirubin levels 1.5–3 times above the upper normal limit should have complete blood counts monitored weekly due to reduced irinotecan clearance (see section "Pharmacokinetics"), which increases the risk of hematotoxicity. Irinotecan Amaksa must not be administered to patients with bilirubin levels exceeding 3 times the upper normal limit (see section "Contraindications").

Nausea and vomiting.

Prophylactic antiemetic therapy is recommended before each administration of Irinotecan Amaksa. Nausea and vomiting are frequently reported during treatment. Patients experiencing vomiting associated with delayed diarrhea require immediate hospitalization for appropriate management.

Acute cholinergic syndrome.

In the absence of clinical contraindications (see section "Adverse reactions"), subcutaneous administration of 0.25 mg atropine sulfate is recommended if acute cholinergic syndrome develops (early diarrhea combined with various other signs and symptoms such as excessive 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. Higher irinotecan doses are expected to increase the frequency of these symptoms.

Patients with asthma should be treated with caution. Patients who experienced severe acute cholinergic syndrome should receive prophylactic atropine sulfate treatment before each subsequent administration of Irinotecan Amaksa.

Respiratory disorders.

Rare cases of interstitial lung disease, characterized by pulmonary infiltrates, may occur during treatment with this drug and may lead to fatal outcomes. Risk factors possibly associated with interstitial lung disease include use of lung-toxic drugs, radiation therapy, and colony-stimulating factors. Patients with these risk factors should be closely monitored for respiratory symptoms before and during 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 the higher frequency of reduced biological functions, particularly liver function, Irinotecan Amaksa dosage should be carefully adjusted in elderly patients (see section "Dosage and administration").

Chronic inflammatory bowel disease and/or bowel obstruction.

Irinotecan Amaksa should not be administered to patients with existing bowel obstruction (see section "Contraindications").

Patients with renal impairment.

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.

Cardiac disorders.

Myocardial ischemia has been reported after irinotecan administration, primarily in patients with pre-existing heart disease, other known risk factors for cardiac disease, or prior 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, hypertension, hyperlipidemia).

Vascular disorders.

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

Radiation therapy.

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

Lactation period.

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

Due to the potential for genotoxicity, women of reproductive potential should 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 lactation").

Other factors.

Since the drug contains D-sorbitol, a source of fructose, it should not be administered to patients with hereditary fructose intolerance (HFI). 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 patients with HFI; therefore, they should not be administered to such patients unless there is an acute clinical need or no alternative.

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

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

Irinotecan Amaksa vials with fill volumes of 2 ml and 5 ml contain less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

The Irinotecan Amaksa vial with a fill volume of 15 ml contains 36 mg/dose of sodium. Caution should be exercised when administering to patients on a sodium-controlled diet.

Use during pregnancy or lactation.

Contraception.

Due to the potential for genotoxicity, women of reproductive potential should use highly effective contraception during treatment and for 6 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. Considering animal study results and the mechanism of action of irinotecan, this drug should not be used during pregnancy, especially in the first trimester, unless absolutely necessary. Irinotecan should not be administered to women of childbearing potential unless pregnancy is excluded. Pregnancy should be avoided if either partner is receiving irinotecan.

Effects on reproductive function.

Information on the effects of irinotecan on human reproductive function is lacking. Adverse effects of irinotecan on reproductive function in offspring have been documented in animal studies. Before initiating treatment, patients should be counseled regarding the possibility of fertility preservation.

Lactation.

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

Ability to influence reaction speed when driving or operating machinery.

Patients should be warned about the possible occurrence of dizziness or visual disturbances within 24 hours after administration of Irinotecan Amaksa and advised not to drive or operate machinery if these symptoms occur.

Administration and Dosage.

The medicinal product is intended exclusively for adults. The infusion solution must be diluted and administered into a peripheral or central vein.

Preparation of the solution for intravenous administration.

As with other injectable medicinal products, the solution of Irinotecan Amaksa should be prepared under aseptic conditions. If visible precipitate is present in the vial or after reconstitution, the medicinal product should be discarded following standard procedures for disposal of cytotoxic agents.

Under aseptic conditions, the required volume of Irinotecan Amaksa solution should be withdrawn using a calibrated syringe from the vial and transferred into a 250 ml bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. The solution should be mixed thoroughly by manually inverting the container.

Recommended doses.

For monotherapy, Irinotecan Amaksa is usually administered once every 3 weeks. However, for patients who may require closer monitoring or who are at increased risk of developing severe neutropenia, a weekly administration schedule may be considered (see section "Pharmacological properties").

Monotherapy (for previously treated patients).

The recommended dose of Irinotecan Amaksa is 350 mg/m² body surface area administered as an intravenous infusion over 30–90 minutes every 3 weeks (see section "Special instructions").

Combination therapy (for previously untreated patients).

The efficacy and safety of irinotecan in combination with 5-FU and LV have been evaluated according to the dosing schedule described below (see section "Pharmacodynamics"). The recommended dose of irinotecan is 180 mg/m² once every 2 weeks as a 30–90 minute intravenous infusion, followed by administration of LV and 5-FU. Information on the dosage and concomitant administration of cetuximab can be found in the summary of product characteristics of this medicinal product. The same dose of irinotecan as used in previous treatment cycles containing irinotecan should generally be administered. Irinotecan should be administered no sooner than 1 hour after completion of cetuximab infusion. For dosage and administration information on bevacizumab, refer to the summary of product characteristics of this medicinal product. Information on the dosage and use of irinotecan in combination with capecitabine is provided in section "Pharmacological properties" and in the relevant sections of the summary of product characteristics of capecitabine.

Dose adjustment.

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

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

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

Hematotoxicity (grade IV neutropenia, febrile neutropenia (grade III–IV neutropenia accompanied by grade II–IV fever), thrombocytopenia, and leukopenia (grade IV));
Non-hematological toxicity (grade III–IV).

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

Information on dose modification of bevacizumab when used in combination with irinotecan/5-FU/LV can be found in the summary of product characteristics of bevacizumab.

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 adjustments in combination therapy, refer to the summary of product characteristics of capecitabine.

Duration of treatment.

Treatment with Irinotecan Amaksa should continue until objective disease progression or until signs of unacceptable toxicity develop.

Patients with hepatic impairment.

Monotherapy.

For patients with WHO performance status ≤ 2, the initial dose of Irinotecan Amaksa should be determined based on serum bilirubin levels (when bilirubin levels are elevated up to 3 times the upper limit of normal). In these patients with hyperbilirubinemia and prothrombin time exceeding 50%, irinotecan clearance is reduced (see section "Pharmacokinetics"), resulting in an increased risk of hematotoxicity. Therefore, such patients should have complete blood counts monitored weekly.
For patients with bilirubin levels up to 1.5 times the upper limit of normal, the recommended dose is 350 mg/m² body surface area.
For patients with bilirubin levels between 1.5 and 3 times the upper limit of normal, the recommended dose is 200 mg/m² body surface area.
Irinotecan should not be administered to patients with bilirubin levels exceeding 3 times the upper limit of normal (see sections "Contraindications" and "Special instructions").

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

Patients with renal impairment.

The use of Irinotecan Amaksa in patients with renal impairment is not recommended, as studies in this patient population have not been conducted (see sections "Pharmacokinetics" and "Special instructions").

Elderly patients.

No specific pharmacokinetic studies have been conducted in elderly patients. However, dose selection should be cautious in this population due to the higher likelihood of decreased physiological functions. These patients require more intensive monitoring (see section "Special instructions").

As with other antineoplastic agents, Irinotecan Amaksa should be prepared and administered with caution. The use of protective goggles, mask, and gloves is mandatory.

In case of contact of concentrate or infusion solution with the skin, the area should be immediately flushed and thoroughly washed with soap and water. In case of contact with mucous membranes, the area should be immediately rinsed with water.

Disposal.

All materials used for reconstitution and administration of the medicinal product should be disposed of according to the standard procedures of the healthcare facility applicable to cytotoxic agents.

Children.

The medicinal product is intended for use in adults only.

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. Intensive supportive treatment should be administered to prevent dehydration due to diarrhea and to treat possible infectious complications.

Adverse reactions.

Clinical trials.

Data on adverse reactions were carefully collected during studies of metastatic colorectal cancer; the frequencies of their occurrence 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 administration of the drug) 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 intensity was very commonly observed.

Its main symptoms were early diarrhea and various other symptoms such as abdominal pain, increased sweating, miosis, and increased salivation, which occurred during or within the first 24 hours after infusion of irinotecan. These symptoms resolved after administration of atropine (see section "Dosage and administration").

Monotherapy

The adverse reactions listed below, considered possibly or probably related to the use of Irinotecan Amaksa, 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. Adverse reaction frequencies are 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).

Adverse reactions reported during monotherapy with irinotecan (at a dose of 350 mg/m² every 3 weeks)
MedDRA System Organ Class	Frequency	Adverse reaction
Infections and infestations	Common	Infections
Blood and lymphatic system disorders	Very common	Neutropenia, anemia
Blood and lymphatic system disorders	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
Gastrointestinal disorders	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, increased transaminases (ALT and AST), increased bilirubin, increased alkaline phosphatase in blood

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 who received 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 usually took up to 22 days.

Febrile neutropenia of severe grade was observed in 6.2% of patients and in 1.7% of all treatment cycles.

Episodes of 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 took up to 22 days.

Acute cholinergic syndrome.

Transient severe acute cholinergic syndrome 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 parameters

Mild 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. Mild or moderate transient elevations in serum creatinine 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 administration have been reported (e.g., acneiform rash in 88% of cases). Information on adverse reactions with combined use of irinotecan and cetuximab is also provided in the respective medicinal product’s instructions for medical use.

The following adverse reactions have been reported in patients receiving capecitabine in combination with irinotecan, in addition to those observed with 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.

Complete information on adverse reactions of capecitabine is provided in the instructions for medical use of this medicinal product.

The following grade III and IV adverse reactions have been reported in patients receiving capecitabine in combination with irinotecan and bevacizumab, in addition to those observed with 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.

Complete information on adverse reactions of capecitabine and bevacizumab is provided in the instructions for medical use of 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/FA. In addition, 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/FA. Additional information on adverse reactions with combination therapy including bevacizumab is provided in the instructions for medical use of 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 from 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, skin and subcutaneous tissue.

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

Adverse reactions reported during combination therapy with irinotecan (regimen 180 mg/m2 every 2 weeks)
MedDRA organ system class	Frequency	Adverse reaction
Infections and infestations	Common	Infections
Blood and lymphatic system disorders	Very common	Thrombocytopenia, neutropenia, anemia
Blood and lymphatic system disorders	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
Gastrointestinal disorders	Common	Abdominal pain, constipation
Skin and subcutaneous tissue disorders	Very common	Alopecia (reversible)
General disorders and administration site reactions	Very common	Mucositis, asthenia
General disorders and administration site reactions	Common	Fever
Investigations	Very common	Elevated transaminases (ALT and AST), increased bilirubin levels, increased alkaline phosphatase in blood

Description of individual adverse reactions (with combination therapy).

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

Severe nausea and vomiting were observed 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, neutrophil count was below 1000 cells/mm³ in 67.3% of patients, including 2.7% with neutrophil count <500 cells/mm³. Complete recovery usually took up to 7–8 days.

Severe febrile neutropenia was observed in 3.4% of patients and in 0.9% of all treatment cycles.

Infectious episodes occurred in approximately 2% of patients (0.5% of all treatment cycles) and were associated with severe neutropenia in 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 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 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 administration 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 Grade 4 adverse reactions of this type were observed.

Very rare reports of increased amylase and/or lipase levels have been received.

Rare cases of hypokalemia and hyponatremia have been reported, which were predominantly associated with diarrhea and vomiting.

Other adverse reactions reported in clinical trials of weekly irinotecan administration.

In clinical trials of irinotecan administration, the following adverse reactions related to drug use have been reported: pain, sepsis, rectal disorders, gastrointestinal candidiasis, hypomagnesemia, rash, skin reactions, gait disturbance, confusion, headache, syncope, flushing, 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 accident, deep vein thrombophlebitis, lower limb vessel embolism, pulmonary embolism, thrombophlebitis, thrombosis, and sudden death) (see section "Special precautions").

Post-marketing surveillance.

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

MedDRA System Organ Class	Adverse Reaction
Infections and infestations	Pseudomembranous colitis, one case of which was confirmed by bacteriological testing (Clostridium difficile); sepsis; fungal infection; viral infection*
Blood and lymphatic system disorders	Peripheral thrombocytopenia with formation of antiplatelet antibodies
Gastrointestinal and metabolism disorders	Dehydration (due to diarrhea and vomiting); hypovolemia
Immune system disorders	Hypersensitivity reactions; anaphylactic reactions
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***
Respiratory, thoracic and mediastinal disorders	Interstitial lung disease, presenting as pulmonary infiltrates, observed infrequently during irinotecan treatment (cases of early effects such as dyspnea have been reported; see section "Special precautions"); dyspnea (see section "Special precautions"); hiccups
Gastrointestinal tract disorders	Intestinal obstruction; ileus: cases of ileus without preceding colitis have also been reported; megacolon; gastrointestinal hemorrhage; colitis, in some cases complicated by ulceration, bleeding, ileus, or infection; typhlitis; ischemic colitis; ulcerative colitis; gastrointestinal bleeding; symptomatic or asymptomatic elevation of pancreatic enzymes; intestinal perforation
Skin and subcutaneous tissue disorders	Skin reactions
General disorders and administration site conditions	Infusion site reactions
Investigations	Elevated blood amylase levels; elevated lipase levels; hypokalemia; hyponatremia, mostly associated with diarrhea and vomiting; very rare reports of increased serum transaminase levels (AST and ALT) in the absence of progressive liver metastases
Musculoskeletal and connective tissue disorders	Muscle contractions or spasms
Renal and urinary disorders	Renal dysfunction and acute renal failure usually observed in patients with infection and/or hypovolemia resulting from severe gastrointestinal toxicity*; renal failure*
Vascular disorders	Hypotension***
Hepatobiliary disorders	Steatohepatitis; hepatic steatosis

*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.

Reporting of suspected adverse reactions

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

Shelf life.

Unopened vial: 4 years.

After dilution: Chemical and physical in-use stability has been demonstrated for solutions for infusion (0.9% w/v sodium chloride solution and 5% w/v glucose solution) at 15–25 °C for 12 hours or at 2–8 °C for 48 hours, provided protected from light.

From a microbiological point of view, the prepared solution should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user. If the solution was not prepared under controlled and validated aseptic conditions, it should be stored at 2–8 °C for no longer than 24 hours.

Storage conditions.

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

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Special precautions for handling".

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

AqVida GmbH / AqVida GmbH.

Manufacturer's address and place of business.

Kaiser-Wilhelm-Str. 89, 20355 Hamburg, Germany / Kaiser-Wilhelm-Str. 89, 20355 Hamburg, Germany.

Marketing Authorization Holder.

Amaxa Ltd / Amaxa Ltd.

Address of the Marketing Authorization Holder.

31 John Islip Street, London SW1P 4FE, United Kingdom / 31 John Islip Street, London SW1P 4FE, United Kingdom.