Instructions for Irinotecan-Amax concentrate for infusions 20 mg/ml 2 ml (40 mg) vial No. 1
Composition
active ingredient: 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.
Dosage form
Concentrate for solution for infusion.
Main physicochemical properties: clear yellow solution.
Pharmacotherapeutic group
Antineoplastic agents. Cytostatic topoisomerase I inhibitors. ATX code L01C E02.
Pharmacological properties
Pharmacodynamics.
Irinotecan Amaxa is a semisynthetic substance derived from camptothecin. It is an antitumor drug that acts as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase in most tissues, the drug is metabolized to the compound SN-38, which, compared with irinotecan, is more active against purified topoisomerase I and more cytotoxic against a number of human and mouse 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 leads to cytotoxic action. It was found that this cytotoxic effect is time-dependent and specific for the S-phase of the cell cycle.
In addition to antitumor activity, the most significant pharmacological action of irinotecan is inhibition of acetylcholinesterase activity.
Patients with reduced UGT1A1 activity.
Uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1) is involved in the metabolic inactivation of SN-38, the active metabolite of irinotecan, to form the inactive SN-38-glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in a wide range of metabolic activity within the population. One particular variant of the UGT1A1 gene contains a polymorphic region in the promoter region, termed UGT1A1*28. This variant, as well as other inherited disorders of UGT1A1 expression (such as Gilbert syndrome or Crigler-Najjar syndrome), are associated with reduced activity of this enzyme. The results of a meta-analysis suggest that patients with Crigler-Najjar syndrome (types 1 and 2) or homozygotes for the UGT1A1*28 allele (Gilbert syndrome) are at increased risk of hematological toxicity (grades III and IV) after administration of medium or high doses of irinotecan (>150 mg/m2). The relationship between UGT1A1 genotype and the occurrence of diarrhea due to irinotecan has not been established.
Patients known to be homozygous for the UGT1A1*28 allele should receive the usual starting dose of irinotecan. However, these patients should be monitored for hematological toxicity. A reduction in the starting dose of irinotecan should be considered for patients who have experienced hematological toxicity during previous courses of treatment. The exact amount of the initial dose reduction for this group of patients has not been established. Any subsequent dose adjustments should be based on patient tolerability (see sections 4.4 and 4.2). There are currently insufficient clinical data to conclude on the usefulness of genotyping patients for the UGT1A1 allele.
Pharmacokinetics.
Following administration of irinotecan at a dose of 100-750 mg/m2 by 30-minute intravenous infusion every 3 weeks, irinotecan exhibits a biphasic or triphasic plasma elimination. 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 elimination half-life during the first phase of the three-phase model was 12 min, during the second phase 2.5 h, and during the third phase 14.2 h. The plasma elimination of SN-38 was biphasic with a mean terminal half-life of 13.8 h.
In vitro plasma protein binding is approximately 65% for irinotecan and 95% for the metabolite SN-38.
More than 50% of an intravenously administered irinotecan dose is excreted unchanged, 33% is excreted in the feces, mainly via bile, and 22% in the urine.
Irinotecan clearance is reduced by almost 40% in patients with bilirubinemia (total serum bilirubin concentration 1.5-3 times the upper limit of normal). In these patients, a dose of 200 mg/m2 of irinotecan results in plasma exposure comparable to that of 350 mg/m2 in cancer patients with normal liver function.
The intensity of the most pronounced toxic effects of irinotecan (e.g. leukoneutropenia and diarrhoea) is related to the exposure (area under the concentration-time curve (AUC)) to unchanged irinotecan and its metabolite SN-38. A significant relationship was observed between hematological toxicity (decrease in leukocyte and neutrophil counts to a minimum) or the intensity of diarrhoea and the AUC of irinotecan and its metabolite SN-38 in monotherapy.
Indication
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 advanced disease;
Irinotecan Amax in combination with cetuximab is indicated for the treatment of patients with metastatic colorectal cancer with wild-type KRAS gene accompanied by increased expression of epidermal growth factor receptor (EGFR) who have not previously received chemotherapy or after ineffective cytotoxic therapy that included irinotecan.
In combination with 5-FU, FC and bevacizumab, Irinotecan Amax is used as first-line therapy for patients with metastatic carcinomas of the colon or rectum.
In combination with capecitabine (with or without the addition of bevacizumab), Irinotecan Amax is used as first-line therapy for patients with metastatic colorectal cancer.
Contraindication
Hypersensitivity to the active substance or to any of the excipients.
Chronic inflammatory bowel disease and/or intestinal obstruction (see section "Special warnings and precautions for use").
Breastfeeding (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
Bilirubin level more than 3 times the upper limit of normal (see section "Special instructions").
Severe bone marrow failure.
Health status according to the WHO index > 2.
Concomitant treatment with St. John's wort (see section "Interaction with other medicinal products and other types of interactions").
Live attenuated vaccines.
Full information on contraindications for cetuximab, bevacizumab or capecitabine is provided in the relevant Summary of Product Characteristics for these medicinal products.
Interaction with other medicinal products and other types of interactions
Medicinal products whose concomitant administration with Irinotecan Amaxa is contraindicated (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% decrease in plasma concentrations of SN-38, the active metabolite of irinotecan, was observed. Therefore, St. John's wort should not be used with irinotecan.
Live attenuated vaccines (e.g. yellow fever vaccine) – risk of systemic diseases with possible fatal outcome (e.g. infections). This risk is increased if patients are already immunosuppressed by underlying disease. Concomitant use of live attenuated vaccines is contraindicated during treatment with irinotecan and for six months after the end of chemotherapy. Inactivated vaccines should be used if available (poliomyelitis), but the response to such vaccines may be reduced.
Medicinal products whose concomitant administration with Irinotecan Amaxa is not recommended (see section "Special warnings and precautions for use"):
The concomitant use of irinotecan and strong inducers/inhibitors of cytochrome P450 3A4 (CYP3A4) should be avoided as this may lead to alterations in the metabolism of irinotecan (see section 4.4).
Strong CYP3A4 and/or UGT1A1 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin or apalutamide) – Several studies have shown that concomitant use of anticonvulsants that are CYP3A4 inducers (carbamazepine, phenobarbital or phenytoin) leads to a decrease in the efficacy of irinotecan, SN-38 and SN-38-glucuronide, which in turn leads to a decrease in the pharmacodynamic effect. The effect of such anticonvulsants was to reduce the AUC of SN-38 and SN-38-glucuronide by 50% or more. In addition to induction of cytochrome P450 3A4, the decrease in exposure to irinotecan and its metabolites may also be due to increased glucuronidation and increased biliary excretion.
Phenytoin – risk of exacerbation of seizures due to reduced absorption of phenytoin in the digestive tract under the influence of a cytotoxic drug.
Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin) – a study found that co-administration of ketoconazole resulted in an 87% decrease in the AUC of the metabolite APC and a 109% decrease in the 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 toxicity of irinotecan due to decreased metabolism when used concomitantly with crizotinib or idelalisib.
Medicines that should be used with caution with Irinotecan Amaxa:
Vitamin K antagonists – increased risk of bleeding and thrombosis in patients with neoplastic diseases. If there are indications for the use of vitamin K antagonists, it is necessary to monitor the International Normalized Ratio (INR) more frequently than usual.
Neuromuscular blockers - an interaction between irinotecan and neuromuscular blockers cannot be excluded. Since irinotecan has anticholinesterase activity, drugs that also have anticholinesterase activity may prolong the duration of neuromuscular blockade of suxamethonium and antagonize the neuromuscular blockade of non-depolarizing drugs.
Other combinations.
5-FU/PC – simultaneous use of 5-FU/PC as part of combination therapy does not change the pharmacokinetics of irinotecan.
Bevacizumab - results of a specific drug-drug interaction study did not demonstrate a significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude any increase in toxicity due to their pharmacological properties.
Cetuximab – there is no information on the effect of cetuximab on the safety profile of irinotecan or on a similar effect of irinotecan on cetuximab.
Antineoplastic agents (including flucytosine as a prodrug of 5-fluorouracil) – side effects of irinotecan, such as myelosuppression, may be potentiated by other antineoplastic agents with a similar side effect profile.
Application features
Irinotecan Amax should only be used in a unit specialized in cytotoxic chemotherapy. It should only be used under the supervision of a qualified physician specialized in the use of anticancer chemotherapy.
Given the nature and frequency of adverse reactions, in the following cases Irinotecan Amax should be used only after assessing the ratio of the expected benefits and possible risks of treatment:
for the treatment of patients with risk factors, including patients with a WHO general condition score of 2;
In rare cases where patients are considered unlikely to comply with recommendations for the management of adverse reactions (need for immediate and prolonged treatment of diarrhea combined with large amounts of fluid intake at the onset of delayed diarrhea), close observation in a hospital setting is recommended for such patients.
When used as monotherapy, irinotecan is usually administered on a dosing schedule of every 3 weeks. However, a once-weekly dosing schedule may be used in patients who may require closer monitoring or who are at particular risk of neutropenia.
Delayed diarrhea.
Patients should be informed of the risk of delayed diarrhoea occurring more than 24 hours after administration of Irinotecan and at any time before the next course of treatment. With monotherapy, the median time to the first episode of loose stools was 5 days after administration of Irinotecan. Patients should promptly report any diarrhoea to their doctor and initiate appropriate treatment immediately.
Patients at increased risk for diarrhea include patients who have previously received radiotherapy to the abdomen or pelvis, patients with hyperleukocytosis at baseline, patients with a WHO health status index ≥ 2, and women. Diarrhea can be life-threatening if not treated appropriately, especially if accompanied by neutropenia.
After the first episode of loose stools, the patient should immediately start drinking plenty of fluids containing electrolytes and receive appropriate antidiarrheal treatment. Antidiarrheal treatment should be given in the department where the patient was administered Irinotecan Amax. After discharge from the hospital, the patient should receive the prescribed medications to be able to start treating diarrhea as soon as it occurs. In addition, the patient should report the occurrence of diarrhea to his doctor or to the doctor of the department where the patient was administered Irinotecan Amax.
The currently recommended antidiarrheal treatment is high-dose loperamide (4 mg for the first dose, then 2 mg every 2 hours). Treatment should be started within 12 hours of the last loose stool. The treatment regimen is not subject to modification. Loperamide in these doses should never be used for more than 48 hours due to the risk of developing paralytic ileus; however, treatment should not be continued for less than 12 hours.
In cases where diarrhea is accompanied by severe neutropenia (neutrophil count below 500 cells/mm3), broad-spectrum antibiotics should be used prophylactically in addition to antidiarrheal treatment.
In addition to the use of antibiotics to treat diarrhea, it is recommended to hospitalize patients in the following cases:
diarrhea accompanied by fever;
severe diarrhea (requiring intravenous rehydration);
diarrhea that persists for 48 hours after starting treatment with high doses of loperamide.
Loperamide should not be used prophylactically, even in patients who have developed delayed diarrhea during previous courses of treatment.
Patients with severe diarrhea are recommended to reduce the dose in subsequent treatment cycles (see section "Method of administration and dosage").
In clinical trials, the incidence of NCI CTC Grade III-IV neutropenia was significantly higher in patients who had received prior pelvic/abdominal radiation compared to patients who had not received prior pelvic/abdominal radiation. Patients with baseline total serum bilirubin of 1.0 mg/dL or greater were also significantly more likely to experience Grade III-IV neutropenia compared to patients with bilirubin levels less than 1.0 mg/dL.
Weekly monitoring of clinical blood counts is recommended during treatment with Irinotecan Amax. Patients should be advised of the risk of neutropenia and the significance of fever. Treatment of febrile neutropenia (temperature >38°C and neutrophil count ≤1000 cells/mm3) should be initiated immediately in a hospital setting with broad-spectrum intravenous antibiotics. Patients with severe haematological complications are advised to reduce the dose in subsequent cycles of treatment (see section 4.2). Patients with severe diarrhoea are at increased risk of developing infections and haematological toxicity. These patients should be monitored for clinical blood counts.
Patients with reduced UGT1A1 activity.
Patients with poor UGT1A1 metabolisers, such as patients with Gilbert's syndrome (e.g. homozygous for UGT1A1*28 or *6 variants), are at increased risk of developing severe neutropenia and diarrhoea following treatment with irinotecan. This risk increases with increasing irinotecan dosage.
Although no specific starting dose reduction has been established, a reduction in the starting dose of irinotecan should be considered for patients who are poor metabolisers of UGT1A1, particularly those receiving doses > 180 mg/m2 or for debilitated patients. The relevant clinical guidelines should be consulted for dosing recommendations in these patients. Subsequent doses may be increased based on individual tolerability.
UGT1A1 genotyping can be used to identify patients at increased risk of severe neutropenia and diarrhoea, however, the clinical benefit of genotyping before treatment is uncertain as UGT1A1 polymorphism does not account for all the toxicity observed with irinotecan therapy (see section 5.2).
Liver disorders.
Liver function tests should be performed at baseline and before the start of each cycle.
Patients with bilirubin levels above 1.5-3 times the upper limit of normal should have their blood counts monitored weekly due to decreased clearance of irinotecan (see section 5.2), which increases the risk of haematological toxicity. Irinotecan Amax should not be administered to patients with bilirubin levels above more than 3 times the upper limit of normal (see section 4.3).
Nausea and vomiting.
It is recommended to administer antiemetics prophylactically before each administration of Irinotecan Amax. Nausea and vomiting have been commonly reported with the use of the drug. Patients with vomiting accompanied by delayed diarrhea require hospitalization as soon as possible for appropriate treatment.
Acute cholinergic syndrome.
In the absence of clinical contraindications (see section "Adverse reactions"), in the event of acute cholinergic syndrome (early diarrhea combined with various other signs and symptoms such as increased sweating, abdominal cramps, miosis and increased salivation), 0.25 mg of atropine sulfate should be administered subcutaneously. The occurrence of these symptoms, which may occur during or immediately after the infusion of irinotecan, is attributed to the anticholinesterase activity of the parent compound irinotecan. It is expected that their incidence will increase with higher doses of irinotecan.
Patients with asthma should be treated with caution. In patients with severe acute cholinergic syndrome, prophylactic treatment with atropine sulfate is recommended before each subsequent administration of Irinotecan Amax.
Respiratory system disorders.
During treatment with this drug, rare cases of interstitial lung disease, manifested by the formation of infiltrates in the lungs, may occur, but the disease can be fatal. Risk factors that may be associated with the development of interstitial lung disease include the use of drugs that are toxic to the lungs, radiation therapy and colony-stimulating factors. Patients with existing risk factors should be carefully monitored for respiratory symptoms before and during treatment.
Extravasation.
Although irinotecan is not a drug that causes tissue necrosis, it should be administered with caution and the infusion site should be monitored for signs of inflammation. In the event of extravascular exposure, it is recommended to flush the infusion site and apply ice.
Elderly patients.
Due to the greater frequency of decline in biological functions, in particular liver function, the dose of Irinotecan Amax should be selected with caution in elderly patients (see section "Method of administration and dosage").
Patients should not use Irinotecan Amax while intestinal obstruction is present (see section “Contraindications”).
Patients with renal impairment.
Elevations in serum creatinine or blood urea nitrogen have been observed. Acute renal failure has been reported. These events have usually been associated with complications of infections or dehydration due to nausea, vomiting or diarrhoea. In addition, isolated cases of renal dysfunction due to tumour lysis syndrome have been reported.
Heart disorders.
Cases of myocardial ischemia have been observed following the use of irinotecan, predominantly in patients with pre-existing cardiac disease, other known risk factors for cardiac disease and in patients who have previously received cytotoxic chemotherapy (see section 4.8). Accordingly, patients with known risk factors should be closely monitored. Measures should be taken to minimize all modifiable risk factors (e.g. smoking, hypertension and hyperlipidemia).
Vascular disorders.
In patients with multiple risk factors in addition to the underlying malignancy, the use of irinotecan has been associated in rare cases with the occurrence of thromboembolic complications (pulmonary embolism, venous thrombosis and arterial thromboembolism).
Radiation therapy.
Patients who have previously received pelvic or abdominal radiation are at increased risk of myelosuppression with irinotecan. Physicians should use this medicine with caution in patients who have previously received extensive radiotherapy (e.g. irradiation of > 25% of the bone marrow within 6 weeks prior to starting irinotecan). This group of patients may require dose adjustment (see section 4.2).
Breastfeeding period.
Due to the possibility of adverse reactions in infants, breastfeeding should be discontinued during treatment with the drug (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Due to the potential for genotoxicity, women of reproductive age 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 lactation”).
Other factors.
As the product contains D-sorbitol, which is a source of fructose, it should not be used in patients with hereditary fructose intolerance (HFI). In infants and young children under 2 years of age, HFI may not yet have been diagnosed. Intravenous fructose-containing medicinal products may have life-threatening effects in people with HFI and should therefore not be given to such patients unless clinically necessary or there is no alternative.
Before using this medicine, a history should be taken from each patient regarding symptoms of SNF.
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, apalutomide) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see section 4.5).
Irinotecan Amax vials with a filling volume of 2 ml and 5 ml contain less than 1 mmol (23 mg) sodium/dose, i.e. essentially sodium-free.
Irinotecan Amax 15 ml vial contains 36 mg sodium/dose. Caution should be exercised when used in patients on a controlled sodium diet.
Use during pregnancy or breastfeeding
Contraception.
Due to the potential for genotoxicity, women of reproductive age are advised to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan (see section 4.4).
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 4.4).
Pregnancy period.
There are limited data on the use of irinotecan in pregnant women. Animal studies have shown that irinotecan is embryotoxic and teratogenic. Based on the results of animal studies and the mechanism of action of irinotecan, this drug should not be used during pregnancy, especially during the first trimester, unless clearly necessary. Irinotecan should not be used in women of childbearing potential unless pregnancy has been ruled out. Pregnancy should be avoided if either partner is receiving irinotecan.
There is no information on the effects of irinotecan on human reproductive function. In animal studies, adverse effects of irinotecan on reproductive function of offspring have been documented. Before initiating treatment, consideration should be given to counseling patients regarding germline preservation.
Breastfeeding period.
Limited data are available, but suggest that irinotecan and its metabolites are excreted in human milk. Therefore, due to the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with irinotecan (see sections 4.3 and 4.4).
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients should be warned about the possibility of dizziness or visual disturbances within 24 hours after using Irinotecan Amax and advised not to drive or operate machinery if the above symptoms occur.
Method of administration and doses
The drug is intended for adults only. The infusion solution must be diluted and administered into a peripheral or central vein.
Preparation of solution for intravenous administration.
As with other injectable drugs, Irinotecan Amax should be prepared using aseptic techniques. If a precipitate is visible in the vial or after reconstitution, the drug should be disposed of according to standard procedures for the disposal of cytotoxic drugs.
Using aseptic technique, withdraw the required amount of Irinotecan Amax solution from the vial with a calibrated syringe and inject the dose into a 250 ml bag or bottle containing 0.9% sodium chloride solution or 5% glucose solution. Mix the solution thoroughly by manually rotating the container.
Recommended doses.
As monotherapy, Irinotecan Amax is usually administered once every 3 weeks. However, a weekly dosing regimen may be considered for patients who may require closer monitoring or who are at increased risk of severe neutropenia (see section 5.1).
Monotherapy (for patients who have previously received treatment).
The recommended dose of Irinotecan Amax is 350 mg/m2 body surface area administered by intravenous infusion over 30–90 minutes every 3 weeks (see section 4.4).
Combination therapy (for patients who have not previously received treatment).
The efficacy and safety of irinotecan in combination with 5-FU and PC have been evaluated using the following dosing regimen (see section 5.1). The recommended dose of irinotecan is 180 mg/m2 every 2 weeks as an intravenous infusion over 30–90 minutes, followed by PC and 5-FU. For information on the dosage and route of administration of cetuximab, refer to the Summary of Product Characteristics for this medicinal product. The usual dose of irinotecan is the same as that used in previous irinotecan-containing regimens. Irinotecan should be administered no earlier than 1 hour after the end of the cetuximab infusion. For information on the dosage and route of administration of bevacizumab, refer to the Summary of Product Characteristics for this medicinal product. For information on the dosage and route of administration of irinotecan in combination with capecitabine, see in the Pharmacological Properties section and in the relevant sections of the capecitabine summary of product characteristics.
Dose adjustment.
Irinotecan Amax should be administered after adequate resolution of all adverse reactions to NCI-CTC grade 0 or 1 and after complete resolution of treatment-related diarrhea.
At the start of the next infusion course, the dose of Irinotecan and 5-FU, if used, should be reduced based on the severity of the adverse reactions observed during the previous infusion. The start of treatment should be delayed for 1-2 weeks to allow for resolution of treatment-related adverse reactions.
If the following adverse reactions develop, the dose of Irinotecan Amax and/or 5-FU, if used, should be reduced by 15–20%:
hematotoxicity (grade IV neutropenia, febrile neutropenia (grade III–IV neutropenia accompanied by grade II–IV fever), thrombocytopenia and leukopenia (grade IV));
non-hematological toxicity (grades III–IV).
Dose modification recommendations for cetuximab when used in combination with irinotecan should be followed as described in the cetuximab Summary of Product Characteristics.
Information on bevacizumab dose modification in combination treatment with bevacizumab with irinotecan/5-FU/FC can be found in the bevacizumab summary of product characteristics.
In patients aged 65 years and older, when using irinotecan and capecitabine, it is recommended to reduce the capecitabine dose to 800 mg/m2 body surface area twice daily. For information on dose adjustments in the case of combination therapy, please refer to the capecitabine summary of product characteristics.
Treatment with Irinotecan Amaxa should be continued until objective disease progression or until signs of unacceptable toxicity develop.
Patients with liver dysfunction.
Monotherapy.
In patients with a WHO performance status score ≤ 2, the initial dose of Irinotecan Amax should be determined by the level of bilirubin in the blood (with an increase in bilirubin levels above the upper limit of normal by no more than 3 times). In such patients with hyperbilirubinemia and a prothrombin time greater than 50%, the clearance of irinotecan is reduced (see section "Pharmacokinetics"), as a result of which the risk of hematotoxicity increases. Therefore, this category of patients should be monitored weekly for clinical blood tests.
For patients with bilirubin levels no more than 1.5 times the upper limit of normal, the recommended dose of the drug is 350 mg/m2 of body surface area.
For patients with bilirubin levels above 1.5–3 times the upper limit of normal, the recommended dose is 200 mg/m2 of body surface area.
Patients with bilirubin levels greater than 3 times the upper limit of normal should not receive irinotecan (see sections 4.3 and 4.4).
There is no information on the use of irinotecan in combination with other drugs in patients with liver damage.
Patients with renal impairment.
The use of Irinotecan Amax in patients with impaired renal function is not recommended, as studies on the use of the drug in this category of patients have not been conducted (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).
Elderly patients.
No specific pharmacokinetic studies have been conducted in elderly patients. However, the dose should be carefully selected for this group of patients, as they are more likely to have decreased biological functions. Patients in this group require more intensive monitoring (see section "Special warnings and precautions for use").
As with other antineoplastic agents, Irinotecan Amax should be prepared and administered with caution. The use of safety glasses, a mask and gloves is mandatory.
If the concentrate or infusion solution comes into contact with the skin, the solution should be washed off immediately and the area of contact should be thoroughly washed with soap and water, and if it comes into contact with mucous membranes, it should be washed off immediately with water.
Utilization.
All materials used for reconstitution and administration of the drug should be disposed of in accordance with standard hospital procedures for cytotoxic drugs.
Children.
The drug is intended for use by adults only.
Overdose
Overdose, which may be fatal, has been reported at doses approximately twice the recommended therapeutic dose. The most significant adverse reactions were severe neutropenia and severe diarrhoea. There is no known antidote to irinotecan. Maximum supportive care should be provided to prevent dehydration due to diarrhoea and to treat possible infectious complications.
Side effects
Clinical studies.
Adverse reaction data have been carefully collected in studies of metastatic colorectal cancer and the frequencies are given below. Similar adverse reactions are expected to occur when the drug is used for indications other than colorectal cancer.
The most common (≥1/10) dose-limiting adverse reactions of irinotecan are delayed diarrhea (occurring more than 24 hours after drug administration) and blood disorders, including
