Indications for use
IRITERO is indicated for the treatment of patients with advanced colorectal cancer:
as monotherapy in patients who have failed a regimen containing 5 fluorouracil
in combination with 5 fluorouracil and folinic acid in patients who have not previously received chemotherapy for the treatment of advanced disease
in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, wild-type KRAS metastatic colorectal cancer who have not previously received treatment or who have failed cytotoxic therapy containing irinotecan
in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated as first-line therapy in the treatment of patients with metastatic colorectal carcinoma
in combination with capecitabine and bevacizumab or in the absence of the latter is indicated as first-line therapy for the treatment of patients with metastatic carcinoma of the colon or rectum.
List of information required before use
Contraindications
chronic inflammatory bowel disease and/or intestinal obstruction
hypersensitivity to irinotecan hydrochloride trihydrate or to any of the excipients of the drug
lactation period
bilirubin concentration exceeding 3 times the upper limit of normal
severe bone marrow failure
general condition assessed by the WHO scale> 2
concomitant use with St. John’s wort
use of live or live attenuated vaccines during treatment with irinotecan
children and adolescents under 18 years of age.

Necessary precautions for use
The use of IRITERO should be limited to departments specializing in the use of cytotoxic chemotherapy and should be carried out only under the supervision of a physician experienced in antitumor chemotherapy.
Interactions with other medicinal products
Contraindicated concomitant use
Yellow fever vaccine: risk of generalized, potentially fatal, vaccine reaction.
St. John’s wort: decreased plasma concentrations of the active metabolite of irinotecan SN-38. In a small pharmacokinetic study (n = 5), concomitant use of irinotecan 350 mg/m² with St. John’s wort (Hypericum perforatum) 900 mg resulted in a 42% decrease in plasma concentrations of the active metabolite of irinotecan SN-38. Therefore, St. John’s wort should not be used concomitantly with irinotecan.
Live attenuated vaccines: risk of generalized, potentially fatal, vaccine reaction. Concomitant use is contraindicated during treatment with irinotecan and for 6 months after discontinuation of chemotherapy. Killed or inactivated vaccines may be used, however, the response to such vaccines may be reduced.
Concomitant use is not recommended
Concomitant administration of irinotecan with strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided.
Drugs that induce CYP3A4 and/or UDP-GT1A1 (e.g., rifampin, carbamazepine, phenobarbital, or phenytoin): risk of decreased activity of irinotecan, SN-38, and SN-38-glucuronide and decreased pharmacodynamic effects. Several studies have shown that concomitant administration of anticonvulsants that induce CYP3A4 results in decreased activity of irinotecan, SN-38, and SN-38-glucuronide and decreased pharmacodynamic effects. The action of such anticonvulsants is manifested by a decrease in the AUC for SN-38 and SN-38-glucuronide by 50% or more. In addition to the induction of CYP3A4 enzymes, increased glucuronidation and bile secretion contribute to a decrease in the activity of irinotecan and its metabolites.
With phenytoin: risk of exacerbation of seizures due to decreased absorption of phenytoin in the gastrointestinal tract caused by cytotoxic substances.
Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycin, erythromycin, telithromycin): a study showed that co-administration of ketoconazole, compared to irinotecan alone, resulted in an 87% decrease in the AUC of the major oxidative metabolite of APC and a 109% increase in the AUC of SN-38.
UGT1A1 inhibitors (e.g. atazanavir, ketoconazole, regorafenib): risk of increased concentrations of the active metabolite of irinotecan SN 38. Physicians should take this into account when co-administering these medicinal products.
Other CYP3 inhibitors A4 (e.g. crizotinib, idelalisib): risk of increased toxicity of irinotecan due to decreased metabolism of irinotecan by crizotinib or idelalisib.
Caution with concomitant use
Vitamin K antagonists: increased risk of bleeding and thrombotic events in neoplastic diseases. When prescribing vitamin K antagonists, more frequent monitoring of INR (international normalized ratio) is necessary.
Concomitant use to be considered
Immunosuppressants (e.g. cyclosporine, tacrolimus): significant immunosuppression with risk of lymphoproliferation.
Neuromuscular blockers: an interaction between irinotecan and neuromuscular blocking agents cannot be excluded. Since irinotecan has anticholinesterase activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effect of suxamethonium and counteract the neuromuscular blockade of non-depolarizing drugs.
Other combinations
5-fluorouracil/folinic acid: co-administration of 5-fluorouracil/folinic acid in a combination regimen does not alter the pharmacokinetics of irinotecan.
Bevacizumab: results of a dedicated drug interaction study demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude increased toxicity due to their pharmacological properties.
Cetuximab: there is no evidence that cetuximab affects the safety profile of irinotecan or vice versa.
Special warnings
Taking into account the nature and frequency of adverse events, the drug is prescribed in the following cases only if the expected benefit outweighs the possible therapeutic risks:
- in patients with risk factors, especially in patients with general condition according to WHO = 2.
- in some rare cases, when it is considered that patients are not able to comply with recommendations for the treatment of adverse events (the need for urgent and prolonged treatment of diarrhea in combination with drinking large amounts of fluid in the event of late diarrhea). For such patients, strict monitoring in a hospital setting is recommended.
When using the drug as monotherapy, it is usually prescribed according to a schedule of administration of the drug once every 3 weeks. However, for patients who need more careful monitoring or for patients with a special risk of neutropenia, a weekly regimen of drug administration can be considered.
Late diarrhea
Patients should be informed of the risk of late diarrhea that develops later than 24 hours after administration of the drug, as well as at any time before the next cycle. With monotherapy, the median time to the first loose stool was 5 days after infusion. Patients should promptly notify their physician of its occurrence and initiate appropriate therapy immediately.
Patients at increased risk of developing diarrhea include those who have previously received abdominal/pelvic radiation therapy, those with hyperleukocytosis at baseline, those with a WHO performance status ≥ 2, and women. If untreated, diarrhea can be life-threatening, especially if the patient is also neutropenic.
At the first sign of loose stool, the patient should be given large amounts of electrolyte-containing solutions and appropriate treatment for diarrhea should be initiated immediately. This treatment for diarrhea should be initiated in the unit where irinotecan was administered. After discharge from the hospital, the patient should be given the prescribed medications so that they can begin treatment for diarrhea immediately upon its occurrence. In addition, they should notify their physician or the unit where they are receiving irinotecan if diarrhea occurs.
The currently recommended treatment for diarrhea is high-dose loperamide (4 mg initially, then 2 mg every 2 hours). This therapy should be continued for the first 12 hours after the last loose stool and should not be changed. Loperamide should never be given at these doses for more than 48 consecutive hours due to the risk of paralytic ileus, or for less than 12 hours.
If diarrhea is associated with severe neutropenia (neutrophil count < 500 cells/mm³), prophylactic broad-spectrum antibiotics should be administered in addition to treatment for diarrhea.
In addition to antibiotic treatment, hospitalization for diarrhea is recommended in the following cases:
- diarrhea associated with fever
- severe diarrhea (requiring intravenous fluids)
- diarrhea persisting for more than 48 hours after starting high-dose loperamide therapy.
Loperamide should not be used for prophylaxis, even in patients with late diarrhea in previous cycles.
In patients with severe diarrhea, a dose reduction is recommended in subsequent cycles.
Complete blood count
During therapy with irinotecan, weekly monitoring of complete blood count parameters is recommended. Patients should be informed of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature >38 °C and neutrophil count ≤ 1000 cells/mm³) should be treated urgently in hospital with intravenous broad-spectrum antibiotics.
In patients with severe blood events, a dose reduction is recommended for subsequent administration of the drug.
An increased risk of infection and hematologic toxicity has been noted in patients with severe diarrhea. A complete blood count should be performed in patients with severe diarrhea.
Hepatic impairment
Liver function tests should be performed at baseline and before each cycle.
In patients with bilirubin concentrations 1.5 to 3 times the ULN, weekly complete blood counts are recommended due to decreased irinotecan clearance, which increases the risk of hematotoxicity in this population. For patients with bilirubin concentrations > 3 ULN.
Nausea and vomiting
Prophylactic treatment with antiemetics is recommended before each administration. Nausea and vomiting have been reported frequently. Patients with vomiting associated with late diarrhea should be hospitalized as soon as possible for follow-up care.
Acute cholinergic syndrome
If acute cholinergic syndrome (defined as early diarrhea and other miscellaneous signs and symptoms such as sweating, abdominal cramps, miosis, and increased salivation) occurs, in the absence of clinical contraindications, atropine sulfate (0.25 mg subcutaneously) should be administered.
These symptoms, sometimes observed during or shortly after irinotecan administration, are thought to be caused by the anticholinesterase activity of the parent compound irinotecan and are expected to occur more frequently with higher doses of irinotecan.
Caution is required when using the drug in patients with bronchial asthma. In patients with acute and severe cholinergic syndrome, prophylactic use of atropine sulfate is recommended followed by the use of irinotecan.
Respiratory system disorders
Interstitial lung disease, presented as pulmonary infiltrates, is uncommon during therapy with irinotecan. Interstitial lung disease can be fatal. Risk factors possibly associated with the development of interstitial lung disease include the use of pneumotoxic drugs, radiation therapy, and colony-stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during therapy with irinotecan.
Extravasation
Although irinotecan is not a known vesicant, care should be taken to avoid hemorrhage and the infusion site should be monitored for signs of inflammation. If extravasation occurs, irrigation of the area and application of ice are recommended.
Elderly patients
Due to a higher incidence of decreased biological functions, especially liver function, in elderly patients, caution should be exercised when selecting irinotecan doses in this population.
Patients with chronic inflammatory bowel disease and/or intestinal obstruction
Patients should not be treated with irinotecan until the intestinal obstruction has resolved.
Patients with renal impairment
Increases in serum creatinine or blood urea nitrogen have been observed. Cases of acute renal failure have been reported. These events are usually attributed to complications of infection or dehydration resulting from nausea, vomiting, or diarrhea. Rare cases of renal dysfunction due to tumor lysis syndrome have also been reported.
No studies have been conducted in this population.
Radiation Therapy
Patients who have previously received abdominal/pelvic radiation therapy are at increased risk of myelosuppression following irinotecan administration. Physicians should exercise caution when treating patients with extensive prior radiation exposure (e.g., >25% of bone marrow irradiated and within 6 weeks prior to initiating irinotecan therapy). Dose adjustments may be appropriate for this population.
Cardiac Disorders
Cases of myocardial ischemia have been reported following irinotecan therapy, primarily in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy.
Therefore, patients with known risk factors should be closely monitored, and steps should be taken to minimize any modifiable risk factors (e.g., smoking, hypertension, and hyperlipidemia).
Vascular disorders
Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial thromboembolic embolia) in patients with multiple risk factors in addition to the underlying malignancy.
Immunosuppressant effects/increased susceptibility to infections
Use of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents, including irinotecan, may result in serious or fatal infections. Vaccination with live vaccines should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be used, but the response to these vaccines may be reduced.
Excipients
Since this medicinal product contains sorbitol, it should not be used in patients with rare hereditary problems of fructose intolerance.
Other
Infrequent cases of renal failure, hypotension, or circulatory failure have been reported in patients with episodes of dehydration associated with diarrhea and/or vomiting, or sepsis.
Contraception must be used for at least 3 months after discontinuing therapy.
Paediatric Use
The drug is contraindicated in children under 18 years of age.
During Pregnancy or Lactation
There are no or limited data on the use of irinotecan in pregnant women.
Irinotecan should not be used during pregnancy unless clearly necessary. In each individual case, the benefits of treatment must be weighed against the potential risk to the fetus.
It is unknown whether irinotecan is excreted in human breast milk. Therefore, due to the possibility of adverse reactions in breastfed children, irinotecan is contraindicated during breastfeeding.
Contraception in Men and Women
Women of childbearing potential and men should use effective contraception during treatment and for 1-3 months after treatment, respectively.
Features of the drug’s effect on the ability to drive vehicles or operate potentially dangerous machinery
Patients should be warned about possible dizziness or visual impairment that may occur within 24 hours after taking irinotecan, and advised to refrain from driving or operating machinery if these symptoms occur.

Recommended Use
For adult patients only.
Dosage regimen
As monotherapy (for patients who have previously received treatment):
The recommended dosage of the drug is 350 mg/m² as an intravenous infusion over 30 to 90 minutes every 3 weeks.
As combination therapy (for patients who have not previously received treatment):
The safety and efficacy of irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were assessed according to the following scheme.
Irinotecan plus 5-FU/FC every other week:
The recommended dose of irinotecan is 180 mg/m² every other week as an intravenous infusion over 30 to 90 minutes, followed by an infusion of folinic acid and 5-fluorouracil.
See the prescribing information for the dosage and administration of cetuximab when co-administered with irinotecan in the prescribing information for that drug. Typically, the irinotecan dose is the same as the last cycle of the previous irinotecan-containing regimen. Irinotecan should not be administered earlier than 1 hour after the end of the cetuximab infusion.
The dosage and administration of bevacizumab are provided in the summary of the drug characteristics in the prescribing information for bevacizumab. Dose adjustments
Irinotecan should be administered after adequate resolution of all adverse events to a National Cancer Institute Common Toxicity Criteria (NCI-CTC) score of 0 or 1 and until treatment-related diarrhea has resolved.
At the start of subsequent infusion therapy, the dose of irinotecan and 5-FU should be reduced, if possible, to reflect adverse events that are greater than those observed prior to the infusion. Treatment should be delayed for 1 to 2 weeks to allow the patient to resolve treatment-related adverse events.
If the following adverse events occur, the dose of irinotecan and/or 5-FU should be reduced by 15-20%, where applicable:
- hematological toxicity (grade 4 neutropenia, febrile neutropenia (grade 3-4 neutropenia and grade 2-4 fever), thrombocytopenia and leukopenia (grade 4)).
- non-hematological toxicity (grade 3-4).
It is necessary to follow the recommendations for dose modification of cetuximab when used in combination with irinotecan according to the instructions for use of this medicinal product.
Dose modifications of bevacizumab when used in combination with irinotecan/5FU/FC are presented in the summary of product characteristics of bevacizumab.
When combined with capecitabine, for patients aged 65 years or older, a reduction in the initial dose of capecitabine to 800 mg/m2 twice daily is recommended in accordance with the summary of product characteristics. The recommendations for dose modifications for combination therapy in the capecitabine summary of product characteristics should also be followed.
Special patient groups
Patients with impaired liver function
As monotherapy:
The starting dose of irinotecan should be adjusted according to serum bilirubin levels (3 times the upper limit of normal (ULN)) in patients with a WHO performance status score ≤ 2. In these patients with hyperbilirubinemia and a prothrombin time greater than 50%, irinotecan clearance is reduced, increasing the risk of hematotoxicity. Therefore, in this group of patients, all blood parameters should be monitored weekly.
In patients with bilirubin levels greater than 1.5 times the ULN, the recommended dose of irinotecan is 350 mg/m².
In patients with bilirubin concentrations 1.5 to 3 times the ULN, the recommended dose of irinotecan is 200 mg/m².
Irinotecan is not recommended for use in patients with bilirubin concentrations greater than 3 times the ULN.
As part of combination therapy:
There are no data on the use of the drug in patients with impaired liver function who have received irinotecan in combination with other drugs.
Patients with impaired renal function
Irinotecan is not recommended for use in patients with impaired renal function, since studies have not been conducted in this group of patients.
Elderly patients
Specific pharmacokinetic studies have not been conducted in the elderly. However, in this population, careful dose selection is necessary due to a higher frequency of decreased biological functions. This population may require more intensive monitoring.
Method and route of administration
After dilution of the drug, the infusion solution is administered into a peripheral or central vein.
Duration of treatment
Treatment should be continued until objective disease progression or unacceptable toxicity is observed.
Measures to be taken in case of overdose
Symptoms: Overdoses of approximately 2 times the recommended therapeutic dose have been reported and may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea.
Treatment: There is no known antidote for irinotecan. Maximal supportive care should be provided to prevent dehydration due to diarrhea and to treat any infectious complications.
Recommendations for seeking advice from a healthcare professional to clarify the use of the medicinal product
Consult a physician for advice before taking the medicinal product.

Description of adverse reactions that occur during standard use of the medicinal product and measures to be taken in this case (if necessary)
The frequency of adverse reactions is determined according to the following criteria: 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), unknown (cannot be estimated from the available data).
Infections and infestations
Uncommon: renal failure, arterial hypotension or cardiovascular failure have been observed in patients who have had sepsis.
Unknown: fungal infections (e.g. Pneumocystis pneumonia, bronchopulmonary aspergillosis, systemic candidiasis). Viral infections (e.g., herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis). Blood and lymphatic system disorders
Very common: neutropenia (reversible and not cumulative), anaemia, thrombocytopenia in case of combination therapy, episodes of infection in case of monotherapy
Common: febrile neutropenia, episodes of infection in case of combination therapy, episodes of infection associated with severe neutropenia, fatal in three cases, thrombocytopenia in case of monotherapy
Unknown: one case of peripheral thrombocytopenia with antiplatelet antibodies has been reported
Immune system disorders
Uncommon: mild allergic reactions
Rare: anaphylactic/anaphylactoid reactions
Metabolic and nutritional disorders
Unknown: tumor lysis syndrome
Nervous system disorders
Very rare: transient speech disorders
Cardiac disorders
Rare: hypertension during or after infusions
Respiratory, thoracic and mediastinal disorders
Uncommon: interstitial lung disease, presenting as pulmonary infiltrates, early effects such as dyspnoea
Gastrointestinal disorders
Very common: severe late diarrhea, severe nausea and vomiting in case of monotherapy
Common: severe nausea and vomiting in case of combination therapy, episodes of dehydration (associated with diarrhea and/or vomiting), constipation associated with irinotecan and/or loperamide
Uncommon: pseudomembranous colitis (one case was bacteriologically confirmed: Clostridium difficile), renal failure, arterial hypotension or cardiovascular failure due to dehydration associated with diarrhea and/or vomiting, intestinal obstruction, ileus, gastrointestinal bleeding
Rare: colitis, including typhlitis, ischemic and ulcerative colitis, intestinal perforation,
other mild effects including anorexia, abdominal pain and mucositis, symptomatic or asymptomatic pancreatitis
Liver and biliary tract disorders
Not known: hepatic steatosis, steatohepatitis
Skin and subcutaneous tissue disorders
Very common: alopecia (reversible)
Uncommon: mild skin reactions
Muscular, skeletal and connective tissue disorders
Rare: early effects such as muscle contraction or convulsions and paraesthesia
General disorders and administration site conditions
Very common: fever in the absence of infection and without concomitant severe neutropenia in case of monotherapy
Common: fever in the absence of infection and without concomitant severe neutropenia in case of combination therapy, severe transient acute cholinergic syndrome (the main symptoms were defined as early diarrhea and other various symptoms such as abdominal pain, conjunctivitis, rhinitis, arterial hypotension, vasodilation, sweating, chills, malaise, dizziness, visual disturbances, miosis, lacrimation and increased salivation), asthenia
Uncommon: reactions at the injection site
Laboratory and instrumental data
Very common: with combination therapy, transient concentrations (grade 1 or 2) of serum transaminases, alkaline phosphatase or bilirubin in the serum were noted in the absence of progressive liver metastases
Common: with monotherapy, transient increases in serum transaminase, alkaline phosphatase or bilirubin concentrations in the blood serum of mild or moderate severity in the absence of progressive liver metastases, with combination therapy, transient concentrations of bilirubin in the blood serum of grade 3 severity, transient increase in creatinine concentration of mild or moderate severity were noted
Rare: hypokalemia and hyponatremia
Very rare: increased amylase and / or lipase levels

If adverse drug reactions occur, contact your health care provider, pharmacist, or directly to the Adverse Drug Reactions (Actions) Information Database, including reports of drug ineffectiveness
Republican State enterprise on the Right of Economic Management National Center for Expertise of Medicines and Medical Devices of the Committee for Medical and Pharmaceutical Control of the Ministry of Healthcare of the Republic of Kazakhstan
http://www.ndda.kz

Additional information
Composition of the drug
One ml of the drug contains
active substance - irinotecan hydrochloride trihydrate - 20.0 mg,
excipients - sorbitol, lactic acid, sodium hydroxide, hydrochloric acid, water for injection.
Description of appearance, smell, taste
Transparent, aqueous solution of light yellow color.

Dosage form and packaging
2 ml (for a concentration of 40 mg / 2 ml) and 5 ml (for a concentration of 100 mg / 5 ml) of the drug in tubular bottles made of dark glass (type 1), with a capacity of 5 ml, with a neck diameter of 13 mm, sealed with gray bromobutyl rubber stoppers with a diameter of 13 mm (Type I) with a siliconization level of 2, crimped with an aluminum cap with a tear-off lining of golden-yellow color (for a concentration of 40 mg / 2 ml) or red-orange color (for a concentration of 100 mg / 5 ml) of the flip-off type, with a diameter of 13 mm.
1 bottle together with instructions for medical use in Kazakh and Russian languages CAMBER are placed in a cardboard box.

Shelf life
2 years
Do not use after the expiration date!
Storage conditions
In a place protected from light at a temperature not exceeding 25 °C.
Keep out of reach of children!

Conditions of dispensing from pharmacies
On prescription