Irinotecan medak - instructions for use, dose, side effects, contraindications

Irinotecan, a semi-synthetic derivative of camptothecin, is a specific inhibitor of the cellular enzyme topoisomerase I. In tissues, the drug is metabolized by the enzyme carboxyl esterase to form the active metabolite SN-38, which is superior in its activity irinotecan with respect to the purified topoisomerase I and shows greater cytotoxicity compared to irinotecan for a number of murine and human tumor cell lines. Inhibition of DNA topoisomerase I by irinotecan or SN-38 causes single-stranded DNA damage, which blocks the replicative DNA plug, and causes cytotoxic effects. It was found that the cytotoxic activity is time-dependent for the cell cycle, namely, it is specific for the S.

In vitro irinotecan and SN-38 were poorly recognized by the P-glycoprotein of multiple drug resistance and had cytotoxicity against doxorubicin - and vinblastine - resistant cell lines.

In vivo experiments, it was shown that irinotecan has a wide spectrum of activity against mouse tumor models (adenocarcinoma of the pancreatic ducts of the ROS, adenocarcinoma of the mammary gland MA16 / C, adenocarcinoma of the large intestine C38, C51) and against human tumor xenografts (adenocarcinoma of the large intestine Co-4, adenocarcinoma of the mammary gland Mx-1, adenocarcinoma stomach ST-15 and SC-16). Irynotekan is also active against tumors expressing P-glycoprotein of multiple drug resistance (vincristine - and doxorubicin - resistant leukemia P388).

In addition to antitumor activity, the most relevant pharmacological effect of irinotecan is the suppression of acetylcholinesterase.

Patients with reduced activity of uridine-diphosphate-glucuronyltransferase 1A1 (UGT1A1): UGT1A1 participates in the metabolic inactivation of the active metabolite of irinotecan SN-38 to form an inactive metabolite SN-38 glucuronide (SN-38G). The expression gene of UGT1A1 is highly polymorphic, and therefore the metabolic activity between individuals is different. One of the specific variations of the UGT1A1 gene involves polymorphism in the promoter region and is known as the UGT1A1 * 28 allele.In patients with this variation and with other congenital forms of reduced expression of UGT1A1 (such as Kriegler-Nyar syndrome and Gilbert's syndrome), the activity of UGT1A1 is decreased. At present, there is insufficient data to conclude that the clinical significance of genotyping of such patients is clinically significant.

Pharmacokinetics:

The pharmacokinetics of irinotecan and SN-38 (its active metabolite) was studied in a 30-minute intravenous infusion of the drug at a dose of 100-750 mg / m² once every three weeks. The pharmacokinetic profile of irinotecan is dose independent. The average clearance from the plasma was 15 l / h / m², the volume of distribution in the stationary phase is 157 l / m². Irynotekan metabolized mainly in the liver under the action of the enzyme carboxyl esterase to the metabolite SN-38.

The distribution of the drug in the plasma is two- or three-phase. The average half-life of the drug in the plasma in the first phase of the three-phase model is 12 minutes, in the second phase - 2.5 hours, in the last phase - 14.2 hours. Excretion SN-38 two-phase, the average half-life in the final phase is 13.8 hours. The maximum plasma concentration of irinotecan and SN-38 was achieved by the end of intravenous infusion at a recommended dose of 350 mg / m² body surface area and averaged 7.7 μg / ml and 56 ng / ml, respectively; mean value of the area under the curve (AUC) was 34 μg * h / ml and 451 ng * h / ml, respectively. In general, there was a significant variability in pharmacokinetics SN- 38 between individuals.

Population pharmacokinetic analysis of irinotecan in patients with metastatic colorectal cancer treated with different regimens of therapy using different doses of irinotecan in phase II trials showed similar pharmacokinetic parameters within the three-compartment model with parameters observed in Phase I studies. Exposure of irinotecan and SN-38 increases in proportion to the administered dose of irinotecan; their pharmacokinetics does not depend on the number of previous cycles and the administration schedule.

In vitro the association with plasma proteins is approximately 65% for irinotecan and 95% for SN-38.

Pharmacokinetic studies confirmed the absence of the effect of fluorouracil and calcium folinate on the pharmacokinetics of irinotecan.

Studies of mass balance and metabolism using irinotecan radiolabelled (C14) showed that more than 50% of the intravenously injected drug is excreted unchanged: 33% with feces mainly with bile, and 22% with urine.

There are 2 ways of metabolism of irinotecan, through each of which at least 12% of the administered dose passes:

- Hydrolysis with carboxyl esterase to form an active metabolite SN-38. Excretion SN-38 occurs mainly through glucuronation and further biliary and renal excretion (less than 0.5% of the administered dose of irinotecan). SN-38 The glucuronide is probably then hydrolyzed in the intestine.

- Oxidation mediated by the enzymes of cytochrome P450 OA, leading to the discovery of the outer piperidine ring with the formation of APC (aminopentanoic acid derivative) and NPC (primary amine derivative).

In plasma, the largest proportion of irinotecan is unchanged, followed by APC, SN-38 glucuronide and SN-38, of which only SN-38 has significant cytotoxic activity.

In patients with bilirubinemia (the concentration of bilirubin exceeds the upper limit of the norm by 1.5-3.0 times), the clearance of irinotecan is reduced by approximately 40%. In such patients after administration of a dose of irinotecan 200 mg / m² the concentration of the drug in the blood plasma is comparable with the concentration after administration of a dose of 350 mg / m² in cancer patients with normal liver parameters.

Indications:

Irinotecan medak is designed to treat patients with locally advanced or metastatic colorectal cancer:

- in combination with fluorouracil and calcium folinate in patients who had not previously received chemotherapy;

- in monotherapy in patients with disease progression after standard antitumor therapy.

Contraindications:

- Chronic inflammatory bowel disease and / or bowel obstruction

- Hypersensitivity to irinotecan or any other component of the drug in history;

- Pregnancy and the period of breastfeeding;

- The concentration of bilirubin in the serum, exceeding the upper limit of the norm by more than 3 times

- Severe oppression of bone marrow hematopoiesis;

- General condition of the patient, assessed on a scale ECOG (Eastern Cooperative Oncology Group) >2;

- Simultaneous use with a yellow fever vaccine;

- Child age (data on safety and efficacy in children are absent).

Carefully:Radiation therapy (in the anamnesis) on the abdominal or pelvic area, leukocytosis, female patients (increased risk of diarrhea), renal failure (safety data absent), hypovolemia, propensity to thrombosis and thromboembolism, elderly age.

Pregnancy and lactation:

Pregnancy

Data on the use of irinotecan in pregnant women are absent.

In animal studies, it was shown that irinotecan has embryotoxic and teratogenic effects. The use of irinotecan during pregnancy is contraindicated.

Breast-feeding

In experiments on lactating rats, the isotope labeled with carbon C14 irinotecan was found in milk. It is not known whether the irinotecan in human milk. Due to the potential negative reactions in children who are breastfeeding, breastfeeding should be discontinued for the duration of treatment with irinotecan.

Dosing and Administration:

The drug is used intravenously infusion.

When choosing a dose and mode of administration, you should refer to the special literature.

Before use, the preparation should be diluted as described below, applied immediately after the preparation of the solution.

Treatment with the drug should be carried out only in adult patients.

Treatment should be carried out by a doctor who has experience in chemotherapy.

Recommended doses

In the regime of monotherapy (in previously treated patients) Irinotecan medak is used at a recommended dose of 125 mg / m body surface weekly for 4 weeks as a 90-minute intravenous infusion with a 2-week break, or at a dose of 350 mg / m3 as a one-hour intravenous infusion every 3 weeks.

As part of combined chemotherapy with fluorouracil and calcium folinate (in patients without previous treatment) the dose of the preparation Irinotecan medak when administered by infusion with a duration of 30 to 90 minutes is with weekly administration of 125 mg / m², with the introduction once every 2 weeks - 180 mg / m² before the administration of fluorouracil and calcium folinate. Doses and administration of fluorouracil and calcium folinate are described in detail in the literature.

Recommendations for dose adjustment

Reduction of the initial dose of the preparation Irinotecan medak from 125 mg / m² up to 100 mg / m² and from 350 mg / m² up to 300 mg / m² in the regime of monotherapy, as well as a decrease in the dose from 125 mg / m² up to 100 mg / m² and from 180 mg / m² up to 150 mg / m²'in the combined therapy regimen can be recommended in patients aged 65 years and older, with prior extensive radiation therapy, with an overall patient score of 2, with an elevated bilirubin concentration in the blood.

Irinotecan should be given only after all the side effects have been reduced to a grade of 0 or 1 by gradation NCI-CTC (General criteria for toxicity of the National Cancer Institute of the United States). The administration of irinotecan medak should not be carried out until the amount of neutrophils in the peripheral blood exceeds 1500 cells / μl of blood, and until such complications as nausea, vomiting and especially diarrhea are completely eliminated. At the beginning of each next injection of the drugs used in therapy irinotecan, and if necessary fluorouracil, should be reduced in accordance with the most pronounced adverse events observed with the previous administration. The administration of the drug before the resolution of all side effects can be postponed for 1-2 weeks. In the event that the expressed inhibition of bone marrow hematopoiesis develops (the number of neutrophils is less than 500 / μl of blood, and / or the number of leukocytes is less than 1000 / μl of blood, and / or the platelet count is less than 100,000 / μl), or febrile neutropenia neutrophils 1000 / μL and less in combination with an increase in body temperature of more than 38 ° C), or infectious complications,or severe diarrhea, or other non-hematological toxicity of 3-4 degrees, subsequent doses of the drug, and if necessary fluorouracil, should be reduced by 15-20%.

Duration of treatment

Treatment with irinotecan is continued until the appearance of objective signs of progression of malignant tumor disease or the development of uncontrolled toxicity. If such signs of treatment with the drug Irinotecan medak should be discontinued.

Special patient groups

Patients with reduced liver function

In monotherapy, the initial dose of irinotecan in patients with a functional condition <2 according to the WHO classification is determined depending on the level of bilirubin in the blood (up to 3 times the value of the upper limit of the norm (VGN)). In this group of patients with hyperbilirubinemia and prothrombin time exceeding the normal value by 50%, the rate of excretion of irinotecan is reduced, and therefore the risk of hematotoxicity is increased. Therefore, in patients in this group, a full blood count should be performed on a weekly basis.

- For patients in whom the bilirubin level exceeds the VGN by no more than 1.5 times, the recommended dose of irinotecan is 350 mg / m².

- For patients who have a bilirubin level higher than IGN 1.5-3.0 times, the recommended dose of irinotecan is 200 mg / m².

- Patients who have a bilirubin level greater than IGV more than 3 times, should not prescribe treatment with irinotecan.

Data on patients with reduced liver function, who underwent combined treatment with irinotecan, are absent.

Patients with decreased renal function

The use of irinotecan in patients with renal insufficiency is not recommended, as studies in this group have not been conducted.

Elderly patients

Special studies of pharmacokinetics in elderly patients have not been conducted. However, the selection of a dose for this group should be carried out with caution in connection with the often manifested decrease in the intensity of biological functions.

Preparation of a solution for infusions

Preparation of a solution for infusions of the preparation Irinotecan medak should be carried out under aseptic conditions.

If a sediment is present in the vials or infusion solution after its preparation, the preparation should be disposed of in accordance with the standard procedure for the disposal of cytotoxic substances.

In aseptic conditions, using a calibrated syringe, the required amount of Irinotecan Medac concentrate concentrate is taken from the vial to prepare a solution for infusion, and transferred to an infusion container containing 250 ml of a 0.9% solution of sodium chloride for injection or a 5% solution of dextrose for injection. The resulting solution for infusions should be thoroughly mixed by hand by rotational movements.

Preparation of the solution of irinotecan medak and other manipulations should be done with caution. If necessary, use glasses, mask and gloves.

From a microbiological point of view, the solution for infusion should be used immediately after preparation.

A solution prepared in accordance with aseptic rules can be used for 6 hours if stored at room temperature, or for 24 hours if stored at 2-8 ° C.

Recycling:

All items used to prepare the drug solution and its use, the entire unused prepared and unprepared preparation, all used materials and waste must be disposed of in accordance with standard operating procedures for the treatment of cytotoxic drugs taken at the medical institution.

The drug is intended for single use only.

Side effects:

The frequency of adverse reactions is presented in accordance with the following classification:

Often	≥ 10%
Often	≥ 1% and <10%
Infrequently	≥ 0.1% and <1%
Rarely	≥ 0.01% and <0.1%
Rarely	< 0,01 %
Frequency unknown	It is impossible to determine the basis of available data

From the hematopoiesis system: very often - Neutropenia, leukopenia, anemia, thrombocytopenia. Neutropenia was observed in 78.7% of patients with monotherapy (with combined chemotherapy in 82.5%), including 22.6% of patients with severe neutrophil count (less than 500 cells / μL). Neutropenia was reversible and did not have a cumulative character. A complete recovery of neutrophil counts usually occurred on the 22nd day when the drug was used in monotherapy and on the 7-8th day when the drug was used as part of a combination chemotherapy. Fever in combination with severe neutropenia was noted in 6.2% and 3.4% of patients, respectively. Infectious complications in monotherapy were observed in 10.3% of patients, 5.3% of patients they were combined with severe neutropenia.

When using the drug in monotherapy, moderate anemia developed in 58.7% of patients.When using the drug as part of combined chemotherapy, anemia was observed in 97.2% of patients.

Using the drug in monotherapy of thrombocytopenia (<100 000 cells / μl) was observed in 7.4% of patients (with combined chemotherapy in 32.6% of patients). When using the drug in combination chemotherapy pronounced thrombocytopenia was not observed. Number of platelets is restored by day 22.

One case of thrombocytopenia was observed in combination with the formation of antiplatelet antibodies.

There were also cases of arterial and venous thromboembolic complications (including angina, arterial thrombosis, stroke, cerebral circulation, deep vein thrombophlebitis of the lower limbs, thromboembolism of lower extremity vessels, cardiac arrest, myocardial infarction, cardiac muscle ischemia, circulatory disturbance in peripheral vessels, pulmonary thromboembolism arteries, sudden death, thrombophlebitis, thrombosis, vascular disorders).

From the gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, anorexia, mucositis, constipation, candidiasis of the gastrointestinal tract, hiccough.

There have been reports of rare cases of pseudomembranous colitis, intestinal obstruction, bleeding from the gastrointestinal tract, intestinal perforation, increased activity of amylase or lipase. Diarrhea that occurs later than 24 hours after the application of irinotecan (delayed diarrhea) is a dose-limiting toxic effect of the drug.

When using the drug in monotherapy, severe diarrhea was observed in 20% of patients (with combined therapy in 13.1%). The average time before the appearance of the first liquid stool after the administration of the drug was 5 days.

When using the drug in monotherapy, approximately 10% of patients using anti-emetics had pronounced nausea and vomiting.

When using the drug in combination chemotherapy, severe nausea and vomiting were less common: in 2.1% and 2.8% of patients, respectively.

Acute cholinergic syndrome, manifested by such symptoms as early diarrhea (diarrhea occurring within 8 hours after the administration of irinotecan), abdominal pain, conjunctivitis, rhinitis, lowering of blood pressure, bradycardia, vasodilation,increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lachrymation, salivation, was observed in 9% of patients who received irinotecan in monotherapy, and in 1.4% of patients with combined chemotherapy. All these symptoms disappeared after the administration of atropine.

From the nervous system: involuntary muscle twitching or cramping, paresthesia, asthenia, gait disturbance, confusion, headache.

On the part of the respiratory system: shortness of breath, pulmonary infiltrates, rhinitis.

Allergic reactions: rarely - skin rash, skin manifestations, anaphylactic shock and anaphylactoid reactions.

Other: alopecia, fever, transient speech disorders, local reactions, transient increase in the activity of transaminases, alkaline phosphatase, gamma glutamyltransferase, bilirubin concentration, serum creatinine and urea nitrogen, hypokalemia, hypomagnesemia, hyponatremia, weight loss, pain, dehydration, hypovolemia, sepsis, syncope, cardiovascular disorders, genitourinary system infections , pain in the chest, tumor lysis syndrome.In rare cases, renal dysfunction and development of acute renal failure, hypotension, or circulatory failure were observed in patients who had experienced episodes of dehydration associated with diarrhea and / or vomiting or in patients with sepsis.

Undesirable effects arising from combined therapy with irinotecan and capecitabine (in addition to those usually observed with capecitabine in monotherapy or occurring more often with combination therapy than with capecitabine alone): thrombosis / thromboembolism, reactions hypersensitivity, ischemia / myocardial infarction, febrile neutropenia.

Overdose:There are reports of an overdose with doses exceeding the recommended therapeutic doses up to two times and that may prove to be fatal. The most significant of the known side effects were severe forms of neutropenia and diarrhea.

The antidote is unknown.

It is necessary to take a maximum of supporting measures to prevent dehydration caused by diarrhea and to treat all types of infectious complications.

Interaction:

Perhaps the interaction between irinotecan and muscle relaxants.As irinotecan has anticholinesterase activity, it is possible to increase the duration of neuromuscular blockade when combined with suxamethonium salts and antagonistic interaction with neuromuscular blockade when combined with nondepolarizing muscle relaxants.

Several studies have shown that a joint application with irinotecan inductors CYP3A (such as carbamazepine, phenobarbital, phenytoin) leads to a decrease in the concentration of irinotecan, SN-38 and SN-38 glucuronide in plasma and reduces the pharmacodynamic effect. The result of the joint use of such anticonvulsants was a decrease in the area under the curve (AUC) SN-38 and SN- 38 glucuronide by 50% or more. In addition to induction of cytochrome P450 enzymes FOR role in lowering plasma concentrations of irinotecan and its metabolites can play increased glucuronidation and increased excretion of bile.

The study showed that the combined use of ketoconazole leads to a decrease AUC the main oxidative metabolite APC by 87% and to an increase AUC SN-38 by 109% in comparison with the case of irinotecan alone.

When combined with drugs that are inhibitors (for example, ketoconazole) or inductors (such as rifampicin, carbamazepine, phenobarbital, phenytoin) metabolism CYP3A4 care must be taken. The joint administration of irinotecan with inhibitors / inducers of this pathway of metabolism can alter the metabolism of irinotecan and, therefore, should be avoided.

In a small pharmacokinetic study (n = 5) irinotecan in a dose of 350 mg / m²was used in conjunction with St. John's Wort (Hypericum perforatum) 900 mg, at the same time there was a 42% decrease in plasma concentration of the active metabolite irinotecan SN-38. St. John's wort kills the concentration SN-38 in the plasma. Therefore, preparations of St. John's wort must not be administered together with irinotecan.

The use of fluorouracil / calcium folinate in combined therapy with irinotecan does not change the pharmacokinetics of irinotecan.

The combined use of irinotecan with atazanavir sulfate, an inhibitor of enzymes CYP3A4 and UGT1A1, can cause an increase in the concentration in the blood plasma of the active metabolite irinotecan SN-38, that it is necessary to take into account the doctor at joint appointment of these preparations.

Interactions characteristic of all cytotoxic drugs

In patients with tumoral diseases, the usual practice is the use of anticoagulants due to the increased risk of thrombotic events. In the case of vitamin K antagonists, the importance of the International Normalized Relationship (MNO) should be more often monitored due to the narrow therapeutic window of such drugs, high intra-individual variability in the ability to clot and the possibility of interaction between oral anticoagulants and antitumor drugs.

Joint use is contraindicated:

- a yellow fever vaccine due to the risk of developing a systemic response to fatal vaccines.

Joint use is not recommended:

- live attenuated vaccines (except yellow fever vaccine) due to the risk of developing systemic diseases (eg, infections) with possible fatal outcome. This risk is increased in patients whose immunity is already weakened by the underlying disease.If possible, inactivated vaccines should be used (for example, against polio).

- phenytoin: risk of exacerbation of seizures due to reduced absorption of phenytoin in the gastrointestinal tract when combined with cytotoxic drugs.

Use with caution:

- cyclosporine, tacrolimus: significant immunosuppression with risk lymphoproliferation.

There are no data confirming the effect of cetuximab on the safety profile of irinotecan and vice versa.

In one study, the concentration of irinotecan was similar in patients who were treated with a combination irinotecan / fluorouracil / calcium folinate, and in patients who used this combination of drugs in combination with bevacizumab. A part of the patients (about 30 in each arm of the study) analyzed the concentration SN-38, of the active metabolite of irinotecan, and was on average 33% higher in patients who were treated with bevacizumab than in patients receiving only irinotecan / fluorouracil / calcium folinate. In view of the high variability between patients and the limited number of samples analyzed, it remains unclear whether the increase in concentration SN-38 is caused by bevacizumab.In patients treated with bevacizumab, there was a slight increase in the incidence of diarrhea and leukopenia, and a reduction in the dosage of irinotecan.

Patients who develop severe diarrhea, leukopenia, or neutropenia in the joint use of bevacizumab and irinotecan require correction of the dose of irinotecan in accordance with the recommendations given in the section "Method of administration and dose".

A special study of drug interaction demonstrated the absence of a significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not exclude the risk of increased toxicity due to the pharmacological properties of these drugs.

Incompatibility

Irinotecan should not be confused with other drugs and substances other than those listed in the section "Preparation of a solution for infusions".

Special instructions:

Use of irinotecan should be performed only in the departments specializing in the field of cytotoxic therapy.

Treatment Irinotecan medak should be performed by a doctor who has experience in the use of cytotoxic drugs.

In case of contact of the preparation in the form of a concentrate or a prepared solution for infusions with skin, the contact site should immediately be rinsed thoroughly with soap and water. In case of contact with the mucosa, the preparation should be rinsed immediately with water.

When using the medication Irynotekan, all instructions adopted for the use of cytotoxic drugs should be observed.

In the following cases irinotecan should be appointed only after an assessment of the expected relationship between the benefits of treatment and the possible risk:

- treatment of patients with risk factors, especially those with a functional status index of 2 (according to WHO classification).

- in some rare cases, when patients are not inclined to follow recommendations for fighting adverse reactions (which is necessary in cases of both urgent and prolonged antidiarrheal therapy in combination with heavy fluid intake during an attack of delayed diarrhea). For such patients, strict surveillance in a hospital is recommended.

In the case of monotherapy with irinotecan, it is usually prescribed every 3 weeks.However, those patients who require enhanced surveillance, and those who are at particular risk of developing severe neutropenia, may administer the drug once a week.

Deferred diarrhea

Patients should be warned about the risk of developing delayed diarrhea, which may occur more than 24 hours after the administration of irinotecan, as well as at any other time before the next cycle. In the case of monotherapy, the average time of the first appearance of the liquid stool occurred on the 5th day after the administration of irinotecan. Patients should promptly notify their attending physician of the occurrence of diarrhea and immediately begin appropriate treatment.

The groups at increased risk of developing diarrhea include patients who have previously undergone abdominal / pelvic radiation therapy, patients with hyperleukocytosis before starting therapy; patients with a functional status ≥2 on the WHO scale, as well as women. If improperly treated, diarrhea can be life threatening, especially if the patient suffers from concomitant neutropenia.

At the first signs of a loose stool, the patient should begin to consume a large number of solutions containing electrolytes, and he must immediately begin adequate antidiarrheal treatment.Such treatment should be prescribed in the same clinical unit where it was assigned irinotecan. Immediately after discharge from the hospital, patients should purchase prescribed medications to immediately begin treatment for diarrhea in the event of its manifestation. In addition, in the case of diarrhea, they must inform their doctor or clinic where they were assigned irinotecan.

Currently, recommended antidiarrheal treatment is to take high doses of loperamide (4 mg for the first time, then 2 mg every 2 hours). This treatment should continue for 12 hours after the last episode of a loose stool, and should not be altered. In no event should you apply loperamide at a given dosage for more than 48 hours in a row due to the risk of developing paralytic ileus, and the drug should not be used for less than 12 hours.

In addition to antidiarrhoeal treatment, antibiotics of a broad spectrum of action should be used for preventive purposes if diarrhea is accompanied by acute neutropenia (neutrophil count <500 cells / mm³).

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

- Diarrhea is accompanied by a fever,

- Severe form of diarrhea (requiring intravenous hydration),

- Diarrhea lasts more than 48 hours after the start of high-dose therapy with loperamide. Loperamide Do not prescribe for prophylactic purposes, even for patients who have had deferred diarrhea in previous treatment cycles.

For patients who have experienced severe diarrhea, it is recommended that the dosage be reduced in subsequent cycles of treatment in accordance with the recommendations in the section on "Method of administration and dose".

Hematologic aspects

In the treatment of irinotecan, it is recommended that a detailed blood test be performed on a weekly basis with the counting of the formed elements. Patients should be warned about the risk of developing neutropenia and the significance of fever. Febrile neutropenia (body temperature> 38 ° C and neutrophil count ≤ 1000 cells / mmD requires urgent hospitalization and intravenous treatment with broad-spectrum antibiotics in a hospital setting.

In patients who underwent severe hematologic abnormalities,it is recommended to reduce the dosage of the drug with subsequent administration in accordance with the recommendations given in the section "Method of administration and dose".

In patients with severe diarrhea, the risk of infection and hematologic toxicity is increased. Such patients should undergo an extensive clinical blood test with the counting of blood cells.

Patients homozygous for alleles 28 and 6 of the uridine diphosphate glucuronosyltransferase gene (UGT1A1)

Patients with Kriegler-Nayyar syndrome (1 and 2 types) and homozygous for UGT1A1 * 28 and / or UGT1A1 * 6 (Gilbert syndrome) are at increased risk of developing grade 3 and 4 hematologic toxicity after medium and high doses of irinotecan (> 150 mg / m²). The relationship between the UGT1A1 genotype and the occurrence of diarrhea caused by irinotecan has not been established.

Patients homozygous for alleles 28 and 6 of the UGT1A1 gene should be given the usual starting dose of irinotecan. However, in such patients, hematologic toxicity should be monitored. Patients who demonstrated hematologic toxicity in previous treatment should consider reducing the starting dose of the drug.For this population of patients are no clear recommendations to reduce the dose, dose adjustment should be based on individual tolerability.

Liver failure

Before the beginning of treatment, and also before the beginning of each cycle, it is necessary to conduct a study of liver function.

In patients with bilirubin levels greater than the ULN 1.5-3 times, it is necessary to conduct a detailed analysis of weekly blood counts of the elements in relation to the reduced clearance of irinotecan, which increases the risk of hematologic toxicity in this group of patients. If the level of bilirubin in a patient exceeds the VGN more than 3 times, the use of irinotecan is contraindicated.

Nausea and vomiting

Before each introduction of irinotecan, a preventive treatment with antiemetic drugs is recommended. There were reports of frequent cases of nausea and vomiting. Patients who are on a background of delayed diarrhea appears vomiting, should be hospitalized as soon as possible for proper treatment.

Acute cholinergic syndrome

In the case of development of acute cholinergic syndrome (characterized by early diarrhea and a number of other symptoms such as increased sweating, abdominal cramps, miosis, excessive salivation), in the absence of contraindications, the use of atropine sulfate (0.25 mg subcutaneously) is indicated. Special precautions should be observed when treating patients with asthma. For patients who have experienced acute and severe cholinergic syndrome, the subsequent administration of irinotecan recommends the preventive use of atropine sulfate.

Respiratory system disorders

When using irinotecan, it is not often possible to develop interstitial lung lesions, manifested as pulmonary infiltrates. Interstitial lesions of the lung tissue can lead to death. The risk factors likely associated with interstitial lung lesions include the use of pneumotoxic drugs, radiotherapy and colony-stimulating factors. Patients with risk factors should be carefully monitored for the presence of respiratory symptoms before and during therapy with irinotecan.

Extravasion

Despite the lack of information on the irritant properties of irinotecan, caution should be exercised to prevent extravasation; The place of administration should be monitored for signs of inflammation. In the case of extravasation, the infusion should be stopped immediately and local symptomatic treatment started. The remaining dose of the drug should be injected into another vein. It is recommended to wash the place of extravasation and apply ice.

Elderly patients

In connection with the high probability of reducing biological functions, especially liver function, patients of this group should carefully select the dosage of irinotecan. Patients in this group need to be closely monitored.

Patients with chronic inflammatory bowel diseases and / or with intestinal obstruction

Patients in this group should not be treated with irinotecan until the intestinal obstruction is eliminated.

Patients with renal insufficiency

Studies in this group of patients were not conducted.

Heart Disease

There have been reports of cases of myocardial ischemia after irinotecan therapy, mainly in patients with concomitant heart disease,risk factors for the development of heart disease, as well as in patients who received chemotherapy earlier with cytotoxic drugs (see section "Side effect.") Accordingly, patients with known risk factors should be closely monitored, and, if possible, measures should be taken to minimize controlled risk factors (such as smoking, high blood pressure, hyperlipidemia).

Immunosuppression / hypersensitivity to infections

Introduction of a live or diluted vaccine to patients with a decreased immune status due to treatment with antitumor chemotherapeutic drugs, including irinotecan, can lead to the development of serious or fatal infections. It is necessary to avoid the use of live vaccine in patients receiving irinotecan treatment. Killed or inactivated vaccines can be used, but the response to such vaccines can be weakened.

Other patient groups

Since the irinotecan medak contains sorbitol, the drug should not be used in patients with a rare hereditary intolerance to fructose.

Infant renal failure, lowering blood pressure, or circulatory failure in patients with cases of dehydration due to diarrhea and / or vomiting, or sepsis has been reported infrequently.

The combined use of strong inhibitors with irinotecan (for example, ketoconazole) or inductors (for example, rifampicin, carbamazepine, phenobarbital, phenytoin, preparations of St. John's wort perforated) cytochrome P450 ZA4 (CYP3A4) can disrupt the metabolism of irinotecan and should be avoided.

Fertility

Women of childbearing age and men should use effective contraception during treatment with irinotecan and for at least 3 months after the end. In case of pregnancy, women should immediately inform their doctor about this. Data on the effects of irinotecan on childbearing function in humans are absent. There are data on the effect of irinotecan on childbearing function in offspring in animals.

Effect on the ability to drive transp. cf. and fur:Patients should be warned about possible dizziness or visual disturbances that can develop within 24 hours after the application of irinotecan.When these symptoms appear, patients should refrain from driving and using equipment.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 20 mg / ml.

Packaging:

2 ml (40 mg), 5 ml (100 mg) or 15 ml (300 mg) in a bottle of brown glass, corked with a rubber stopper and crimped with an aluminum cap with a polymer protective cap.

One vial with instructions for use in a cardboard pack.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C.

Do not freeze.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001030

Date of registration:18.10.2011 / 10.05.2017

Expiration Date:Unlimited

The owner of the registration certificate:medac GmbHmedac GmbH Germany

Manufacturer: & nbsp

ONCOTEC PHARMA PRODUKTION, GmbH Germany

Representation: & nbspKorPharma, Open CompanyKorPharma, Open CompanyRussia

Information update date: & nbsp30.11.2017

Illustrated instructions

Instructions

Irynotekan medak (Irinotecan medac)