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Composition:


active ingredient: irinotecan;


1 ml of the concentrate contains irinotecan hydrochloride trihydrate 20 mg (in terms of irinotecan 17.33 mg);

excipients: lactic acid, sorbitol (E 420), sodium hydroxide, water for injection.


Dosage form. Concentrate for preparing a solution for infusions.


Basic physical and chemical properties: clear yellow solution.


Pharmacotherapeutic group.


Antineoplastic agents. ATX code L01X X19.


Pharmacological properties.


Pharmacodynamics.


Irinotecan is a semi-synthetic derivative of Camptothecin. It is an antitumor drug that is a specific inhibitor of DNA topoisomerase I. under the action of carboxyl esterase in most tissues, the drug is metabolized to the compound SN-38, which is more active against purified topoisomerase I and more cytotoxic compared to irinotecan against a number of human and mouse tumor cell lines.  Inhibition of DNA topoisomerase and under the action of irinotecan or SN-38 causes damage to one DNA strand, which blocks the replication fork and leads to cytotoxic effects. This cytotoxic effect was found to be time-dependent and specific to the S-phase of the cell cycle.


Irinotecan and SN-38 were not found in vitro to be significantly recognized by P-glycoprotein, a multi-resistant protein, and to have cytotoxic effects on cell lines resistant to doxorubicin and vinblastine.


In addition, irinotecan has a broad spectrum of antitumor activity in vivo against mouse tumor models (pancreatic ductal adenocarcinoma P03, breast adenocarcinoma MA16/C, colon adenocarcinoma C38 and C51) and human tumor xenografts (colon adenocarcinoma Co-4, breast adenocarcinoma MX-1, gastric adenocarcinoma ST-15 and St-16). Irinotecan is also effective against tumors expressing P-glycoprotein, a multi - resistant protein (vincristine and doxorubicin-resistant leukemia P 388).


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


Pharmacokinetics / pharmacodynamics.


The severity of the main manifestations of toxicity observed with the use of the drug (for example, leukopenia and diarrhea) is associated with the level of exposure (AUC) of the active substance and the SN-38 metabolite. 


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 inactive SN-38-glucuronide (SN-38g). The UGT1A1 gene is characterized by a high polymorphism, which ensures the presence of various variants of metabolic intensity in the group. 1 a particular variant of the UGT1A1 gene contains a polymorphic region in the promoter region; this variant is called UGT1A1*28. This variant, as well as other hereditary disorders of UGT1A1 expression (such as Gilbert's syndrome or Krigler-Nayyar syndrome), are associated with reduced activity of this enzyme. The results of the meta-analysis indicate that patients with Krigler-Nayyar syndrome (types 1 and 2) or with UGT1A1*28 and/or UGT1A1*6 (Gilbert's syndrome) are at an increased risk of hematological toxicity (grades 3 and 4) after administration of medium or high doses of irinotecan (>150 mg/m2). The relationship between the UGT1A1 genotype and the occurrence of diarrhea due to irinotecan has not been established.


Patients who are known homozygotes for the UGT1A1*28 and/or UGT1A1*6 alleles should receive the usual initial dose of irinotecan. At the same time, such patients should be monitored for manifestations of hematological toxicity. For patients who have already experienced hematological toxicity during previous courses of treatment, consideration should be given to reducing the initial dose of irinotecan. The exact amount of initial dose reduction in this group of patients has not been established. Any further dosage changes should be made depending on how the patient tolerates treatment.


To date, there are insufficient clinical data to conclude that genotyping of patients by UGT1A1 alleles is appropriate.


Pharmacokinetics.


In a Phase I study involving 60 patients treated with irinotecan at doses ranging from 100 to 750 mg/m2 as a 30-minute intravenous infusion every 3 weeks, two - or three-phase plasma elimination of irinotecan was observed. The average plasma clearance of irinotecan was 15 L/H/m2, and the volume of distribution at steady state (Vss) was 157 L/m2. The average plasma half – life during the first phase of the three – phase model was 12 minutes, during the second phase-2.5 hours, during the third phase-14.2 hours. Plasma elimination of SN-38 was biphasic with an average final half-life of 13.8 hours.


At the end of the infusion, at the recommended dose of 350 mg/m2 of body surface area, the average maximum plasma concentrations were 7.7 mcg/ml for irinotecan and 56 g/mL for SN-38, and the average area values under the pharmacokinetic curve (AUC) were 34 MCG•H/ML and 451 ng•H/mL, respectively. SN-38 is usually characterized by pronounced individual changes in pharmacokinetic characteristics.


The population pharmacokinetics of irinotecan were analyzed in a sample of 148 patients with metastatic colorectal cancer. These patients received irinotecan at different doses and according to different dosage regimens in Phase II studies. The pharmacokinetic parameters established using the three-chamber model were similar to those obtained during Phase I Studies. The results of all studies show that exposure to irinotecan (CPT-11) and SN-38 increases in proportion to the dose of CPT-11. the pharmacokinetics of these compounds do not depend on the number of previous treatment cycles and dosage regimen.


Plasma protein binding for irinotecan and SN-38 in vitro was approximately 65% and 95%, respectively.


Studies of the mass balance and metabolism of irinotecan labeled with the 14C isotope have shown that more than 50% of the intravenous dose is excreted unchanged, with 33% excreted in the faeces, mainly in bile, and 22% in the urine.


Each of the 2 metabolic pathways listed below provides conversion of at least 12% of the dose:


- hydrolysis under the action of carboxylesterase with the formation of the active metabolite SN-38, which is mainly eliminated from the body by glucuronidation, followed by elimination of the glucuronic conjugate through the liver and kidneys (less than 0.5% of the irinotecan dose). It is believed that SN-38-glucuronide further undergoes hydrolysis in the intestinal tract;


- oxidation by cytochromes P450 3A leads to the rupture of the outer piperidine ring to form an aminopepnatoic acid derivative and a primary Amine derivative.


Unchanged irinotecan makes up the main fraction of the drug in blood plasma. Other components, in order of decreasing volume fraction, are the aminopepnatoic acid derivative, SN-38-glucuronide, and SN-38. only SN-38 has a significant cytotoxic effect.


Irinotecan clearance decreases by approximately 40% in patients with bilirubin, whose bilirubin levels exceed the ULN by 1.5–3 times. In such patients, a dose of irinotecan of 200 mg/m2 leads to plasma exposure of the drug, which is comparable to that at a dose of 350 mg/m2 in cancer patients with normal liver function parameters.


Clinical characteristics.

Indications.


For the treatment of advanced colorectal cancer:


* in combination with 5-fluorouracil and folinic acid in patients who have not previously received chemotherapy to treat a common disease;


* as monotherapy in patients for whom the established treatment regimen with 5-fluorouracil was ineffective.


In combination with cetuximab, irinotecan medac is used to treat metastatic colorectal cancer with the wild-type KRAS gene expressing epidermal growth factor receptors in patients who have not previously received treatment for metastatic cancer or for whom cytotoxic treatment with irinotecan has been ineffective.


In combination with 5-fluorouracil, folinic acid and bevacizumab, irinotecan medac is used as a first-line therapy in patients with metastatic colon or rectal carcinomas.


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


Contraindications.


- Chronic inflammatory bowel diseases and / or intestinal obstruction;


- a history of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to any of the excipients of the drug;


- breast-feeding period;


- the level of bilirubin in the blood, which is 3 times higher than the upper limit of normal;


- severe bone marrow failure;


- general condition of the patient > 2 (according to the WHO classification);


- concomitant use of St. John's wort.


In the case of combined treatment with cetuximab or bevacizumab, see additional contraindications given in the instructions for medical use of the corresponding medications. 


Special security measures.


As with other antineoplastic agents, precautions should be taken regarding the safe handling of irinotecan medac during dilution and use. Wear safety glasses, a mask, and gloves when handling this medicine.


If the concentrate or the resulting infusion solution accidentally gets on the skin, it should be washed immediately and thoroughly with soap and water. If the concentrate or the resulting infusion solution gets on the mucous membranes, they should be immediately rinsed with water.


Preparation of a solution for intravenous administration.


A solution of irinotecan Medak for infusions should be prepared under aseptic conditions.


If any sediment is observed in the vials after dilution of the concentrate, the drug should be destroyed in accordance with standard procedures for cytostatics.


Observing aseptic conditions, the required amount of concentrate is taken from the vial using a calibrated syringe and injected into an infusion bag with a capacity of 250 ml or into a vial containing either 0.9% sodium chloride solution or 5% glucose solution. The infusion solution should be thoroughly mixed by rotating the bottle manually.


Recycling


All materials used for dilution and administration of the drug should be destroyed in accordance with standard procedures for cytostatics.


Interactions with other drugs and other types of interactions.


Interactions between irinotecan and drugs that cause neuromuscular blockade cannot be excluded. Since irinotecan exhibits anticholinesterase activity, the duration of neuromuscular blockade under the action of suxamethonium may increase, and antagonistic interaction with neuromuscular transmission is also possible when used concomitantly with non-depolarizing muscle relaxants.


The results of several studies have shown that concomitant use of anticonvulsant CYP3A inducers (such as carbamazepine, phenobarbital, or phenytoin) reduces the level of exposure to irinotecan, SN-38, and SN-38-glucuronide and leads to a decrease in the pharmacodynamic effect. The effect of such anticonvulsants was to reduce the AUC for SN-38 and SN-38-glucuronide by 50% or even more. In addition to induction of cytochrome P450 3A, reduced exposure to irinotecan and its metabolites may also be due to increased glucuronidation and more intensive bile excretion.


As a result of the study, it was found that concomitant use of ketoconazole resulted in an 87% decrease in the AUC of the ARS metabolite, and the AUC of the SN-38 metabolite decreased by 109% compared to the use of irinotecan as monotherapy.


Caution should be exercised when co-administration of drugs that are inhibitors (ketoconazole) or inducers (rifampicin, carbamazepine, phenobarbital or phenytoin) of drugs metabolized by the cytochrome P450 3A4 system. Concomitant use of irinotecan with inhibitors or inducers of this metabolic process may disrupt the metabolism of irinotecan, so this combination of drugs should be avoided. In a small pharmacokinetic study (n = 5), where irinotecan at a dose of 350 mg/m2 of body surface was administered in combination with St. John's wort (Hypericum perforatum) at a dose of 900 mg, a decrease in the concentration of SN-38, the active metabolite of irinotecan, in blood plasma was observed by 42 %.


St. John's wort reduces the level of SN-38 in blood plasma. Therefore, St. John's wort should not be used simultaneously with irinotecan.


Concomitant administration of 5-fluorouracil and folinic acid with a combined treatment regimen does not change the pharmacokinetics of irinotecan.


Atazanavir sulfate. Concomitant use of irinotecan with atazanavir sulfate (a potent inhibitor of CYP3A4 and UGT1A1) may increase systemic exposure to the active metabolite of irinotecan SN-38. 


Interactions inherent in all cytotoxic drugs.


Patients with tumors have an increased risk of developing thromboembolic events. Therefore, anticoagulants are usually used in such patients. If there are indications for the use of anticoagulants-vitamin K antagonists, it is necessary to monitor the indicator of the international normalized ratio more often than usual. This is due to the narrow therapeutic range of these drugs, the high individual variability of blood thrombogenicity indicators, and the possibility of interaction between anticoagulants for internal use and anti-cancer chemotherapeutic drugs.


Concomitant use is contraindicated.


- Yellow fever vaccine-the risk of developing a generalized reaction to the vaccine with a fatal outcome.


Concomitant use is not recommended:


- Live attenuated vaccines (with the exception of the yellow fever vaccine) – risk of developing systemic diseases with a possible fatal outcome (for example, infectious diseases). This risk increases in patients with suppressed immunity due to the underlying disease. Inactivated vaccines should be used if they exist (polio).


- Phenytoin-the risk of exacerbation of seizures due to a decrease in the intensity of phenytoin uptake in the digestive tract under the influence of a cytotoxic drug; the risk of increased toxicity due to an increase in the intensity of hepatic metabolism under the influence of phenytoin.


Use with caution.


Cyclosporine and tacrolimus are the risk of excessive suppression of the immune system with the risk of developing lymphocyte proliferation.


There is no information on the effect of cetuximab on the safety profile of irinotecan or on the similar effect of irinotecan on cetuximab.


In one study, irinotecan concentrations were similar in patients treated with irinotecan/5-FU/FC alone and irinotecan/5-FU/FC in combination with bevacizumab. In a subgroup of patients (approximately 30 people per treatment group), the concentration of the active metabolite irinotecan (SN-38) in blood plasma was analyzed. SN-38 concentrations were on average 33% higher in patients treated with irinotecan/5-FU/FC in combination with bevacizumab compared to patients treated with irinotecan/5-FU/FC as monotherapy. Due to the high interpersonal variability of indicators and limited sample size, it is impossible to determine exactly whether the increase in SN-38 concentration is associated with bevacizumab. In the treatment group treated with bevacizumab, there was a slight increase in diarrhea and leukopenia. Patients who used irinotecan / 5-FU/FC in combination with bevacizumab were more likely to reduce the dose of irinotecan.


For patients who experience severe diarrhea, leukocytopenia, or neutropenia when using a combination of bevacizumab and irinotecan, the dose of irinotecan should be adjusted.

Dosage and administration.


The drug is intended for the treatment of adults only. After dilution, irinotecan infusion solution is injected into the peripheral or central vein.


Monotherapy (for patients who have previously received treatment).


The recommended dose of irinotecan is 350 mg/m2 and is administered by intravenous infusion lasting 30-90 minutes every 3 weeks.


Combined treatment (for patients who have not previously received treatment).


The efficacy and safety of the drug in combination with 5-fluorouracil (5-FU) and folinic acid (FC) were evaluated according to the following dosage regimen.


Irinotecan/5-FU / FC 1 time in 2 weeks.


The recommended dose of irinotecan is 180 mg/m2 1 time in 2 weeks as an intravenous infusion for 30-90 minutes, after which folic acid and 5-Fluorouracil are administered.


Information about the dose and methods of concomitant administration of cetuximab can be found in the description of this drug. Usually, the same dose of irinotecan is used as in previous courses of treatment using regimens that include irinotecan. Irinotecan should be administered no earlier than 1 hour after the end of the cetuximab infusion.


Information about the dose and method of administration of bevacizumab can be found in the instructions for use of this medicine.


Dose selection.


Irinotecan should be administered after all side effects have completely disappeared according to the NCI-CTC rating scale (general toxicity criteria of the US National Cancer Institute) with a severity of 0 or 1, and when treatment-related diarrhea completely disappears.


At the beginning of the next infusion, the dose of irinotecan and 5-FU, if used, should be reduced in accordance with the highest level of toxicity observed during the previous infusion. Treatment should be postponed for 1-2 weeks until the side effects associated with the use of the drug disappear.


If the following side effects occur, the dose of irinotecan and/or 5-FU, if used, should be reduced by 15-20 %:


* hematological symptoms of toxicity (neutropenia of the 4th level of toxicity, neutropenia accompanied by fever (neutropenia of the 3rd-4th levels of toxicity and fever of the 2nd-4th levels of toxicity), thrombocytopenia and leukopenia (4th level of toxicity));


* non-hematological symptoms of toxicity (levels 3-4).


You should follow the recommendations for adjusting the dose of cetuximab when using it in combination with irinotecan according to the information provided in the instructions for use of this drug.


Information on dose modification of bevacizumab in combination treatment with bevacizumab with irinotecan/5-FU/FC can be found in the instructions for use of this drug.


Patients over 65 years of age with irinotecan and capecitabine are recommended to reduce the dose of capecitabine to 800 mg/m2 of body surface area 2 times a day according to the instructions for medical use of capecitabine. See also the recommendations for changing the dose of the combination of drugs given in the instructions for medical use of capecitabine.


Duration of treatment.


Treatment with irinotecan medac should be continued as long as there is an objective progression of the disease or unacceptable symptoms of toxicity.


Special groups of patients.


Patients with impaired liver function


Monotherapy


In patients with a general condition index ≤ 2, the initial dose of irinotecan medac should be determined by the level of bilirubin in the blood (if the bilirubin level increases above the upper limit of normal by no more than 3 times). In such patients with hyperbilirubinemia and prothrombin time, the clearance of irinotecan decreases by more than 50%, so the risk of hematotoxicity increases. Therefore, this group of patients should have a complete blood test performed weekly.


* For patients with bilirubin levels exceeding the ULN by ≤ 1.5 times, the recommended dose of irinotecan is 350 mg/m2.


* For patients with bilirubin levels exceeding the ULN by 1.5–3 times, the recommended dose of irinotecan is 200 mg/m2.


* Patients with bilirubin levels > 3 times higher than the ULN should not use irinotecan.


Combined treatment


There are no data on patients with hepatic insufficiency who received irinotecan during combination therapy.


Patients with impaired renal function


Irinotecan is not recommended for use in patients with impaired renal function, as no studies have been conducted in this group of patients.


Elderly patients


Special pharmacokinetic studies have not been conducted in elderly patients. Caution should be exercised when selecting the dose on a case-by-case basis due to the natural decrease in biological functions. This group of patients requires closer monitoring.


Children.


Irinotecan is prescribed only for adults.


Overdose.


There have been reports of overdose, which can be fatal, when using doses of the drug that were approximately twice the recommended therapeutic dose. The most significant adverse reactions were severe neutropenia and severe diarrhea. There is no known antidote to irinotecan medac. The most intensive maintenance treatment should be carried out to prevent dehydration due to diarrhea and to cure possible infectious complications.

Tags: Irinotecan