Irinotel - instructions for use, dose, side effects, contraindications

Active substance:
Irinotecan hydrochloride trihydrate	20.0 mg
Excipients:
Sorbitol	45.0 mg
Lactic acid	0.9 mg
Hydrochloric acid	q.s. to adjust the pH value
Sodium hydroxide	q.s. to adjust the pH value
Water for injections	q.s. up to 1 ml

Description:

A clear solution of light yellow color.

Pharmacotherapeutic group:Antitumor agent - alkaloid

ATX: & nbsp

L.01.X.X.19 Irynotekan

Pharmacodynamics:

Irinotecan, a semi-synthetic derivative of camptothecin, is a specific inhibitor of the cellular enzyme topoisomerase I. In tissues irinotecan metabolized to form an active metabolite SN-38, which surpasses it in its activity. Irynotekan and metabolite SN-38 stabilize the topoisomerase I complex with DNA, which prevents its replication. In the experiments in vivo it was shown that irinotecan is also active against tumors expressing the P-glycoprotein of multiple drug resistance (vincristine and doxorubicin-resistant leukemias P388).

Pharmacokinetics:

The pharmacokinetics of irinotecan and SN-38 (its active metabolite) was studied with a 30-minute intravenous infusion of the drug at a dose of 100-750 mg / m². The pharmacokinetic profile of irinotecan is dose independent.

Irinotecan is metabolized by various enzyme systems, including esterases, resulting in the formation of a metabolite SN-38.

Inactive metabolite SN-38G is formed by the mediated uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) glucuronization. Irynotekan can also be subjected to oxidative metabolism mediated by an isoenzyme CYP3A4, which leads to the formation of pharmacologically inactive oxidation products, one of which can be hydrolysed with carboxyl esterases to form SN-38.

The distribution of irinotecan in blood plasma is two- or three-phase. The average half-life of irinotecan in the blood 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. 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 surface of the body.

It is allocated by the kidneys in an unchanged form (an average of 19.9%) and in the form of metabolite SN-38 (0.25%). About 30% of the drug is excreted in the bile, both in the unchanged form and in the form of the metabolite SN-38 glucuronide.

The association with blood plasma proteins for irinotecan is approximately 65%, for SN-38 - 95%.

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

Indications:

The drug Irinotel is intended for the treatment of patients with locally advanced or metastatic colorectal cancer:

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

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

Contraindications:

- Hypersensitivity to irinotecan or other components of the drug;

- chronic inflammatory bowel disease and / or intestinal obstruction;

- pronounced oppression of bone marrow hematopoiesis:

- the concentration of bilirubin in the blood serum, which exceeds the upper limit of the norm by more than 3 times:

- general condition of patients, assessed on a scale ECOG (Eastern Cooperative Oncology Group) >2;

- simultaneous application with the yellow fever vaccine:

- pregnancy and the period of breastfeeding:

- children's age (data on safety and effectiveness in children are absent).

Carefully:

Radiation therapy (in the anamnesis) on the abdominal or pelvic area (high risk of myelosuppression), leukocytosis, female patients (increased risk of diarrhea),renal failure (safety data absent), hypovolemia, increased risk of venous thromboembolic complications, elderly age.

Pregnancy and lactation:

Irinotecan can cause fetal damage when used in pregnant women. Adequate well-controlled studies of the use of irinotecan in pregnant women have not been conducted.

Patients of childbearing age and their partners should use reliable contraceptive methods during therapy and within three months after completion of treatment. If irinotecan is used during pregnancy, or pregnancy occurred during the period of irinotecan therapy, the patient should be warned about possible harm to the fetus.

For the duration of the drug, breastfeeding should be discontinued.

Dosing and Administration:

The drug is intended only for adults.

The drug Irinotel is used both in the form of monotherapy, and in combination with fluorouracil and calcium folate. When choosing a dose and mode of administration, you should refer to the special literature. The drug Irinotel is administered as an intravenous infusion lasting at least 30 minutes and not more than 90 minutes.

In the monotherapy regime the drug Irinotel is used at a dose of 125 mg /m² body surface weekly for 4 weeks in the form of a 90-minute intravenous infusion with a break of 2 weeks, as well as 350 mg /m² in the form of a one hour intravenous infusion every 3 weeks.

As part of combined chemotherapy with fluorouracil and calcium folinate, the dose of Irinotel is 125 mg / m once weekly², when administered by continuous infusion once every 2 weeks - 180 mg / m². Doses and administration of fluorouracil and calcium folinate are described in detail in the literature.

With any of the proposed schemes of drug use Irynotekan Therapy should be continued as long as there is a response to treatment or there is no growth of the tumor. It is necessary to constantly monitor the patient's condition during the development of toxicity, which is not compensated by a reduction in the dose of the drug and maintenance therapy.

Recommendations for dose modification

In the monotherapy regime reduction of the initial dose of the drug Irinotel from 125 mg / m² up to 100 mg / m² and from 350 mg / m² up to 300 mg / m², as well as a reduction in the dose of 125 mg / m² up to 100 mg / m² and from 180 mg / m² up to 150 mg / m² in the regime of combined therapy can be recommended to patients aged 65 years and older, with previous extensive radiation therapy, with an overall patient status of 2, with increased bilirubin concentration in the blood, with concomitant stomach cancer.

When using Irinotel in combination with capecitabine in patients aged 65 years and older, the dose of capecitabine should be reduced to 800 mg / m³ twice a day, according to the instructions for the use of capecitabine. You should also refer to the guidelines for the use of capecitabine in combination therapy in specialist literature.

The administration of Irinotel 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. 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 platelet count below 100,000 / μl), or febrile neutropenia (neutrophil counts 1000 / μL or less in combination with fever over 38 ° C), or infectious complications, or severe diarrhea, or other non-hematologic toxicity of 3-4 degrees , subsequent doses of irinotel and, if necessary, fluorouracil should be reduced by 15-20%.

If there is an objective indication of the progression of a malignant neoplasm or the development of uncontrolled toxicity, therapy with irinothel should be discontinued.

Patients with impaired hepatic function

At a concentration of bilirubin in the blood serum that exceeds the upper limit of the norm by no more than 1.5 times, in connection with the increased risk of development of severe neutropenia, blood parameters in patients should be closely monitored. With an increase in the concentration of bilirubin more than 3 times, treatment with Irinotel should be discontinued.

Patients with impaired renal function

Safety and efficacy data are not available. The drug should be used with caution. The drug is not recommended for patients receiving hemodialysis.

Elderly patients

There are no specific features of the use of the drug Irinotel in the elderly. The dose of the drug in each case should be selected with caution. It is necessary to carefully monitor the condition of patients aged 65 years and older due to an increased risk of developing early diarrhea in this group of patients.

Instructions for preparing a solution for infusion

The solution of the preparation Irinotel should be prepared in aseptic conditions.

The required amount of the drug should be diluted in 250 ml of a 5% solution of dextrose or 0.9% solution of sodium chloride and mix the resulting solution by rotating the container or vial. Before administration, the solution should be visually inspected for clarity, presence of mechanical inclusions, sediment or discoloration. If found, the drug must be disposed of.

The solution of the drug Irinotel should be used immediately after dilution.

If the dilution is performed in accordance with aseptic rules (for example, in a laminar air flow installation), the irinotel solution may be used for 12 hours (including infusion time) if stored at room temperature, and within 24 hours after opening the vial with concentrate Storage at a temperature of 2 ° C - 8 ° C.

Side effects:

The frequency of unwanted reactions is represented by 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	Can not be determined from existing data

On the part of 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. The complete recovery of neutrophil counts usually occurred on the 22nd day with the use of Irinotel in monotherapy and on the 7-8th day with Irinotel as a combination chemotherapy. Fever in combination with severe neutropenia was noted in 6.2% and 3.4% of patients, respectively. Infectious complications with monotherapy took place in 10.3% of patients, in 5.3% of patients they were combined with severe neutropenia.

With the use of the drug Irinotel in monotherapy, moderate anemia developed in 58.7% of patients. When using Irinotel in combination chemotherapy anemia was observed in 97.2%.

When using the drug Irinotel in monotherapy of thrombocytopenia (<100 000 cells / μl) was observed in 7.4% (with combined chemotherapy in 32.6%) patients. When using the drug Irinotel as part of combined chemotherapy, severe thrombocytopenia was not observed. The number of platelets is restored to the 22nd day.

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 extremities, thromboembolism of lower extremity vessels, cardiac arrest, myocardial infarction, cardiac ischemia, circulatory disorders in peripheral vessels, pulmonary embolism , 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 drug is used (delayed diarrhea) is a dose-limiting toxic effect of Irinotel.

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 Irinotel was 5 days.

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

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

Acute cholinergic syndromeManifesting such symptoms as early diarrhea (diarrhea occurring within 8 hours after the administration of irinotecan), abdominal pain, conjunctivitis, rhinitis, lowering blood pressure, bradycardia, vasodilation, enhanced intestinal motility, sweating, fever, malaise, dizziness, visual disturbances, myosis, lacrimation, salivation was observed in 9% of patients receiving Irinotel drug in monotherapy and as part of combination chemotherapy only in 1.4% of patients.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.

OtherAlopecia, fever, transient speech disorders, local reactions, transient increase in the activity of transaminases, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, creatinine and urea nitrogen in the blood serum, hypokalemia, hypomagnesemia, hyponatremia, weight loss, pain, dehydration, hypovolemia, sepsis , syncope, cardiovascular disorders, genitourinary system infections, chest pain, 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 due to combined therapy with irinotecan and capecitabine (additional to those usually observed with capecitabine in monotherapy or occurring more often with combination therapy than with capecitabine alone): thrombosis / thromboembolism, hypersensitivity reactions, ischemia / myocardial infarction, febrile neutropenia.

Overdose:

The main expected manifestations of an overdose are neutropenia and diarrhea. The specific antidote to irinotecan is unknown. Treatment is symptomatic. In case of an overdose, the patient should be hospitalized and carefully monitor the function of vital organs.

Interaction:

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.

With the combined use of irinotecan with myelosuppressive drugs and radiation therapy, the toxic effect on the bone marrow (leukopenia, thrombocytopenia) is aggravated.

When combined with irinotecan with glucocorticosteroid drugs (eg, with dexamethasone), the risk of developing hyperglycemia increases (especially in patients with diabetes mellitus or with reduced glucose tolerance) and lymphocytopenia.

With the combined use of irinotecan with diuretics, dehydration, resulting from diarrhea and vomiting, can be aggravated.

Joint use of laxatives against irinotecan therapy may aggravate the frequency or severity of diarrhea.

Joint intake of irinotecan and prochlorperazine increases the likelihood of manifestation of signs of akathisia.

In the joint application of irinotecan with preparations of plant origin on the basis of St. John's wort (perforated (Hypericum perforatum), as well as with anticonvulsant drugs - inducers CYP3A (carbamazepine, phenobarbital and phenytoin) is the concentration in the plasma of the active metabolite SN-38 decreases. One should evaluate the possibility of taking anticonvulsant drugs that do not induce isoenzymes, or switching to them at least one week before starting irinotecan therapy in patients who need anticonvulsant drugs.Hypericum perforatum should not be taken concomitantly with irinotecan, it should be discontinued at least one week before starting therapy with irinotecan.

Irinotecan and active metabolite SN-38 metabolized by isoenzyme CYP3A4 and UTT1A1. Simultaneous application of irinotecan and inhibitors of isoenzyme CYP3A4 and / or UGT1A1 may lead to an increase in the systemic exposure of irinotecan and the active metabolite SN-38. This should be taken into account when using irinotecan with such drugs.

Joint reception of irinotecan with atazanavir, inhibitor of isoenzymes CYP3A4 and UGT1A1, as well as with ketoconazole may cause an increase in the concentration in the blood plasma of the active metabolite SN-38. This must be taken into account when taking these drugs at the same time. Ketoconazole should be discontinued at least one week before the start of therapy and do not take ketoconazole during therapy with irinotecan.

Irinotecan should not be mixed with other drugs in one bottle.

The introduction of a live or diluted vaccine to patients undergoing antitumor treatment, including irinotecan, can lead to serious or fatal infections. It is necessary to avoid vaccination with live vaccine in patients receiving irinotecan. A killed or inactivated vaccine can be administered, but the response to such a vaccine can be weakened.

With simultaneous use of irinotecan and bevacizumab, no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its metabolite SN-38, nevertheless this does not exclude an increase in mutual toxicity.

Interactions characteristic of all antitumor drugs

In patients with tumorous diseases, the use of anticoagulants is a common practice in view of the increased risk of thrombotic events. If the use of vitamin K antagonists is indicated, the International Normalized Relationship (INR) values should be monitored more often. This is due to the fact that this group of drugs has a narrow therapeutic index, as well as due to the high intra-individual variability of the ability for blood clots and the possibility of interaction between oral anticoagulants and antitumor drugs.

Simultaneous use is contraindicated:

- yellow fever vaccine: the risk of a systemic reaction to vaccines, including fatal.

Simultaneous use is not recommended:

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

- Phenytoin: the risk of exacerbation of seizures due to a decrease in the absorption of phenytoin in the gastrointestinal tract against a background of simultaneous use with antitumor drugs or an increased risk of increased toxicity against a background of more active metabolism in the liver induced by phenytoin.

Use with caution:

- cyclosporine, tacrolimus: significant immunosuppression with risk of lymphoproliferation.

There is no information that irinotecan is affected by cetuximab or vice versa.

Special instructions:

Treatment with Irinotel should be carried out in specialized chemotherapy departments under the supervision of a doctor who has experience working with antitumor drugs.

In patients receiving the preparation of Irinotel, it is necessary to evaluate the detailed clinical blood test weekly and monitor the liver function.

Diarrhea that occurs as a result of the cytotoxic effect of the drug (delayed diarrhea), usually occurs no earlier than 24 hours after the administration of the drug Irinotel (in most patients, an average of 5 days). When the first episode of a loose stool occurs, it is necessary to administer a copious drink containing electrolytes and immediately perform antidiarrheal therapy, including the administration of loperamide in high doses (4 mg for the first dose and then 2 mg every 2 hours). This therapy is continued for at least 12 hours after the last episode of a loose stool, but no more than 48 hours because of the possibility of developing a small intestine paresis.

If diarrhea is considered severe (more than 6 episodes of loose stool during the day or pronounced tenesmus), and if it is accompanied by vomiting or fever, the patient should be urgently hospitalized for complex treatment, including the introduction of broad-spectrum antibiotics.

With moderate or mild diarrhea (less than 6 episodes of loose stool during the day and moderate tenesmus), which does not stop within the first 48 hours,it is necessary to begin reception of antibiotics of a wide spectrum of action inside, thus the patient is recommended to be hospitalized.

With the simultaneous occurrence of diarrhea and severe neutropenia (the number of leukocytes less than 500 cells / μl of blood) in addition to antidiarrheal therapy with a preventive purpose, antibiotics of a wide spectrum of action are prescribed internally. Loperamide should not be prescribed prophylactically, including patients who have had diarrhea during previous injections of Irinotel.

The patient must be warned in advance about the possibility of developing delayed diarrhea. Patients should immediately inform their doctor about the occurrence of diarrhea and immediately begin appropriate treatment.

If the treatment of diarrhea is inadequate, a condition threatening the patient's life may develop, especially if diarrhea develops against a background of neutropenia.

Patients with febrile neutropenia (body temperature> 38 ° C and neutrophil count <1000 cells / μL) should immediately begin the introduction of broad-spectrum antibiotics in hospital settings.

With the development of acute cholinergic syndrome,the development of which is the appearance of early diarrhea and a combination of such symptoms as sweating, abdominal cramps, lacrimation, miosis and increased salivation, in the absence of contraindications, the administration of 0.25 mg of atropine subcutaneously is indicated. Care should be taken when using the drug in patients with bronchial asthma. Patients with indications for the development of an acute cholinergic syndrome in history, including severe ones, before the appointment of the drug Irinotel recommended the preventive administration of atropine.

Before each cycle of therapy with Irinotel, the prophylactic use of antiemetics is recommended. They should be taken on the day of therapy, at least 30 minutes before the introduction of irinotecan. Also, consideration should be given to the need for antiemetic drugs in the future as needed. Patients who develop vomiting against delayed diarrhea should immediately be hospitalized for appropriate treatment.

Since the dosage form of the preparation as an auxiliary substance contains sorbitol, Irinotel should not be used in patients with hereditary intolerance to fructose.

Against the background of the use of irinotecan, there was an increase in the concentration of creatinine in the blood plasma, as well as blood urea nitrogen. Also noted were rare cases of acute renal failure. These effects can usually be explained by infectious complications, as well as by dehydration caused by nausea, vomiting or diarrhea.

In addition, they noted the development of kidney failure in tumor lysis syndrome.

Patients homozygous for the 28 alleles of the UGT1A1 gene should receive the usual starting dose of the drug. Nevertheless, such patients should be carefully monitored for the development of hematological toxicity. It should be considered the possibility of using smaller doses in patients who had previously experienced hematologic toxicity symptoms during previous treatment. For this patient population there are no clear recommendations for dose adjustment and a reduction in the dose of the drug should be carried out on the basis of individual tolerability of treatment.

During the period of treatment with the drug Irinotel should not take drugs based on St. John's wort (perforated (Hypericum perforatum) (it is necessary to cancel at least one week before starting therapy with irinotecan), antiepileptic drugs (carbamazepine, phenobarbital and phenytoin), atazanavir and ketoconazole (it is necessary to cancel at least one week before starting therapy with irinotecan), which alter the clearance of irinotecan.

During treatment with Irinotel, reliable methods of contraception should be used for at least 3 months after discontinuation of therapy.

Care should be taken when preparing the solution of the Irinotel preparation and handling the drug, as well as when using other antitumour agents.

It is necessary to use gloves, a mask and glasses.

If you get a solution of the drug Irinotel or infusion solution on the skin, immediately wash it with water and soap. If Irinotel or its solution gets into the mucous membranes, immediately rinse them with water.

All materials used to prepare the solution and for its administration must be disposed of in accordance with the standard procedure for cytotoxic drug disposal adopted in this hospital.

Effect on the ability to drive transp. cf. and fur:

Patients should be warned about the possible appearance during the treatment of Irinotel with dizziness and visual disorders, which develop within 24 hours after the administration of Irinotel. The use of the drug Irinotel can provoke the development of seizures. In the event of these symptoms, patients are advised to refrain from driving and other mechanisms, and to exercise caution when dealing with potentially hazardous activities.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

By 2 ml, 5 ml or 15 ml in bottles of dark glass (type I in US Pharmaceuticals). The bottle is sealed with a rubber stopper and sealed with an aluminum cap with a polypropylene disc.

One bottle on a plastic substrate or without it, coated with or without a film, is placed in a cardboard box together with an instruction for use.

Storage conditions:

Store at a temperature of 15 to 30 ° C, in a place protected from light. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000021

Date of registration:01.11.2010 / 25.01.2016

Expiration Date:Unlimited

The owner of the registration certificate:Fresenius Kabi Deutschland GmbHFresenius Kabi Deutschland GmbH Germany

Manufacturer: & nbsp

FRESENIUS KABI ONCOLOGY, Limited India

Representation: & nbspFRESENIUS KABI DEYCHLAND GmbH FRESENIUS KABI DEYCHLAND GmbH Germany

Information update date: & nbsp31.01.2017

Illustrated instructions

Instructions

Irinotel (Irinotel)