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

Excipients: sorbitol 45.0 mg, lactic acid 0.90 ml, sodium hydroxide 5% q.s., hydrochloric acid 5% q.s, water of the day of injections q.s. up to 1 ml.

Description:

Transparent solution from light yellow to yellow, without visible inclusions.

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 of topoisomerase 1. In tissues, the drug is metabolized by the enzyme carboxyl esterase to form an active metabolite SN-38, which is superior irinotecan by its activity. Inhibiting the topoisomerase 1, irinotecan and its metabolite SN-38 cause linear DNA damage, which prevents its replication in Sphase of the cell cycle. 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).

Another pharmacological effect of irinotecan is its ability to inhibit acetylcholinesterase.

Pharmacokinetics:

The pharmacokinetic profile of irinotecan is dose independent. The distribution of the drug in the plasma is two- or three-phase.The volume of distribution is 157 l / m². The maximum plasma concentration (C_mOh) of irinotecan and SN-38 is reached by the end of intravenous infusion at the recommended dose of 350 mg / m² and is 7.7 μg / ml and 56 ng / ml, respectively, and the area under the concentration-time curve (AUC) - 34 μg / h / ml and 451 ng / h / ml. In the blood plasma irinotecan is basically unchanged.

The drug is metabolized in the liver in two ways: under the action of the enzyme carboxyl esterase to the active metabolite SN-38 with subsequent glucuronation and under the action of isoenzyme CYP3A4 to form aminopentanoic acid derivatives and amines. Significant cytotoxic activity has only SN-38. The association with blood plasma proteins for irinotecan is approximately 65%, for its active metabolite SN-38 - 95%.

The average half-life of the drug in the first phase is 12 minutes, in the second phase - 2.5 hours and in the last phase - 14.2 hours. The average value of the plasma clearance is 15 l / h / m². It is excreted by the kidneys in an unchanged form (an average of 19.9%) and in the form of a metabolite SN-38 (0.25%). About 30% of the drug is excreted in bile, both in unchanged form and in the form of a metabolite SN-38 glucuronide. Fluorouracil and calcium folinate do not affect the pharmacokinetics of irinotecan.

Excretion of irinotecan was reduced by approximately 40% in patients with bilirubin concentration exceeding the upper limit of the norm by 1.5-3 times.

Indications:

Locally advanced colorectal cancer:

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

- in the form of 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;

- severe oppression of bone marrow hematopoiesis;

- the concentration of bilirubin in the serum, exceeding the upper limit of the norm (VGN) by more than 3 times;

- general condition of patients, assessed by WHO scale> 2;

- pregnancy and lactation;

- children's age (data on efficiency and safety are absent);

- kidney failure (data on safe use in patients with renal failure are absent).

Carefully:

The general condition of the patient, assessed on a WHO scale of 2, leukocytosis,female patients (increased risk of diarrhea), radiation therapy (in the anamnesis) on the abdominal or pelvic area, neutropenia, impaired liver function, simultaneous use of pneumotoxic drugs, colony-stimulating factors, elderly age, hypovolemia, propensity to thrombosis and thromboembolism.

Dosing and Administration:

The drug is intended only for adults.

It is administered as an intravenous infusion lasting at least 30 minutes and not more than 90 minutes.

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

In the monotherapy regime The dose of the drug Irinotecan-Teva is 125 mg / m²body 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 the dose of the preparation Irinotecan-Teva amounts to fluorouracil and calcium folinate with a weekly administration of 125 mg / m², 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.

Recommendations for dose modification

In the monotherapy regimen, a decrease in the initial dose of the preparation Irinotecan-Teva 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 combination therapy, it can be recommended in patients aged 65 years and older, with previous extensive radiation therapy, with an indicator of the general condition of the patient, estimated on the WHO scale, equal to 2.

The administration of Irinotecan-Teva 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. If 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 (neutrophil count 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-hematologic toxicity of 3-4 degrees, subsequent doses of the drug Irinotecan-Teva and, if necessary, fluorouracil should be reduced by 15-20%.

If there are objective signs of progression of the tumor disease or the development of unacceptable toxic manifestations, therapy with Irinotecan-Teva should be discontinued.

Patients with impaired hepatic function

Monotherapy

- If the concentration of bilirubin does not exceed 1.5 times the IVH, then dose adjustment is not required, the hematologic parameters of the patient should be closely monitored in connection with an increased risk of developing severe neutropenia.

- If the concentration of bilirubin exceeds IGN from 1.5 to 3 times, the recommended dose of the drug Irinotecan-Teva is 200 mg / m², hematologic parameters of the patient should be closely monitored in connection with an increased risk of developing severe neutropenia.

- If the bilirubin concentration exceeds the VGN by more than 3 times, irinotecan should not be treated.

Combination Therapy

Data on the use of irinotecan in the regime of combined therapy for liver dysfunction are absent.

Patients with impaired renal function

There is no application data.

Instructions for preparing a solution for infusions

The solution of the preparation Irinotecan-Teva should be prepared under aseptic conditions.The necessary amount of the preparation should be diluted in 250 ml of a 5% solution of dextrose or 0.9% sodium chloride solution and the resulting solution is mixed by rotating the vial. Before administration, the solution should be visually inspected for clarity. If a sediment is found, the preparation must be destroyed.

The solution should be used immediately after dilution.

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

Side effects:

Side effects are classified according to the following frequency; very often: ≥10%, often: ≥1% - <10%, sometimes: ≥0.1% - <1%, rarely: ≥0.01% - <0.1%, very rarely: <0.01 %, including isolated cases.

On the part of the hematopoiesis system: very often - neutropenia, leukopenia, anemia; often - febrile neutropenia, thrombocytopenia with the appointment of the drug as part of monotherapy; very rarely - the formation of antiplatelet antibodies.

Neutropenia was observed the 78.7% of patients with monotherapy (with combined chemotherapy in 82.5%), including 22.6% of patients it was 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 after the end of monotherapy and on 7-8 days after the end of the use of the preparation Irinotecan-Teva as part of combined 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 monotherapy and in 2% of patients receiving the preparation Irinotecan-Teva in combination therapy.

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

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

There was one case of thrombocytopenia with the formation of antiplatelet antibodies.

From the gastrointestinal tract: very often - late diarrhea; often - nausea, vomiting, constipation; sometimes - pseudomembranous colitis (in one case it was detected FROM difficile), intestinal obstruction, gastrointestinal bleeding; rarely - colitis, including tiflitis, ischemic and ulcerative colitis, intestinal perforation, anorexia, abdominal pain, inflammation of the mucous membranes, pancreatitis.

When using the drug as a 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 Irinotecan-Teva was 5 days.

When using the drug as a monotherapy in approximately 10% of patients who used anti-emetics, there was pronounced nausea and vomiting. With the use of the drug Irinotecan-Teva in combination chemotherapy, pronounced 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, abdominal pain, conjunctivitis, rhinitis, lowering of arterial pressure, bradycardia, vasodilation, increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lacrimation, salivation was observed in 9% of patients who received the drug Irinotecan-Teva as a monotherapy and as part of combined chemotherapy in only 1.4% of patients. All these symptoms disappeared after the administration of atropine.

From the nervous system: rarely - involuntary muscle contractions, seizures, paresthesia, asthenia; very rarely transient speech disorders.

From the cardiovascular system: sometimes - lowering blood pressure, hypovolemic shock due to dehydration; rarely - increased blood pressure during or after infusion.

On the part of the respiratory system: sometimes - shortness of breath, fever, pulmonary infiltrates.

Allergic reactions: sometimes - a skin rash; rarely - the development of anaphylactic shock.

From the skin and subcutaneous fat: very often - reversible alopecia; sometimes - mild skin reactions.

From the laboratory indicators: very often - a transient increase in the activity of serum transaminases, alkaline phosphatase or bilirubin concentrations (combination therapy); often - transient increase in serum transaminase, alkaline phosphatase or bilirubin concentration (monotherapy), increased serum creatinine concentration; rarely - hypokalemia and hyponatremia; very rarely - an increase in the activity of serum amylase and / or lipase.

Other: very often - an increase in body temperature; often - increased fatigue; rarely - local post-fusion reactions, attachment of secondary infections.

Overdose:

The main expected manifestations of an overdose are neutropenia and diarrhea. The specific antidote to irinotecan is unknown. If the therapeutic dose is exceeded by a factor of 2, a lethal outcome is possible. In case of an overdose, the patient should be hospitalized and carefully monitor the function of vital organs.

Treatment: symptomatic.

Interaction:

As irinotecan has acetylcholinesterase activity, it is possible to increase the duration of neuromuscular blockade when combined with salts of suxamethonium and antagonistic interaction 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 increase the frequency or severity of diarrhea.

The combined use of irinotecan and prochlorperazine increases the likelihood of signs of akathisia.

With the joint application of irinotecan with preparations of plant origin on the basis of St. John's wort perfumed (Hypericum perforatum), as well as with anticonvulsants - isoenzyme inducers CYP3A (carbamazepine, phenobarbital and phenytoin) is the concentration in the plasma of the active metabolite SN-38 decreases.

Joint use 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.

Introduction of live attenuated vaccines to patients undergoing treatment with antitumour agents, including irinotecan, can lead to serious or fatal infections. Vaccination with live vaccines should be avoided for patients receiving irinotecan. A killed or inactivated vaccine can be injected, but the immune response to such a vaccine can be weakened.

The drug Irinotecan-Teva should not be mixed with other drugs in one bottle.

Special instructions:

Treatment with the drug Irinotecan-Teva should be carried out in specialized chemotherapy departments under the supervision of a doctor who has experience with antitumor drugs.

In patients receiving the drug Irinotecan-Teva, it is necessary to do a detailed clinical blood test every week and monitor liver function.

Diarrhea that occurs as a consequence of the cytotoxic effect of the drug (delayed diarrhea), usually occurs no earlier than 24 hours after the administration of the drug Irinotecan-Teva (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 regarded as 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 taking broad-spectrum antibiotics inwards, while 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 the drug Irinotecan-Teva.

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 signs of development of which are 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. In patients with a history of developing an acute cholinergic syndrome, including severe, before the appointment of the drug Irinotecan-Teva recommended preventive administration of atropine.

Before each cycle of therapy with the drug Irinotecan-Teva, the prophylactic use of antiemetics is recommended.

Since the dosage form of the preparation as an auxiliary substance contains sorbitol, the drug Irinotecan-Teva can not be used in patients with hereditary intolerance to fructose.

Simultaneous administration of inhibitors should be avoided (ketoconazole) or inductors (rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort puffed) isoenzyme CYP3A4 due to a change in the pharmacokinetics of irinotecan.

During the treatment with Irinotecan-Teva, 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 irinotecan-Teva preparation and handling the preparation as well as when using other antitumour agents. It is necessary to use gloves, a mask and glasses.

If you get a solution of irinotecan or infusion solution on skin immediately wash it with soap and water. If Irinotecan or its solution comes into contact with mucous membranes, immediately rinse 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 irinotecan dizziness and visual disorders, which develop within 24 hours after the administration of irinotecan. The use of irinotecan can provoke the development of seizures. If these symptoms occur, patients are advised to refrain from controlling the car and other mechanisms, as well as to use caution when dealing with potentially hazardous activities.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

To 2 ml, 5 ml in bottles of dark glass type I (Hebrew Pharm.) With plugs of bromobutyl rubber and aluminum caps equipped with a protective cap made of colored polypropylene; 1 bottle, placed in a transparent pallet of PVC, together with instructions for use in a cardboard bundle.

When packing kit # 1 LLC MC "Ellara" or OOO "Ellara"

1 carton pack, elements of the device for infusion systems and syringes for dilution and administration of "Tevadaptor" drugs (adapter to the vial, adapter to the syringe, connection device and instructions for use of the device) in a cardboard box with corrugated cardboard box sealer or without it. The control of the first opened cardboard box is a transparent oval sticker with the logo of TEVA ..

When packing kit number 2 Open Company MC "Ellara" or Open Company "Ellara"

1 carton pack, device elements for infusion systems and syringes for dilution and administration of "Tevadaptor" drugs (adapter to vial, adapter for syringe, syringe adapter, and instructions for use of the device) in a cardboard box with a corrugated cardboard box sealer or without him. Control of the first opening of the cardboard box - a transparent oval sticker with a logo image TEVA.

Storage conditions:

Store at a temperature of no higher than 30 ° C, in a place protected from light.

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:LSR-000972/10

Date of registration:15.02.2010 / 18.05.2012

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

LEMERY, S.A. de C.V. Mexico

Representation: & nbspTeva Teva Israel

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Irinotecan-Teva (Irinotecan-teva)