Irinaks - instructions for use, doses, side effects, contraindications

It is a specific inhibitor of the cellular enzyme topoisomerase I. In tissues, the drug is metabolized to form an active metabolite SN-38, which excels in its activity irinotecan. Irynotekan and its metabolite SN-38 stabilize the topoisomerase I complex with DNA, which in turn blocks its replication. Cytotoxic activity is specific for S-phases of mitosis.

Irinotecan in an animal experiment demonstrated extensive antitumor activity in vivo concerning tumor models: pancreatic duct adenocarcinoma, adenocarcinoma of the mammary gland, adenocarcinoma of the stomach and colon.

Also irinotecan is active against tumors expressing the P-glycoprotein of multiple drug resistance (vincristine and doxorubicin-resistant leukemia).

In addition to antitumor activity irinotecan inhibits adetylcholine esterase.

Pharmacokinetics:

Pharmacokinetics of irinotecan and its metabolite SN-38 was studied with a 30-minute intravenous infusion at a dose of 100 to 750 mg / m² every three weeks.

After intravenous administration of a dose of 350 mg / m² maximum concentrations of irinotecan and its metabolite SN-38 in blood plasma were 7.7 μg / ml and 56 ng / ml, respectively. The association with plasma proteins (predominantly albumin) of irinotecan is 65%, its metabolite SN-38 - 95%. The volume of distribution is 157 l / m².

Metabolized in the liver by hydrolysis under the influence of carboxyl esterase in the active metabolite SN-38 (has a basic cytotoxic activity), which is then glucuronized and excreted with bile or kidney. Then the glucuronide SN-38 may be hydrolyzed in the intestine.

The second way of metabolism of irinotecan is possible - enzyme-dependent under the influence of the cytochrome P450 3A system with the formation of an aminopentanoic acid derivative and a primary amine derivative.

The pharmacokinetics of irinotecan are two- or three-phase and are dose-dependent (the pharmacokinetic profile of irinotecan does not depend on the dose for the originator). The average plasma clearance of irinotecan is 15 l / h / m², the average half-life of irinotecan from the plasma during the first phase of the three-phase model is 12 minutes, during the second phase, 2.5 hours, during the third phase, 14.2 hours.

Plasma metabolite elimination SN-38 corresponds to a two-phase model with an average final half-life of 13.8 hours.

Displayed kidneys within 24 hours: 11-20% - unchanged, less than 1% - in the form of unchanged metabolite SN-38, 1-3% in the form of glucuronide SN-38; 30% is excreted by the intestine both in the unmodified form and in the form of a metabolite.

In patients with impaired liver function and hyperbilirubinemia, irinotecan clearance is reduced by 40%.

Indications:

Treatment of locally advanced or metastatic cancer of the colon and rectum:

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

- as a monotherapy in patients whose treatment with fluorouracil was not effective.

Treatment in combination with cetuximab metastatic colorectal cancer, accompanied by enhanced expression of the epidermal growth receptor, in which cytotoxic therapy was not effective.

Contraindications:

- Hypersensitivity to irinotecan or other components of the drug;

- marked suppression of bone marrow hematopoiesis;

- general condition of the patient, assessed by WHO classification more than 2 degrees;

- severe hyperbilirubinemia (excess of the normal concentration of total bilirubin in the blood serum more than 3 times);

- chronic inflammatory bowel diseases (including ulcerative colitis) and / or intestinal obstruction;

- pregnancy;

- lactation period;

- children's age (safety and efficacy not established).

Carefully:

Patients with moderate hepatic impairment, hyperbilirubinemia, not exceeding normal levels of total serum bilirubin more than 3 times, with cardiovascular diseases, with inhibition of medullary hemopoiesis (including with concurrent radiotherapy or chemotherapy), acute infectious diseases of viral, fungal or bacterial origin (including chicken pox, shingles), radiotherapy (in history) in the region of the abdominal cavity or pelvis; leukocytosis; with Karnovsky index less than 50% (risk of diarrhea development); with lung diseases, with bronchial asthma, respiratory insufficiency, the elderly (safety and efficacy have not been established).

Pregnancy and lactation:

Women of childbearing age, using irinotecan, should take contraceptives and immediately inform the doctor if pregnancy occurs.

Adequate and strictly controlled clinical trials on the safety of the drug in pregnant women were not conducted. but irinotecan demonstrated embryotoxic, fetotoxic and teratogenic effects in rabbits and rats. Therefore, do not apply irinotecan pregnant women.

There is no data on the excretion of irinotecan with human milk. In laboratory studies irinotecan was found in the milk of rats, therefore during lactation it is necessary to refuse from taking irinotecan or to stop breastfeeding.

Dosing and Administration:

Irinotecan, a solution for infusions, should be injected into the peripheral or central vein.

Treatment with irinotecan should be conducted until objective disease control methods prove the progression of the disease or the development of symptoms of hypersensitivity.

Preparation of a solution for intravenous infusion

Observing aseptic conditions, the necessary amount of concentrate is taken from the vial using a calibrated syringe and injected intoa 250 ml bottle containing 0.9% sodium chloride solution or 5% dextrose solution. The solution should be thoroughly mixed by rotating the bottle.

Treatment of colorectal cancer

Monotherapy (for patients who received previous chemotherapy)

The recommended dose of irinotecan is 350 mg / m², administered intravenously for 30-90 minutes at intervals of 3 weeks.

Combination therapy (for patients who have not previously received chemotherapy)

Irynotekan in a dose of 125 mg / m² weekly or 180 mg / m² with an interval of 2 weeks in combination with fluorouracil / calcium folate. Enter intravenously for 30-90 minutes, then enter calcium folinate and fluorouracil.

Recommendations for dose adjustment

Irinotecan should be administered after the disappearance of all adverse reactions, i.e. when the toxicity level reaches 0-1 (according to the general criteria for the toxicity of the National Cancer Institute, USA) and the treatment-related diarrhea completely stops.

At the beginning of the next treatment cycle, the dose of irinotecan and fluorouracil, if used, should be reduced according to the level of toxicity observed in the previous cycle. Treatment is recommended to be discontinued for 1-3 weeks prior to resolution of all side effects of toxicity associated with treatment.

With the development of hematological (fourth-degree neutropenia, fever (grade 2-4), thrombocytopenia) and non-hematologic symptoms of toxicity (grade 3-4), the dose of irinotecan and fluorouracil, if used, should be reduced by 15-20%.

Patients with impaired liver function and hyperbilirubinemia it is necessary to carefully select the initial dose of irinotecan.

Patients with a concentration of total bilirubin in the blood serum exceeding the normal values by 1.5 times, the recommended dose of irinotecan is 350 mg / m².

Patients with a total serum bilirubin concentration in blood serum exceeding the normal values of 1.5-3 times, the recommended dose of irinotecan is 200 mg / m².

In patients with a concentration of total bilirubin in the serum, exceeding the normal values by more than 3 times, irinotecan not applicable.

Since there are no data on the use of irinotecan in patients with impaired renal function, then the use of irinotecan in this category of patients is not recommended.

Adequate and controlled studies of pharmacokinetics in elderly patients not conducted. However, care should be taken to select the dose in each individual case because of the potential for reducing the liver and kidney function in them.

Side effects:

The incidence of side effects is described in accordance with the following gradation: very frequent - more than 10%, frequent - from 1 to 10%, infrequent - from 0,1% to 1%, rare - from 0,01 to 0,1%, very rare - less than 0.01%.

From the digestive system: very frequent; late diarrhea (occurring more than 24 hours after application), nausea, vomiting, constipation; rare: colitis, tiflitis, intestinal perforation, anorexia, abdominal pain, mucositis; very rare: intestinal obstruction, gastrointestinal bleeding, pancreatitis, pseudomembranous colitis.

From the side of the cardiovascular system: very rare: increased blood pressure, lower blood pressure.

On the part of the respiratory system: infrequent: dyspnea, pulmonary infiltrates.

From the nervous system: frequent: involuntary muscle contractions or cramps, paresthesia, asthenia, drowsiness, dizziness; very rare: transient speech impairment.

From the genitourinary system: very rare: renal failure due to dehydration.

From the skin side: frequent: alopecia (has a reversible character); very rare: a skin rash of an allergic nature, the development of anaphylactic shock.

From the side of the circulatory system: very frequent: leukopenia, neutropenia (dose-dependent toxic effect), febrile neutropenia, anemia, thrombocytopenia.

Laboratory indicators: infrequent: transient increase in the activity of "liver" transaminases, concentration of alkaline phosphatase, total bilirubin in the serum, in the absence of progressive liver metastases; very rare: increased activity of amylase and / or lipase, hypokalemia, hyponatremia (due to diarrhea and vomiting).

Local Reactions: frequent: reactions at the injection site.

Other: frequent: fever, infection, acute cholinergic syndrome, early diarrhea, abdominal pain, conjunctivitis, rhinitis, lowering of arterial pressure, vasodilation, sweating, chills, malaise, impaired vision, miosis, lacrimation, increased salivation.

Overdose:

Symptoms: severe diarrhea, severe neutropenia.

Treatment: intensive symptomatic therapy, supporting treatment to prevent dehydration caused by diarrhea, treatment of infectious complications. There is no specific antidote.

Interaction:

When combined with cholinesterase inhibitors (eg, suxamethonium), an extension of the neuromuscular block can occur.

When combined with Nondepolarizing muscle relaxants possible competition with acetylcholine, which leads to a recovery of neuromuscular conduction.

Care should be taken when using irinotecan and drugs inhibiting (e.g., ketonazole) or inducing (eg, rifampicin, carbamazepine, phenobarbital) metabolism of irinotecan with cytochrome P450 isoenzyme CYP3A4, which may increase or decrease, respectively, the pharmacodynamic effect of irinotecan.

Do not use irinotecan at the same time aswith St. John's wort perfumery (Hypericum perforatum), since the preparations of St. John's wort penetrate reduce the concentration of the active metabolite SN-38 in blood plasma by 42%

Hematotoxic drugs increase the risk of leukopenia and thrombocytopenia.

Radiation therapy aggravates the degree of myelodepression.

Glucocorticosteroids increase the risk of developing hyperglycemia (especially in diabetes mellitus or intolerance to glucose) and lymphocytopenia.

Diuretics can aggravate the dehydration that results from diarrhea and vomiting.

Joint application laxatives can aggravate the frequency or severity of diarrhea. Co-administration with prochlorperazine increases the likelihood of akathisia.

Immunosuppressive drugs (in t, h. azathioprine, chlorambucol, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine, muroomonab-CDS) increase the risk of developing infectious complications.

Do not mix with other drugs in the same bottle.

In combination with live or inactivated viral vaccines can enhance the replication of the vaccine virus (increased side effects of the vaccine) and reduce the production of antibodies (requires a failure of immunization in the range of 3 to 12 months after taking the drug).

Special instructions:

Infusion with Irenax ® should be given only in specialized institutions where cytotoxic chemotherapy is performed, and only under the supervision of a doctor who has experience with chemotherapy in oncology.

Given the nature and incidence of adverse reactions, the Irenax® preparation is prescribed only in those cases,when the expected benefit of using the drug exceeds the possible risk. Therapy is discontinued at the appearance of signs of disease progression, toxicity.

Patients should be aware of the risk of developing late diarrhea, which may occur more than 24 hours after drug administration and at any time before the subsequent cycle. Patients with severe diarrhea have a high risk of developing infection and hematological toxicity. At the first appearance of liquid feces, drink plenty of liquids containing electrolytes, antidiarrheal therapy with loperamide - 4 mg for the first time, then 2 mg every 2 hours and for 12 hours after the last liquid feces, but not more than 48 hours. With the development of severe diarrhea (more than 6 episodes of liquid feces a day, intestinal colic, tenesmus combined with vomiting, fever) treatment is performed in the intensive care unit. For diarrhea (less than 6 episodes of liquid feces per day), antibiotics of a broad spectrum of action are administered orally for prophylactic purposes.

Do not use loperamide prophylactically, incl. patients who had diarrhea during previous irinotecan injections.

When treating with Irenax®, weekly monitoring of the clinical picture of blood is recommended. Patients who had severe adverse reactions from the blood system, with subsequent administration of the drug is recommended to reduce its dose.

Research of liver function should be performed before treatment and before each cycle. Patients with a concentration of total bilirubin in blood serum, 1.5-2 times higher than the upper limit of the norm, it is necessary to conduct a full blood test weekly, due to a decrease in clearance of the Irenax® preparation and, thus, an increase in hepatotoxicity in this group of patients.

When there is an acute cholinergic syndrome (early diarrhea, sweating, abdominal cramps, lacrimation, miosis, salivation), in the absence of contraindications, it is necessary to introduce atropine (0.25 mg subcutaneously).

Women and men of reproductive age during the use of the drug Irenax® and for at least 3 months after stopping therapy should use contraceptives.

Patients with febrile neutropenia (hyperthermia - more than 38 degrees C, neutrophils - less than 1 thousand / μL) should be administered intravenously antibiotics of a wide spectrum of action.

Special precautions for the destruction of unused medications

The remnants of the preparation and all instruments and materials used to prepare the infusion solution of the Irenax® preparation must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account the existing regulatory acts on the destruction of hazardous waste.

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

Because of the likelihood of side effects when taking Irenax®, such as drowsiness, dizziness, caution should be exercised in exercising potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

For 2 ml, 5 ml, 7.5 ml, 15 ml or 25 ml in a bottle of dark glass type I, sealed with a rubber stopper, crimped with an aluminum cap.

For 1, 5 or 10 vials, together with the instruction for medical use, is placed in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000755

Date of registration:29.09.2011

Expiration Date:29.09.2016

Date of cancellation:2016-09-29

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Irenax® (Irinax®)