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

Irinotecan, a semisynthetic derivative of camptothecin, 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 metabolite SN-38 stabilize the topoisomerase I complex with DNA, which prevents its replication.

Pharmacokinetics:

The pharmacokinetic profile of irinotecan is dose independent.

Metabolized, mainly in the liver under the action of the enzyme carboxyesterase to the active 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 first phase is 12 minutes, in the second phase - 2.5 hours and in the last phase - 14.2 hours. The maximum plasma concentration of irinotecan and SN-38 was reached by the end of intravenous infusion at a recommended dose of 350 mg / m². With urine within 24 hours, an average of 20 % unchanged drug and 0.25% in the form of a metabolite SN-38.About 30% of the drug is excreted in bile, both in unchanged form and in the form of a metabolite SN-38 glucuronide.

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.

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

Fluorouracil and calcium folinate do not affect the pharmacokinetics of irinotecan.

Indications:

Locally 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:

- Hypersensitivity to irinotecan or other components of the drug;

- chronic inflammatory bowel diseases and / or intestinal obstruction;

- severe oppression of bone marrow hematopoiesis;

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

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

- pregnancy and the period of breastfeeding;

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

Carefully:

- Acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles);

- liver failure;

- Radiation therapy (in the anamnesis) on the abdominal cavity or pelvis;

- leukocytosis;

- patients with Karnovsky index less than 50% (risk of diarrhea development);

- lung disease, respiratory failure;

- elderly age.

Dosing and Administration:

The drug is intended only for adults.

It is necessary to avoid getting the drug outside the vascular bed and to control the possible appearance of signs of inflammation at the site of infusion.

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

In the monotherapy mode: Irnokam® applied at a dose of 350 mg / m² body surface in the form of a 30-90 minute intravenous infusion every 3 weeks, and also at a dose of 125 mg / m²body surface weekly for 4 weeks as a 90-minute intravenous infusion and a 2-week break.

In the regime of combined chemotherapy with fluorouracil and calcium folinate, the dose of the drug Irnokam® is, when administered by continuous infusion, once every 2 weeks, 180 mg / m² body surface, and with weekly administration for 4 weeks followed by a 2-week break of 125 mg / m body surface. Dosage and regimen in the administration of fluorouracil and folinata calcium are described in detail in the literature.

Recommendations for dose modification

In the monotherapy regime reduction of the initial dose of irinotecan from 125 mg / m²up to 100 mg / m² and from 350 mg / m² up to 300 mg / m², as well as reducing the dose from 125 mg / m² up to 100 mg / m² and from 180 mg / m² up to 150 mg / m² in the combination therapy regimen, can be recommended in patients aged 65 years and older, with prior extensive radiation therapy, with a patient's overall patient score, assessed by the ECOG-WHO scale of 2.

The administration of Irnokam® should not be followed until the amount of neutrophils in the peripheral blood exceeds 1500 cells / μl, 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.

When developing against the background of treatment of severe oppression of bone marrow hematopoiesis (the number of neutrophils is less than 500 / μL,and / or the number of white blood cells less than 1000 / μl, and / or the platelet count is less than 100,000 / μl), febrile neutropenia (neutrophil counts 1000 / μL blood and less in combination with fever over 38 ° C), infectious complications, severe diarrhea or another non-hematological toxicity of 3-4 degrees, subsequent doses of the drug Irnokam® and, if necessary, fluorouracil should be reduced by 15-20%.

Patients with impaired hepatic function

At a level 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, the patient's blood parameters should be closely monitored. With an increase in the level of bilirubin by more than 1.5 times, the treatment with the drug Irnokam^®should be discontinued.

Patients with impaired renal function

There is no application data.

Elderly patients

Any special instructions for use irinotecan in the elderly are absent. The dose of the drug in each case should be selected with caution.

Instructions for preparing a solution for infusions

The necessary amount of the preparation should be diluted in 250 ml of a 0.5% 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. In case of a sediment, the drug must be destroyed. The solution should be used immediately after dilution.

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

Side effects:

Determination of the frequency of adverse reactions: very often (≥10%), often (≥1% - <10%), sometimes (≥0.1% - <1%), rarely (≥0.01% - <0.1% ), very rarely (<0.01%, including single cases).

From the hematopoiesis: neutropenia is observed, on average, in 80% of patients, including half of them with a decrease in neutrophils of less than 1000 cells per 1 μl. Restoration of the number of neutrophils is usually observed in 7-20 days from the beginning of treatment. Anemia of varying severity is found, on average, in 60% of patients, thrombocytopenia - in 7% of patients. One case of thrombocytopenia with the formation of antiplatelet antibodies is described.

From the side of the digestive system: Late diarrhea that occurs more than 24 hours (on average, 5 days) after drug administration is a dose-limiting toxic effect and is observed in approximately 87% of patients, with a severe degree in 38%. Nausea and vomiting occurs usually on the first day of administration or after 24 hours in 85% of patients. Dehydration was reported on the background of vomiting and diarrhea, very rarely with the development of renal failure, hypotension and heart failure. Possible abdominal pain, anorexia, mucositis, constipation. There have been reports of rare cases of pseudomembranous colitis, intestinal obstruction, bleeding from the gastrointestinal tract, intestinal perforation, increased activity of amylase and lipase.

Acute cholinergic syndrome: manifested by early diarrhea within 24 hours after the administration of the drug, as well as: conjunctivitis, rhinitis, bradycardia, vasodilation, increased intestinal peristalsis.

From the central nervous system: involuntary muscle contraction or cramps, 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.

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

From the laboratory indicators: very often transient increase in the activity of serum transaminases, alkaline phosphatase or bilirubin concentration (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.

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

Other: increased fatigue, local post-fusion reactions, attachment of secondary infections, fever, local reactions.

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 closely monitor the function of vital organs.

Interaction:

Glucocorticosteroids increase the risk of developing hyperglycemia (especially in diabetes mellitus or with reduced glucose tolerance) and lymphocytopenia.

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

In combination with live or inactivated viral vaccines, it can enhance the replication of the vaccine virus (increased vaccine side effect) and reduce antibody production (requires immunization from 3 to 12 months after taking the drug).

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 - inducers CYP3A (carbamazepine, phenobarbital and phenytoin) - the concentration in the plasma of the active metabolite SN-38 is reduced.

As irinotecan has anticholinesterase 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.

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.

Joint use of irinotecan with atazanavir, an enzyme inhibitor 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.

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

Special instructions:

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

In patients receiving Irnokam®, it is necessary to perform a detailed clinical blood test on a weekly basis and monitor liver function.

Diarrhea that occurs as a result of the cytotoxic effect of the drug is usually noted no earlier than 24 hours after the administration of Irnokam® (in most patients, on average, after 5 days).When the first episode of a loose stool appears, it is necessary to administer a copious drink containing electrolytes and immediately perform antidiarrheal therapy, including taking loperamide in high doses (4 mg at the first dose, 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 six 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 in the intensive care unit for complex treatment, including the introduction of broad-spectrum antibiotics. With moderate or mild diarrhea (less than six 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 antibiotics in a wide range of action. With the simultaneous occurrence of diarrhea and severe neutropenia (the number of white blood cells is less than 500 / mm3), in addition to antidiarrheal therapy, antibiotics of a wide spectrum of action are prescribed internally for prophylactic purposes.

Loperamide should not be prescribed prophylactically, including to patients who have had diarrhea during previous injections of Irnokam®.

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 / μL) should immediately begin the introduction of broad-spectrum antibiotics in hospital settings.

Acute cholinergic syndrome, usually occurring during the administration of the drug or in the first 24 hours after administration, is quickly and effectively suppressed by subcutaneous administration of 0.25 mg of atropine (caution should be exercised in patients with bronchial asthma).

Patients with a history of developing an acute cholinergic syndrome, including severe ones, before the appointment of the drug Irnokam®, recommended the preventive administration of atropine.

The dosage form of the drug as an auxiliary substance contains sorbitol, in connection with which Irnokam® can not be used in patients with hereditary intolerance to fructose.

During treatment with the drug Irnokam® and for at least three months after discontinuing therapy, reliable contraceptive measures should be used.

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.

Patients should be warned about the possible occurrence during the treatment of Irnokam® with dizziness and visual disorders that develop within 24 hours after the administration of the drug. If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Care should be taken when preparing the solution of the Irnokam® preparation and handling the drug as well as with other antitumour agents.It is necessary to use gloves, a mask and glasses.

If you get a solution of the drug Irnokam® or infusion solution on the skin or mucous membranes, the skin should be washed immediately with soap and water, mucous membranes simply with water.

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

Taking the drug can provoke the development of seizures, so during treatment should be careful when managing vehicles and other complex mechanisms.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

2 ml in a bottle of dark glass class 1 (USP), Sealed with a rubber stopper and crimped with an aluminum cap with a green plastic safety cover. One bottle with instructions for use is put in a cardboard box.

5 ml in a bottle of dark glass class 1 (USP), Corked with a rubber stopper and crimped with an aluminum cap with a plastic safety cover of purple. One bottle with instructions for use is put in a cardboard box.

Storage conditions:

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

Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-001869

Date of registration:30.03.2012 / 05.11.2013

Expiration Date:Unlimited

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDR REDDY'S LABORATORIS LTD. DR REDDY'S LABORATORIS LTD. India

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Irnokam® (Irnocam®)