Iriten, 20 mg/ml 5 ml

Irinotecan is a semi-synthetic derivative of camptothecin, a specific inhibitor of the cellular enzyme topoisomerase I. In tissues, the drug is metabolized to form the active metabolite SN-38, which is superior to irinotecan in its activity. Irinotecan and SN-38 stabilize the complex of topoisomerase I with DNA, which prevents the replication of the latter.

Pharmacokinetics

The pharmacokinetic profile of irinotecan is not dose dependent. Maximum plasma concentrations of irinotecan and SN-38 were reached by the end of the IV infusion at the recommended dose of 350 mg/m2. Binding to plasma proteins for irinotecan is approximately 65%, for its active metabolite SN-38 – 95%.

The distribution of the drug in plasma is biphasic or triphasic. It is metabolized mainly in liver under the action of carboxylesterase enzyme to the active metabolite – SN-38. Average T1/2 of the drug in the first phase is 12 min, in the second phase – 2.5 h and in the last phase – 14.2 h.

The drug is excreted in the urine within 24 hours as unchanged drug (20%) and as SN-38 (0.25%). About 30% of the drug is excreted with the bile, both as unchanged and as SN-38 glucuronide. 5-fluorouracil and calcium folinate do not affect the pharmacokinetics of irinotecan.

Indications

Locally advanced or metastatic colorectal cancer: as monotherapy in patients with disease progression after conventional treatment; in combination with 5-fluorouracil and calcium folinate in patients who have not previously received chemotherapy.

Active ingredient

Composition

Active ingredient:

irinotecan hydrochloride trihydrate;

Auxiliary substances:

D-sorbitol,

lactic acid,

sodium hydroxide,

water d/i.

How to take, the dosage

The drug is administered in adults only. Irithin is administered as an IV infusion lasting at least 30 minutes and no longer than 90 minutes. In colorectal cancer Irithin is used both as monotherapy and in combination with 5-fluorouracil and calcium folinate. When choosing a dose and mode of administration it is necessary to refer to special literature. In monotherapy, Iriten is used in a dose of 350 mg/m2 of body surface every 3 weeks.

In combination therapy with continuous infusion of 5-fluorouracil and calcium folinate, Iriten is administered weekly at a dose of 80 mg/m2; once every 2 weeks, 180 mg/m2; when administered in combination with a bolus of 5-fluorouracil and calcium folinate, 125 mg/m2 weekly. Iriten should not be administered until the neutrophil count in peripheral blood exceeds 1500 cells/μL and until complications such as nausea, vomiting, and especially diarrhea have completely resolved. Administration of the drug until all side effects are resolved can be delayed for 1-2 weeks.

. If marked suppression of medullary hematopoiesis develops against the background of treatment (neutrophil count is less than 500/μL, and/or leukocyte count is less than 1000/μL, and/or platelet count is less than 100,000/μL), or febrile neutropenia (neutrophil count of 1,000/µL or less combined with fever greater than 38°C), or infectious complications, or severe diarrhea, or other non-hematologic toxicity of grade 3-4, subsequent doses of Iriten or if necessary 5-fluorouracil are reduced by 15-20%.

Iriten treatment is continued until objective signs of tumor disease progression or development of unacceptable toxic manifestations appear. Patients with liver dysfunction and serum bilirubin level not more than 1.5 times higher than BHN due to increased risk of development of significant neutropenia should carefully control peripheral blood values.

Iriten should be discontinued if bilirubin levels exceed 1.5 times the ULN. It is not recommended to treat patients with impaired renal function, since the drug use in this category of patients has not been studied. There are no special instructions for Iriten use in elderly patients. The dose of the drug should be chosen with caution in each case.

The safety and efficacy of Iritin administration in children have not been studied sufficiently. Rules for preparation of the solution for intravenous infusion Iritin solution should be prepared under aseptic conditions. Required quantity of the drug is diluted in 250 ml of 5% dextrose solution or 0.9% sodium chloride solution and the resulting solution is stirred by rotating the container or vial. Before injection the solution should be visually inspected for transparency.

If a precipitate is found, the drug must be destroyed. Iriten solution must be used immediately after dilution. If the dilution is done in an aseptic manner (e.g., in a laminar airflow unit), Iritin solution can be used when stored at room temperature for 12 h (including infusion time) and when stored at 2° to 8°C for 24 h after opening the vial of concentrate.

Interaction

As Iriten has anticholinesterase activity, the duration of neuromuscular blockade may be increased when combined with suxamethonium and antagonistic interaction with respect to neuromuscular blockade when combined with nondepolarizing myorelaxants.

Pharmaceutical interaction Iriten should not be mixed with other drugs in the same bottle.

Special Instructions

The treatment with Iriten should be carried out in specialized chemotherapy departments under the supervision of a physician experienced in working with antitumor drugs. Patients receiving Iriten should have a weekly gross clinical blood count and monitor liver function.

Diarrhea resulting from cytotoxic action of the drug (delayed diarrhea) usually occurs not earlier than 24 hours after administration of Iriten (on average 5 days in most patients). In case of the first episode of liquid stools it is necessary to administer abundant drinking containing electrolytes and immediate anti-diarrheal therapy, including high doses of loperamide (4 mg at first administration and then 2 mg every 2 hours).

This therapy is continued for at least 12 hours after the last episode of liquid stool, but no longer than 48 hours because of the possibility of small-bowel paresis. If the diarrhea is considered severe (more than 6 episodes of liquid stools during 24 hours or marked tenesmus), or if accompanied by vomiting or fever, the patient should be transferred to a hospital urgently for complex treatment, including administration of a broad spectrum of antibiotics.

In mild to moderate diarrhea (less than 6 episodes of liquid stools during 24 hours and mild tenesmus) that does not resolve within the first 48 hours, oral antibiotics should be started, and the patient should be hospitalized. If diarrhea and severe neutropenia (leukocyte count is less than 500/μL) occur simultaneously, broad-spectrum antibiotics are administered orally in addition to anti-diarrheal therapy for prophylactic purposes.

Loperamide should not be administered prophylactically, including in patients who have had diarrhea during previous administration of Iriten. Patients should be warned in advance about the possibility of delayed diarrhea. Patients should tell their physician immediately if diarrhea breaks out, and appropriate treatment should be started immediately. If diarrhoea is not treated appropriately, a life-threatening condition can develop, especially if it occurs together with neutropenia. Patients with febrile neutropenia (body temperature >38°C and neutrophil count less than 1000/µl) should be started immediately with broad spectrum antibiotics in a hospital setting.

If acute cholinergic syndrome develops and there are no contraindications, 0.25 mg of atropine sulfate should be administered by injection. Caution should be exercised when using the drug in patients with bronchial asthma. In patients with signs in anamnesis of acute cholinergic syndrome, including a severe form, before administration of Iritin it is recommended to use antiemetic preparations for prophylactic treatment.

Iriten should not be used in patients with hereditary fructose intolerance since the dosage form of the drug contains D-sorbitol as an excipient. Care should be taken when preparing a solution of Iriten and when handling the drug. Gloves, mask and goggles should be used.

In case of contact of Iritin solution or infusion solution with skin or mucous membranes the skin should be washed immediately with soap and water, mucous membranes with just water.

Influence on driving and operating machinery

Patients should be warned about the possibility of dizziness and visual disturbances during treatment with Iriten, which develop within 24 hours after administration of the drug. If these symptoms occur, patients are advised to refrain from driving or operating other machinery.

Contraindications

– chronic inflammatory bowel disease and/or intestinal permeability disorders;

– marked suppression of bone marrow hematopoiesis;

– serum bilirubin level exceeding IUF by more than 1.5 times;

– patients’ general condition as assessed by the WHO>2 scale;

– pregnancy;

– period of lactation (breastfeeding);

– hypersensitivity to irinotecan or other components of the drug.

The drug should be used with caution in case of radiotherapy (in anamnesis) to the abdomen or pelvis, leukocytosis, female patients (increased risk of diarrhea).

Side effects

Blood organs: neutropenia is observed in an average of 80% of patients, including. Half of them have a decrease in neutrophils to

In the digestive system: late diarrhea occurring more than 24 hours (on average 5 days) after drug administration is a dose-limiting toxic manifestation and occurs in approximately 87% of patients, of whom 38% have a severe degree. Nausea and vomiting usually occur on the first day of administration or 24 h later in 85% of patients.

The development of dehydration with vomiting and diarrhea has been reported, very rarely with the development of renal failure, hypotension and heart failure. Abdominal pain, anorexia, mucositis, constipation are possible.

Acute cholinergic syndrome is seen in 9% of patients within the first 24 h after administration of Iriten and is manifested by diarrhea, abdominal pain, increased sweating, miosis, visual disturbances, lacrimation, salivation, decreased BP, dizziness, chills and general malaise.

CNS disorders: involuntary muscle twitching or convulsions, paraesthesia, asthenia.

Allergic reactions: rare – skin rash and very rare – development of anaphylactic shock. Other: shortness of breath, alopecia, increased body temperature, local reactions.

Overdose

As Iriten has anticholinesterase activity, the duration of neuromuscular blockade may be increased when combined with suxamethonium and antagonistic interaction with respect to neuromuscular blockade when combined with nondepolarizing myorelaxants.

Pharmaceutical interaction Iriten should not be mixed with other drugs in the same bottle.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breast-feeding). During treatment with the drug Iriten and at least for 3 months after discontinuation of therapy, reliable contraceptive measures should be used.