Irinotecan-Teva (Concentrate) Instructions for Use

ATC Code

L01CE02 (Irinotecan)

Active Substance

Irinotecan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Irinotecan is a semisynthetic derivative of camptothecin and is a specific inhibitor of the cellular enzyme topoisomerase I.

In tissues, the drug is metabolized by the enzyme carboxylesterase to form the active metabolite SN-38, which is more potent than Irinotecan.

By inhibiting topoisomerase I, Irinotecan and its metabolite SN-38 cause linear DNA damage, which prevents its replication in the S-phase of the cell cycle.

In vivo experiments have shown that Irinotecan is also active against tumors expressing P-glycoprotein of multidrug resistance (vincristine- and doxorubicin-resistant P388 leukemias).

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 plasma is bi- or triphasic.

The V_d is 157 L/m².

The C_max of irinotecan and SN-38 is reached by the end of the IV 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) is 34 µg·h/ml and 451 ng·h/ml.

In blood plasma, Irinotecan is mainly in unchanged form.

The drug is metabolized in the liver by two pathways: under the action of the enzyme carboxylesterase to the active metabolite SN-38 with subsequent glucuronidation, and under the action of the isoenzyme CYP3A4 to form aminopentanoic acid derivatives and amines.

Only SN-38 has significant cytotoxic activity.

Plasma protein binding for irinotecan is approximately 65%, and for its active metabolite SN-38 it is 95%.

The mean elimination half-life of the drug in the first phase is 12 min, in the second phase it is 2.5 h, and in the final phase it is 14.2 h.

The mean plasma clearance value is 15 L/h/m².

It is excreted by the kidneys unchanged (on average 19.9%) and as the metabolite SN-38 (0.25%).

About 30% of the drug is excreted in the bile, both unchanged and as the metabolite SN-38 glucuronide.

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

The elimination of irinotecan is reduced by approximately 40% in patients with a bilirubin concentration exceeding the upper limit of normal by 1.5 to 3 times.

Indications

Locally advanced colorectal cancer

• In combination with fluorouracil and calcium folinate in patients who have not previously received chemotherapy;
• As monotherapy in patients with disease progression after standard anticancer therapy.

ICD codes

Dosage Regimen

Concentrate

The drug is intended for adults only.

It is administered as an IV infusion with a duration of at least 30 minutes and no more than 90 minutes.

When choosing the dose and administration regimen in each individual case, reference should be made to specialized literature.

In the monotherapy regimen, the dose of Irinotecan-Teva is 125 mg/m² of body surface area weekly for 4 weeks as a 90-minute IV infusion with a 2-week break, and also 350 mg/m² as a one-hour IV infusion every 3 weeks.

As part of combination chemotherapy, the dose of Irinotecan-Teva with fluorouracil and calcium folinate is 125 mg/m² for weekly administration, and 180 mg/m² for administration by prolonged infusion once every 2 weeks.

The doses and administration regimen of fluorouracil and calcium folinate are described in detail in specialized literature.

Recommendations for dose modification

In the monotherapy regimen, a reduction of the initial dose of Irinotecan-Teva from 125 mg/m² to 100 mg/m² and from 350 mg/m² to 300 mg/m², as well as a dose reduction from 125 mg/m² to 100 mg/m² and from 180 mg/m² to 150 mg/m² in the combination therapy regimen, may be recommended for patients aged 65 years and older, with prior extensive radiation therapy, with a patient performance status assessed by the WHO scale equal to 2.

Administration of Irinotecan-Teva should not be performed until the number of neutrophils in the peripheral blood exceeds 1500 cells/µl of blood, and until complications such as nausea, vomiting, and especially diarrhea have completely resolved.

Administration of the drug before the resolution of all adverse events can be delayed for 1-2 weeks.

If severe bone marrow suppression develops during treatment (neutrophil count less than 500/µl of blood and/or leukocyte count less than 1000/µl of blood, and/or platelet count less than 100,000/µl) or febrile neutropenia (neutrophil count 1000/µl or less in combination with an increase in body temperature above 38°C (100.4°F)), or infectious complications, or severe diarrhea, or other non-hematological toxicity of grade 3-4, subsequent doses of Irinotecan-Teva and, if necessary, fluorouracil should be reduced by 15-20%.

If objective signs of tumor disease progression appear, or unacceptable toxic manifestations of therapy develop, treatment with Irinotecan-Teva should be discontinued.

Patients with impaired liver function

Monotherapy

• If the bilirubin concentration does not exceed 1.5 times the ULN, then dose adjustment is not required, but the patient’s hematological parameters should be carefully monitored due to an increased risk of severe neutropenia;
• If the bilirubin concentration exceeds the ULN from 1.5 to 3 times, then the recommended dose of Irinotecan-Teva is 200 mg/m², and the patient’s hematological parameters should be carefully monitored due to an increased risk of severe neutropenia;
• If the bilirubin concentration exceeds the ULN by more than 3 times, then treatment with irinotecan should not be carried out.

Combination therapy

There are no data on the use of irinotecan in a combination therapy regimen for impaired liver function.

Patients with impaired renal function

No data on use are available.

Instructions for preparation of infusion solution

The solution of Irinotecan-Teva should be prepared under aseptic conditions.

The required amount of the drug should be diluted in 250 ml of 5% dextrose solution or 0.9% sodium chloride solution and the resulting solution should be mixed by rotating the vial.

Before administration, the solution should be visually inspected for clarity. If sediment is detected, the drug must be destroyed.

The solution should be used immediately after dilution.

If dilution is performed in compliance with aseptic rules (for example, in a laminar airflow cabinet), the drug solution can be used if stored at room temperature for 12 hours (including infusion time) and if stored at a temperature of 2-8°C (35.6-46.4°F) for 24 hours after opening the concentrate vial.

Adverse Reactions

Side effects are classified according to the following frequency: very common: ≥10%, common: ≥1% – <10%, uncommon: ≥0.1 - <1%, rare: ≥0.01 - <0.1, very rare: <0.01, including isolated cases.

From the hematopoietic system very common – neutropenia, leukopenia, anemia; common – febrile neutropenia, thrombocytopenia when the drug is prescribed as monotherapy; very rare – formation of antiplatelet antibodies.

Neutropenia was observed in 78.7% of patients with monotherapy (with combination chemotherapy in 82.5%), including severe neutropenia in 22.6% of patients (neutrophil count less than 500 cells/µl).

Neutropenia was reversible and non-cumulative.

Complete recovery of neutrophil count usually occurred on the 22nd day after the end of monotherapy and on the 7-8th day after the end of the use of Irinotecan-Teva as part of combination chemotherapy.

Fever combined with severe neutropenia was noted in 6.2% and 3.4% of patients, respectively.

Infectious complications with monotherapy occurred in 10.3% of patients, in 5.3% of patients they were combined with severe neutropenia with monotherapy and in 2% of patients receiving Irinotecan-Teva as part of combination therapy.

With the use of Irinotecan-Teva as monotherapy, anemia developed in 58.7% of patients.

With the use of Irinotecan-Teva as part of combination chemotherapy, anemia was observed in 97.2%.

With the use of Irinotecan-Teva as monotherapy, thrombocytopenia (<100,000 cells/µl) was observed in 7.4% (with combination chemotherapy in 32.6%) of patients.

With the use of Irinotecan-Teva as part of combination chemotherapy, severe thrombocytopenia was not observed.

The platelet count recovers by the 22nd day after the end of the drug administration.

One case of thrombocytopenia with the formation of antiplatelet antibodies was observed.

From the gastrointestinal tract: very common – late diarrhea; common – nausea, vomiting, constipation; uncommon – pseudomembranous colitis (in one case C. difficile was detected), intestinal obstruction, gastrointestinal bleeding; rare – colitis, including typhlitis, ischemic and ulcerative colitis, intestinal perforation, anorexia, abdominal pain, inflammation of mucous membranes, pancreatitis.

When using the drug as monotherapy, severe diarrhea was observed in 20% of patients (with combination therapy in 13.1%).

The mean time to the first loose stool after administration of Irinotecan-Teva was 5 days.

When using the drug as monotherapy, approximately 10% of patients using antiemetics had severe nausea and vomiting.

With the use of Irinotecan-Teva as part of combination chemotherapy, severe nausea and vomiting were observed less frequently: in 2.1% and 2.8% of patients, respectively.

Acute cholinergic syndrome, manifested by symptoms such as early diarrhea, abdominal pain, conjunctivitis, rhinitis, decreased blood pressure, bradycardia, vasodilation, increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lacrimation, salivation was observed in 9% of patients receiving Irinotecan-Teva as monotherapy and in combination chemotherapy only in 1.4% of patients.

All these symptoms disappeared after the administration of atropine.

From the nervous system : rare – involuntary muscle contractions, convulsions, paresthesia, asthenia; very rare – transient speech disorders.

From the cardiovascular system uncommon – decreased blood pressure, hypovolemic shock due to dehydration; rare – increased blood pressure during or after infusion.

From the respiratory system uncommon – dyspnea, fever, pulmonary infiltrates.

Allergic reactions: uncommon – skin rash; rare – development of anaphylactic shock.

From the skin and subcutaneous tissue: very common – reversible alopecia; uncommon – mild skin reactions.

From laboratory parameters very common – transient increase in serum transaminase activity; alkaline phosphatase or bilirubin concentration (combination therapy); common – transient increase in serum transaminase activity, alkaline phosphatase or bilirubin concentration (monotherapy), increase in serum creatinine concentration; rare – hypokalemia and hyponatremia; very rare – increase in serum amylase and/or lipase activity.

Other very common – increased body temperature; common – increased fatigue; rare – local post-infusion reactions, secondary infections.

Contraindications

• Hypersensitivity to irinotecan or other components of the drug;
• Chronic inflammatory bowel diseases and/or intestinal obstruction;
• Severe bone marrow suppression;
• Serum bilirubin concentration exceeding the upper limit of normal (ULN) by more than 3 times;
• Patient’s general condition assessed by the WHO scale >2;
• Pregnancy and lactation;
• Childhood (data on efficacy and safety are absent);
• Renal failure (data on safe use in patients with renal failure are absent).

With caution: patient’s general condition assessed by the WHO scale equal to 2; leukocytosis; female patients (increased risk of developing diarrhea); radiation therapy (in history) to the abdominal or pelvic area; neutropenia; impaired liver function; simultaneous use of pneumotoxic drugs; therapy with colony-stimulating factors; elderly age; hypovolemia; tendency to thrombosis and thromboembolism.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Patients with impaired liver function

Monotherapy

• If the bilirubin concentration does not exceed 1.5 times the ULN, then dose adjustment is not required, but the patient’s hematological parameters should be carefully monitored due to an increased risk of severe neutropenia;
• If the bilirubin concentration exceeds the ULN from 1.5 to 3 times, then the recommended dose of Irinotecan-Teva is 200 mg/m², and the patient’s hematological parameters should be carefully monitored due to an increased risk of severe neutropenia;
• If the bilirubin concentration exceeds the ULN by more than 3 times, then treatment with irinotecan should not be carried out.

Combination therapy

There are no data on the use of irinotecan in a combination therapy regimen for impaired liver function.

Use in Renal Impairment

Contraindicated for use in patients with impaired renal function.

Pediatric Use

Contraindicated in childhood (data on efficacy and safety are absent).

Geriatric Use

Use with caution in the elderly.

Special Precautions

Treatment with Irinotecan-Teva should be carried out in specialized chemotherapy departments under the supervision of a physician experienced in working with anticancer drugs.

In patients receiving Irinotecan-Teva, a complete blood count should be performed weekly and liver function should be monitored.

Diarrhea resulting from the cytotoxic effect of the drug (delayed diarrhea) is usually noted no earlier than 24 hours after the administration of Irinotecan-Teva (in most patients on average after 5 days).

When the first episode of loose stools appears, it is necessary to prescribe plenty of fluids containing electrolytes and immediately initiate antidiarrheal therapy, including taking 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 loose stools, but not more than 48 hours due to the possibility of developing small intestine paresis.

If diarrhea is assessed as severe (more than 6 episodes of loose stools per day or severe tenesmus), and also if it is accompanied by vomiting or fever, the patient should be urgently hospitalized for comprehensive treatment, including the administration of broad-spectrum antibiotics.

For moderate or mild diarrhea (less than 6 episodes of loose stools per day and moderate tenesmus), which does not resolve within the first 48 hours, it is necessary to start taking broad-spectrum antibiotics orally, and the patient is recommended to be hospitalized.

If diarrhea and severe neutropenia (leukocyte count less than 500 cells/µl of blood) occur simultaneously, in addition to antidiarrheal therapy, broad-spectrum antibiotics are prescribed orally for prophylactic purposes.

Loperamide should not be prescribed prophylactically, including to patients who had diarrhea during previous administrations of Irinotecan-Teva.

The patient should 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.

Inadequate treatment of diarrhea can lead to a life-threatening condition, especially if diarrhea develops against the background of neutropenia.

Patients with febrile neutropenia (body temperature > 38°C (100.4°F) and neutrophil count < 1000 cells/µl) should immediately begin administration of broad-spectrum antibiotics in a hospital setting.

If an acute cholinergic syndrome develops, the signs of which are the appearance of early diarrhea and a combination of symptoms such as sweating, cramping abdominal pain, lacrimation, miosis and increased salivation, in the absence of contraindications, the administration of 0.25 mg of atropine subcutaneously is indicated.

Caution should be exercised when using the drug in patients with bronchial asthma.

In patients with a history of acute cholinergic syndrome, including in severe form, prophylactic administration of atropine is recommended before prescribing Irinotecan-Teva.

Before each cycle of therapy with Irinotecan-Teva, prophylactic administration of antiemetic drugs is recommended.

Since the dosage form of the drug contains sorbitol as an excipient, Irinotecan-Teva should not be used in patients with hereditary fructose intolerance.

Simultaneous administration of inhibitors (ketoconazole) or inducers (rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort) of the isoenzyme CYP3A4 should be avoided due to changes in the pharmacokinetics of irinotecan.

During treatment with Irinotecan-Teva and for at least 3 months after cessation of therapy, reliable methods of contraception should be used.

When preparing the solution of Irinotecan-Teva and handling the drug, as well as when using other anticancer agents, caution should be exercised.

Gloves, a mask and goggles must be used.

If the irinotecan solution or infusion solution gets on the skin, immediately wash it with soap and water. If irinotecan or its solution gets on the mucous membranes, immediately rinse them with water.

All materials used for the preparation of the solution and for its administration must be disposed of in accordance with the standard procedure for the disposal of cytotoxic drugs adopted in the given hospital.

Effect on the ability to drive vehicles and operate machinery

Patients should be warned about the possibility of dizziness and visual disturbances during treatment with irinotecan, which develop within 24 hours after the administration of irinotecan. The use of irinotecan may provoke the development of seizures. If these symptoms occur, patients are recommended to refrain from driving vehicles and operating machinery, as well as to exercise caution when engaging in potentially hazardous activities.

Overdose

The main expected manifestations of overdose are neutropenia and diarrhea. A specific antidote for irinotecan is unknown. A fatal outcome is possible when the therapeutic dose is exceeded by 2 times. In case of overdose, the patient should be hospitalized and vital organ functions should be carefully monitored. Treatment is symptomatic.

Drug Interactions

Since Irinotecan has acetylcholinesterase activity, it may increase the duration of neuromuscular blockade when used concomitantly with suxamethonium salts and have an antagonistic interaction with non-depolarizing muscle relaxants.

When irinotecan is used concomitantly with myelosuppressive drugs and radiation therapy, the toxic effect on the bone marrow (leukopenia, thrombocytopenia) is exacerbated.

When irinotecan is used concomitantly with glucocorticoid drugs (for example, dexamethasone), the risk of hyperglycemia (especially in patients with diabetes mellitus or reduced glucose tolerance) and lymphocytopenia increases.

When irinotecan is used concomitantly with diuretics, dehydration resulting from diarrhea and vomiting may be exacerbated. Concomitant use of laxatives during therapy with irinotecan may increase the frequency or severity of diarrhea.

Concomitant use of irinotecan and prochlorperazine increases the likelihood of signs of akathisia.

When irinotecan is used concomitantly with herbal preparations based on St. John’s wort ( Hypericum perforatum ), as well as with anticonvulsant drugs that are inducers of the CYP3A isoenzyme (carbamazepine, phenobarbital and phenytoin), the plasma concentration of the active metabolite SN-38 decreases.

Concomitant use of irinotecan with atazanavir, an inhibitor of CYP3A and UGT1A1 isoenzymes, as well as with ketoconazole, may cause an increase in the plasma concentration of the active metabolite SN-38.

Administration of live attenuated vaccines to patients undergoing a course of treatment with antitumor agents, including Irinotecan, may lead to serious or fatal infections. Vaccination with live vaccines should be avoided in patients receiving Irinotecan. A killed or inactivated vaccine may be administered, but the immune response to such a vaccine may be weakened.

The drug Irinotecan-Filaxis should not be mixed with other drugs in the same vial.

Storage Conditions

The drug should be stored at a temperature between 15°C (59°F) and 30°C (86°F) in a place protected from light. Keep out of reach of children.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.