Kolotecan (Concentrate) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

L01CE02 (Irinotecan)

Active Substance

Irinotecan (Rec.INN registered by WHO)

Dosage Form

Kolotecan

Concentrate for solution for infusion 20 mg/ml: fl. 2 ml or 5 ml 1 pc.

Dosage Form, Packaging, and Composition

2 ml – dark glass bottles (1) – cardboard packs.
5 ml – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

Antineoplastic agent. The mechanism of action is associated with inhibition of the cellular enzyme topoisomerase I, which is involved in DNA synthesis. It has immunosuppressive activity.

Inhibits acetylcholinesterase.

Pharmacokinetics

Following IV infusion, Irinotecan is metabolized in the liver by the enzyme carboxylesterase to the active metabolite SN-38.

Plasma distribution is bi- or triphasic. The mean T_1/2 in the first phase is 12 min, in the second phase – 2.5 h, and in the final phase – 14.2 h. C_max of irinotecan and SN-38 was reached by the end of the IV infusion at the recommended dose of 350 mg/m². On average, 20% of unchanged irinotecan and 0.25% as the metabolite SN-38 are excreted by the kidneys within 24 hours. Approximately 30% of irinotecan is excreted in the bile – both unchanged and as the metabolite SN-38 glucuronide.

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

Indications

Locally advanced or metastatic colorectal cancer (as part of mono- or combination therapy).

ICD codes

Dosage Regimen

Determine the dosage individually based on the therapeutic regimen, disease stage, and patient’s hematological status.

Administer as an intravenous infusion over 90 minutes.

For monotherapy in metastatic colorectal cancer, use a starting dose of 125 mg/m² once weekly for 4 weeks, followed by a 2-week rest period. This constitutes one treatment cycle. Alternatively, administer 350 mg/m² once every 3 weeks.

For combination therapy with 5-fluorouracil (5-FU) and leucovorin, use a starting dose of 180 mg/m² every 2 weeks.

Adjust subsequent doses based on individual tolerance and the severity of observed toxicities, particularly neutropenia and diarrhea.

Withhold therapy if neutropenic fever occurs or if the neutrophil count falls below 1500/µl. Do not administer until hematological recovery.

Reduce the dose for patients with moderate hepatic impairment (serum bilirubin 1.5 to 3.0 times the upper limit of normal). Discontinue therapy in patients with severe hepatic impairment (serum bilirubin >3.0 times ULN).

Premedicate with antiemetics. Administer atropine (0.25-1.0 mg IV) for early-onset cholinergic symptoms, such as diarrhea, sweating, or abdominal cramping occurring during or shortly after infusion.

Initiate antidiarrheal therapy immediately at the first episode of late-onset diarrhea (occurring more than 24 hours post-infusion). Use loperamide; administer 4 mg at the onset, followed by 2 mg every 2 hours until the patient is free of diarrhea for at least 12 hours.

Monitor complete blood count with differential weekly. Assess liver function prior to each cycle.

Adverse Reactions

From the hematopoietic system very common – neutropenia, febrile neutropenia, leukopenia, anemia, thrombocytopenia.

From the digestive system nausea, vomiting, diarrhea, abdominal pain, anorexia, mucositis, constipation, gastrointestinal candidiasis, hiccups, decreased appetite; rarely – pseudomembranous colitis, intestinal obstruction, gastrointestinal bleeding, intestinal perforation, increased activity of amylase or lipase. Diarrhea occurring later than 24 hours after irinotecan administration (delayed diarrhea) is its dose-limiting toxic effect.

Acute cholinergic syndrome early diarrhea (within 8 hours after irinotecan administration), abdominal pain, conjunctivitis, rhinitis, decreased BP, bradycardia, vasodilation, increased intestinal peristalsis, increased sweating, chills, malaise, dizziness, visual disturbance, miosis, lacrimation, salivation.

From the nervous system involuntary muscle contractions or cramps, paresthesia, asthenia; very rarely – transient speech disorders.

From the cardiovascular system sometimes – decreased BP, hypovolemic shock due to dehydration; rarely – increased BP during or after infusion.

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

From the skin and subcutaneous tissues: very common – reversible alopecia; sometimes – skin reactions.

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

Allergic reactions rarely – skin rash; very rarely – development of anaphylactic shock.

Other: increased fatigue, secondary infections, increased body temperature, local reactions.

Contraindications

Hypersensitivity to irinotecan; chronic inflammatory bowel diseases and/or intestinal obstruction; severe bone marrow suppression; serum bilirubin concentration more than 3 times the ULN; general condition of patients assessed by the ECOG (Eastern Cooperative Oncology Group) scale >2; pregnancy, breastfeeding period; childhood (no safety and efficacy data in children), renal failure (no safety data).

With caution radiotherapy (in history) to the abdominal or pelvic area (high risk of myelosuppression), leukocytosis, female patients (increased risk of diarrhea), hypovolemia, increased risk of venous thromboembolic complications, elderly age.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Patients of childbearing potential should use reliable methods of contraception during treatment and for 3 months after its completion.

Use in Hepatic Impairment

If the serum bilirubin concentration exceeds the ULN by no more than 1.5 times, due to the increased risk of severe neutropenia, blood counts should be carefully monitored. If the bilirubin concentration increases more than 3 times, irinotecan therapy should be discontinued.

Use in Renal Impairment

Use in patients with renal failure is contraindicated. Irinotecan is not recommended for use in patients with impaired renal function.

Pediatric Use

Use of irinotecan in children is contraindicated.

Geriatric Use

Should be prescribed with caution to patients over 65 years of age due to the increased risk of early diarrhea in this category of patients.

Special Precautions

Treatment with irinotecan should be carried out in specialized chemotherapy departments under the supervision of a physician experienced in working with antineoplastic drugs.

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

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.

When the first episode of diarrhea develops, measures should be taken immediately to correct it. The duration of neutropenia is most often 8 days, with complete recovery of neutrophils observed by day 22. Acute cholinergic syndrome is observed in approximately 83% of patients, occurring during administration or within 24 hours after administration.

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

If neutropenia, nausea, vomiting, or diarrhea develops during treatment, dose adjustment is required. Do not use until the neutrophil count in the peripheral blood is restored (>1500/µl).

Patients of childbearing potential should use reliable methods of contraception during treatment and for 3 months after its completion.

Effect on ability to drive vehicles and operate machinery

During treatment with irinotecan, especially within 24 hours after its administration, it is not recommended to engage in potentially hazardous activities that require concentration and high speed of psychomotor reactions.

Drug Interactions

Due to the anticholinesterase activity of irinotecan, it is possible to increase the duration of neuromuscular blockade caused by suxamethonium chloride; antagonistic interaction in relation to neuromuscular blockade caused by non-depolarizing muscle relaxants.

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

When irinotecan is used concomitantly with corticosteroids (e.g., 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 irinotecan therapy may exacerbate the frequency or severity of diarrhea.

Concomitant administration 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, as well as with anticonvulsant drugs – inducers of the CYP3A isoenzyme (carbamazepine, phenobarbital and phenytoin), the plasma concentration of the active metabolite SN-38 decreases. The possibility of taking anticonvulsant drugs that do not induce isoenzymes, or switching to them at least 1 week before starting irinotecan therapy, should be assessed in patients requiring treatment with anticonvulsant drugs. St. John’s wort should not be taken concomitantly with irinotecan; it should be discontinued at least 1 week before starting irinotecan therapy.

Irinotecan and the active metabolite SN-38 are metabolized via the CYP3A4 isoenzyme and UGT1A1. Concomitant use of irinotecan and inhibitors of the CYP3A4 isoenzyme and/or UGT1A1 may lead to an increase in the systemic exposure of irinotecan and the active metabolite SN-38.

Concomitant administration of irinotecan with atazanavir, an inhibitor of CYP3A4 and UGT1A1 isoenzymes, as well as with ketoconazole, may cause an increase in the plasma concentration of the active metabolite SN-38. Ketoconazole should be discontinued at least 1 week before starting therapy and should not be taken during irinotecan therapy.

Irinotecan should not be mixed with other drugs in the same vial.

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

When irinotecan is used concomitantly with phenytoin, there is a risk of exacerbation of seizures due to decreased absorption of phenytoin in the gastrointestinal tract against the background of concomitant use with antineoplastic drugs or an increased risk of increased toxicity due to more active metabolism in the liver induced by phenytoin.

When irinotecan is used concomitantly with cyclosporine, tacrolimus, significant immunosuppression with a risk of lymphoproliferation is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.