Irinotecan


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : IV Metastatic colorectal cancer As conventional formulation: As monotherapy in patients who failed treatment with 5-FU-containing regimen: 350 mg/m2 every 3 weeks. Alternatively, 125 mg/m2 given on days 1, 8, 15, and 22 followed by 2-week rest. In combination with 5-FU and folinic acid in patients without prior chemotherapy: 180 mg/m2 once every 2 weeks. Alternatively, 125 mg/m2 given every week on days 1, 8, 15, and 22 of a 6-week cycle. Continue until disease progression or unacceptable toxicity occurs. Metastatic adenocarcinoma of pancreas As liposomal formulation: In combination with 5-FU and leucovorin in patients whose disease progressed following gemcitabine-based chemotherapy: 80 mg/m2 given every 2 weeks. All doses may be given via infusion over 90 minutes. Dose reduction, modification, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Dosage Details
Intravenous
Metastatic colorectal cancer
Adult: As conventional formulation: As monotherapy in patients who failed treatment with 5-fluorouracil (5-FU)-containing regimen: 350 mg/m2 via infusion over 30-90 minutes every 3 weeks. Alternatively, 125 mg/m2 via infusion over 90 minutes on days 1, 8, 15, and 22 followed by 2-week rest. In combination with 5-FU and folinic acid in patients without prior chemotherapy: 180 mg/m2 once every 2 weeks via infusion over 30-90 minutes, followed by folinic acid and 5-FU infusion. Alternatively, 125 mg/m2 via infusion over 90 minutes given every week on days 1,8,15, and 22 of a 6-week cycle. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, modification, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline). In combination with cetuximab for patients with epidermal growth factor receptor (EGFR)-expressing RAS wild-type cases without prior metastatic disease treatment, or after failure of irinotecan-including cytotoxic treatment; As 1st-line treatment in combination with 5-FU, folinic acid, and bevacizumab, or in combination with capecitabine with or without bevacizumab: Refer to the detailed product guidelines of cetuximab, bevacizumab, and capecitabine.

Intravenous
Metastatic adenocarcinoma of pancreas
Adult: As liposomal formulation: In combination with 5-FU and leucovorin in patients whose disease progressed after gemcitabine-based chemotherapy: 80 mg/m2 via infusion over 90 minutes, then leucovorin 400 mg/m2 via infusion over 30 minutes, then 5-FU 2,400 mg/m2 via infusion over 46 hours, given every 2 weeks. Dose reduction, modification, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Special Patient Group
Pharmacogenomics

The metabolism of Irinotecan by carboxylesterases to an active metabolite, SN-38, which further undergo glucuronidation is mediated by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzyme, this process transforms lipophilic metabolites into water-soluble metabolites that can be excreted from the body. Individuals that have reduced UGT1A1 has a genetic polymorphism of UGT1A1*28 may alter SN-38 pharmacokinetic activity. According to the study, the most variant allele is UGT1A1*28 which commonly found in African-American (0.42-0.45 allele frequency), Caucasians (0.26-0.31 allele frequency), and less common in Asians (0.09-0.16 allele frequency). The prevalence of individuals with UGT1A1*28/*28 has approx 10% in North America. This genetic polymorphism affects the variability on adverse effects.

Genetic testing for UGT1A1 may be considered as a guide to optimise irinotecan dosing and to enable irinotecan as part of other gastrointestinal tumour treatment without the risk of haematologic toxicity.

UGT1A1*1/*28 genotype, and UGT1A1 intermediate metabolisers
More common in Western populations than the wild-type *1/*1 genes.
No dosage adjustment needed.

UGT1A1*28/*28

Reduced conversion of irinotecan to inactive metabolites resulting in increased risk of life-threatening adverse events (e.g. severe neutropenia, severe diarrhoea). Based from the DPWG 2018 guideline, initiate irinotecan with 70% of the standard dose, may be increased according to patient tolerance and guided by neutrophil count.

UGT1A1 poor metabolisers
Reduced conversion of irinotecan to inactive metabolites resulting in increased risk of serious, fatal adverse effects (e.g. severe neutropenia, severe diarrhoea). Based from the DPWG 2018 guideline, initiate irinotecan with 70% of the standard dose, may be increased according to patient tolerance and guided by neutrophil count.
Renal Impairment
Metastatic colorectal cancer:
Not recommended.
Hepatic Impairment
Metastatic colorectal cancer:
As conventional formulation: As monotherapy in patients who failed treatment with 5-FU-containing regimen: Bilirubin up to 1.5 times the upper limit of normal range (ULN): 350 mg/m2; Bilirubin from 1.5-3 times the ULN: 200 mg/m2; Bilirubin >3 times the ULN: Contraindicated.

Metastatic adenocarcinoma of pancreas:
As liposomal formulation: Bilirubin: >2 mg/dL, or AST/ALT >2.5 times the ULN or >5 times the ULN if liver metastasis is present: Contraindicated.
Reconstitution
Conventional formulation: Dilute in 5% dextrose in water (preferred) or 0.9% NaCl inj to make a final concentration of 0.12-2.8 mg/mL. Liposomal formulation: Dilute the appropriate dose in 500 mL 5% dextrose in water or 0.9% NaCl inj. Mix by gentle inversion.
Contraindications
Chronic inflammatory bowel disease and/or bowel obstruction, severe bone marrow failure, WHO performance status >2. Conventional formulation: Bilirubin >3 times the ULN. Liposomal formulation: Bilirubin >2 mg/dL, or AST/ALT >2.5 times the ULN or >5 times the ULN if liver metastasis is present. Pregnancy and lactation. Concomitant use with live attenuated vaccines (e.g. yellow fever vaccine) and St. John’s wort.
Special Precautions
Patients with abnormal or deficient bilirubin glucuronidation (e.g. Gilbert syndrome), hyperbilirubinaemia, previously received pelvic/abdominal irradiation, history of Whipple procedure, asthma, underlying cardiac disease, other risk factors for cardiac disease (e.g. hypertension, hyperlipidaemia, smoking); underweight patients (BMI <18.5 kg/m2). Avoid extravasation. Renal and hepatic impairment. UGT1A1 poor metabolisers and those who are homozygous for UGT1A1*28 alleles.
Adverse Reactions
Significant: Bone marrow suppression (e.g. lymphopenia, leucopenia, anaemia, thrombocytopenia), gastrointestinal toxicity (e.g. nausea, vomiting), acute cholinergic syndrome, myocardial ischaemic events, renal toxicity (e.g. increased serum creatinine or BUN, acute renal failure), severe hypersensitivity reactions (including anaphylaxis).
Gastrointestinal disorders: Abdominal pain, constipation, dysgeusia, stomatitis, colitis, pancreatitis, hiccups.
General disorders and admin site conditions: Pyrexia, asthenia, fatigue, mucosal inflammation, peripheral oedema, infusion related reaction.
Hepatobiliary disorders: Hypoalbuminaemia.
Infections and infestations: Infection gastroenteritis, oral candidiasis.
Investigations: Weight decreased, increased blood bilirubin, elevated ALT/AST and blood alkaline phosphatase, increased INR.
Metabolism and nutrition disorders: Decreased appetite, hypokalaemia, dehydration, hypomagnesaemia, hypoglycaemia, hyponatraemia, hypophosphataemia.
Nervous system disorders: Dizziness.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, dysphonia, pneumonia.
Skin and subcutaneous tissue disorders: Alopecia (reversible).
Vascular disorders: Hypotension, haemorrhoids.
Potentially Fatal: Severe neutropenic fever or sepsis, severe neutropenia, severe myelosuppression, severe late-onset diarrhoea, severe interstitial lung disease, thromboembolic events (e.g. pulmonary embolism, venous thrombosis, arterial thromboembolism).
Patient Counseling Information
This drug may cause potential dizziness or visual disturbances, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor CBC with differential, platelet count, and Hb with each dose; LFTs at baseline and before each cycle; bilirubin and electrolytes especially during severe diarrhoea; bowel movements and hydration status; genotyping of UGT1A1. Assess for signs and symptoms of neutropenia, delayed diarrhoea, sepsis, cholinergic reactions, pulmonary toxicity, hypersensitivity or infusion site reactions (e.g. inflammation, extravasation).
Overdosage
Symptoms: Severe neutropenia and severe diarrhoea. Management: Supportive treatment.
Drug Interactions
Reduced exposure with strong CYP3A4 and/or UGT1A1 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin). Increased toxic effect and plasma levels with bevacizumab. Increased systemic exposure and risk of toxicity with strong CYP3A4 inhibitors (e.g. ketoconazole, voriconazole, protease inhibitors, clarithromycin, erythromycin, crizotinib, idelalisib), and UGT1A1 inhibitors (e.g. atazanavir, gemfibrozil, regorafenib). Increased risk of excessive immunosuppression and lymphoproliferation with immunodepressant agents (e.g. ciclosporin, tacrolimus). May prolong neuromuscular blocking effects of suxamethonium.
Potentially Fatal: Increased risk of fatal generalised reactions with yellow fever vaccine and live attenuated vaccines. Increased risk of haemorrhage and thrombotic events with vitamin K antagonists.
Food Interaction
Avoid St. John’s wort as it decreases the plasma levels of irinotecan. Increased plasma concentrations with grapefruit or grapefruit juice.
Action
Description: Irinotecan, a camptothecin derivative and topoisomerase inhibitor, act specifically for S phase of DNA synthesis by reversibly binding to topoisomerase I-DNA complex which prevents the re-ligation of the cleaved DNA strand, leading to the accumulation of cleavable complexes and irreparable double-strand DNA breaks, thereby resulting in cell death and termination of cellular replication.
Pharmacokinetics:
Absorption: Bioavailability: 9%. Time to peak plasma concentration: After 90-minute infusion: Approx 1 hour (SN-38).
Distribution: Distributed into pleural fluid, sweat, and saliva. Volume of distribution: 138 L/m2 (conventional formulation); 2.6 L/m2 (liposomal formulation). Plasma protein binding: Conventional formulation: 30-68% (irinotecan); approx 95% (SN-38), mainly to albumin. Liposomal formulation: <1%.
Metabolism: Metabolised in the liver primarily via hydrolysis by carboxylesterases to its active metabolite, SN-38 (7-ethyl-10-hydroxycaptothecin), which further undergo conjugation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzyme to form a glucuronide metabolite. May also undergo by CYP3A4-mediated metabolism to inactive metabolites.
Excretion: Via urine (11-20% as unchanged drug, 3% as SN-38 glucuronide, <1% as SN-38). Elimination half-life: Conventional formulation: 6-12 hours (irinotecan); approx 10-20 hours (SN-38). Liposomal formulation: Approx 26 hours (total irinotecan); approx 68 hours (SN-38).
Chemical Structure

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Storage
Conventional formulation: Store between 15-30°C. Protect from light. Liposomal formulation: Store between 2-8°C. Do not freeze. Protect from light. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01XX19 - irinotecan ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Disclaimer: This information is independently developed by MIMS based on Irinotecan from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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