Drug reference

Irinotecan

Antineoplastic

CDSCO approvedSchedule H

EXCRETION

—

not curated

INTERACTIONS

12 major

SEVERE in our sources

PREGNANCY

Avoid—toxicity in animal studies.

FDA category + note

Top interactionssee all 12 →

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Mechanism

Irinotecan is a prodrug that is converted by hepatic carboxylesterases to its active metabolite SN-38, which is approximately 1000-fold more potent as a topoisomerase I inhibitor. SN-38 stabilizes the topoisomerase I-DNA cleavable complex, preventing religation of single-strand DNA breaks, which are converted to lethal double-strand breaks when the replication fork collides with the trapped complex. SN-38 is inactivated by hepatic UGT1A1 glucuronidation, and patients with Gilbert syndrome (UGT1A1*28) are at increased risk of severe neutropenia and diarrhea.

Indications

Previously untreated epidermal growth factor receptor-expressing, RAS wild-type metastatic colorectal cancer (in combination with 5-fluorouracil and folinic acid (FOLFIRI))AnticancerChemotherapy of solid tumorsAdvanced colorectal cancer (first-line therapy in combination with fluoropyrimidines)Advanced colorectal cancer (single agent or in combination with cetuximab following failure of a 5FU/oxaliplatin regimen)Small cell lung cancerMetastatic pancreatic cancer (liposome injection in combination with 5FU and leucovorin, after disease progression following gemcitabine therapy)Metastatic colorectal carcinomaAdvanced colorectal carcinomaCancer lungCancer cervixOvary cancerStomach cancer

Dosing

Adult: with paclitaxel for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents.…

Pharmacokinetics

Half-life

11.5 h (SN-38, active metabolite)

Bioavailability

—

Protein binding

I: 30–68%; SN-38: 95%

Metabolism

Converted to SN-38 by a carboxylesterase after intravenous administration. SN-38 is subsequently conjugated with glucuronic acid in the liver.

Excretion

Biliary excretion appears to be the primary elimination route of irinotecan, SN-38, and metabolites, although urinary excretion also contributes (14%–37%).

Side effects

Common

OligopeniaVomitingWeight decreasedDelayed diarrhea (35%, dose-limiting)NauseaFatigueVasodilation or skin flushingMucositisElevation in liver transaminasesAlopeciaDiarrhoeaNeutropeniaThrombocytopeniaHaemorrhageBodyacheWeaknessCholinergic effects

Serious

Encephalopathy
Necrotising fasciitis
Chest pain
Chills
Flushing
Gallbladder perforation
Hyperglycaemia
Hypotension
Nasal septum perforation
Osteonecrosis of jaw
Pulmonary hypertension
Renal thrombotic microangiopathy
Congestive heart failure
Posterior reversible encephalopathy syndrome (presenting as seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without hypertension)
Late-onset gastrointestinal toxicities
Severe diarrhea
Hematological toxicities (leukopenia, neutropenia)
Damage to intestinal epithelial cells
Acute ileocolitis
Life-threatening ileocolitis
serious toxicities (with reduced UGT1A1 activity, e.g., in Gilbert’s syndrome, due to higher SN-38 levels)
Neutropenia (with delayed diarrhea, dose-limiting)
Severe neutropenia (14% to 47% with 3-week schedule)
Febrile neutropenia (3%, may be fatal, particularly when associated with concomitant diarrhea)
Cholinergic syndrome (within first 24 h after administration, symptoms include acute diarrhea, diaphoresis, hypersalivation, abdominal cramps, visual accommodation disturbances, lacrimation, rhinorrhea, asymptomatic bradycardia; responds to atropine)
Dyspnea (case reports)
Interstitial pneumonitis (case reports)
neutropenia and diarrhoea (more in patients with UGT1A1 *28 allele)