Irinotecan — Drug Monograph

Brand names: Camptosar, Onivyde (liposomal)

Drug class: Topoisomerase Inhibitor

Mechanism of Action

Prodrug converted by carboxylesterase to SN-38 (active metabolite, 100–1000× more potent than irinotecan). SN-38 stabilizes the topoisomerase I-DNA cleavage complex, causing irreversible DNA single-strand breaks during replication. S-phase specific. SN-38 is glucuronidated by UGT1A1 — UGT1A1*28 polymorphism (present in ~10% of the US population) reduces glucuronidation, increasing SN-38 exposure and toxicity.

FDA Indications

• Metastatic colorectal cancer — first-line with 5-FU/leucovorin (FOLFIRI)
• Metastatic colorectal cancer — second-line after prior 5-FU therapy (monotherapy)
• Pancreatic cancer — first-line: NALIRIFOX (nal-IRI + oxaliplatin + 5-FU/LV every 2 weeks; NAPOLI-3 trial: mOS 11.1 mo, ORR 42% vs. gem/nab-P; FDA-approved 2024)
• Pancreatic cancer — second-line: liposomal irinotecan (Onivyde) + 5-FU/leucovorin after gemcitabine-based therapy (NAPOLI-1 trial)

Common Side Effects

• Diarrhea (early and late — most characteristic toxicity)
• Myelosuppression (neutropenia)
• Nausea and vomiting (moderate risk)
• Alopecia
• Abdominal cramping
• Elevated liver enzymes
• Cholinergic symptoms during infusion (sweating, flushing, salivation)

Clinical Pearl

The loperamide regimen for late-onset diarrhea is high-dose: 4 mg at first loose stool, then 2 mg every 2 hours around the clock (including overnight) until 12 hours after the last loose stool — not the standard consumer dose. Patients must be counseled proactively and sent home with a loperamide prescription. Do not withhold until Grade 3 diarrhea develops.

Related Therapies & Mechanisms

• 5-Fluorouracil (5-FU) (Adrucil) — CRC
• Capecitabine (Xeloda) — CRC
• Mitomycin (Mitosol) — CRC
• Nivolumab (Opdivo) — Gastric