Introduction
Camptosar (irinotecan hydrochloride) is a topoisomerase I inhibitor chemotherapy agent used primarily in the treatment of colorectal cancer. It is a semi-synthetic derivative of camptothecin, a natural alkaloid extracted from the Camptotheca acuminata tree. First approved by the FDA in 1996, Camptosar has become a cornerstone in the management of metastatic colorectal cancer, both as first-line therapy and in refractory disease.
Mechanism of Action
Irinotecan exerts its cytotoxic effects through inhibition of topoisomerase I, a nuclear enzyme essential for DNA replication and transcription. The drug and its active metabolite SN-38 bind to the topoisomerase I-DNA complex, preventing religation of single-strand DNA breaks. This interaction results in double-strand DNA damage during DNA synthesis, ultimately leading to apoptosis (programmed cell death) of rapidly dividing cancer cells.
Indications
- First-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFIRI regimen)
- Second-line monotherapy for metastatic colorectal cancer that has progressed following 5-FU-based therapy
- Off-label uses include treatment of small cell lung cancer, pancreatic cancer, and certain gynecological malignancies
Dosage and Administration
Standard dosing:- 125 mg/m² IV over 90 minutes weekly for 4 weeks, followed by a 2-week rest period
- 180 mg/m² IV over 90 minutes every 2 weeks (FOLFIRI regimen)
- 350 mg/m² IV over 90 minutes every 3 weeks
- Reduce dose by at least one level for National Cancer Institute (NCI) Grade 3/4 toxicities
- Consider dose reduction in patients with UGT1A1*28 polymorphism
- Hepatic impairment: Reduce dose in patients with bilirubin >1.5 mg/dL
- Renal impairment: No specific recommendations, use with caution
- Administer as IV infusion only
- Premedicate with antiemetics and consider atropine for cholinergic symptoms
- Hydrate adequately before and after administration
Pharmacokinetics
Absorption: Administered intravenously, achieving complete bioavailability Distribution: Widely distributed throughout body tissues; volume of distribution ~100 L/m²; 30-68% protein bound Metabolism: Primarily hepatic via carboxylesterase conversion to active metabolite SN-38, which undergoes glucuronidation by UGT1A1 Elimination: Primarily biliary/fecal excretion (60-70%); renal excretion (10-20%); terminal half-life: 6-12 hours for irinotecan, 10-20 hours for SN-38Contraindications
- History of severe hypersensitivity reaction to irinotecan or its components
- Concurrent use with strong CYP3A4 inducers (unless clinical benefit outweighs risk)
- Pregnancy (Category D)
- Severe bone marrow suppression
- Bowel obstruction
Warnings and Precautions
Myelosuppression: Severe neutropenia may occur; monitor blood counts frequently Diarrhea: Both early-onset (cholinergic) and late-onset (severe) diarrhea can occur Pulmonary toxicity: Interstitial lung disease reported; discontinue if symptoms develop Thromboembolism: Increased risk of venous thromboembolic events Hepatic impairment: Increased exposure to SN-38 in patients with hyperbilirubinemia UGT1A1 polymorphism: Patients with UGT1A1*28 allele have increased risk of neutropenia Extravasation: May cause severe local tissue damageDrug Interactions
Strong CYP3A4 inducers: (e.g., rifampin, phenytoin, St. John's wort) - Decreased irinotecan levels Strong CYP3A4 inhibitors: (e.g., ketoconazole, clarithromycin) - Increased irinotecan levels UGT1A1 inhibitors: (e.g., atazanavir) - Increased SN-38 exposure Anticoagulants: Increased risk of bleeding Live vaccines: Avoid concurrent administration Other myelosuppressive agents: Enhanced bone marrow suppressionAdverse Effects
Very common (>10%):- Diarrhea (early and late onset)
- Nausea/vomiting
- Neutropenia
- Anemia
- Alopecia
- Fatigue
- Anorexia
- Febrile neutropenia
- Thrombocytopenia
- Abdominal pain/cramping
- Increased liver enzymes
- Dehydration
- Dyspnea
- Interstitial lung disease
- Anaphylaxis
- Renal impairment
- Ileus
- Thrombotic microangiopathy
Monitoring Parameters
Prior to each cycle:- Complete blood count with differential
- Liver function tests
- Renal function tests
- Assessment of performance status
- Monitor for hypersensitivity reactions
- Monitor for cholinergic symptoms
- Daily temperature monitoring
- Strict monitoring of bowel movements
- Assessment for signs/symptoms of infection
- Monitoring for dehydration
- UGT1A1 genotyping considered for high-risk populations
- Closer monitoring in elderly patients
Patient Education
- Report any diarrhea immediately (especially if occurring >24 hours after treatment)
- Maintain adequate hydration (2-3 liters daily unless contraindicated)
- Monitor temperature daily and report fever >100.4°F (38°C)
- Use anti-diarrheal medication as prescribed (loperamide for late-onset diarrhea)
- Practice good hand hygiene to reduce infection risk
- Avoid crowds and people with infections
- Use effective contraception during and for 3 months after treatment
- Report unusual bleeding, bruising, or shortness of breath
- Maintain nutritional intake; small frequent meals may help with nausea
- Arrange for assistance with activities if experiencing fatigue
References
1. National Comprehensive Cancer Network. Colon Cancer Guidelines Version 2.2023 2. Camptosar® (irinotecan hydrochloride) Prescribing Information. Pfizer Inc. 3. Innocenti F, et al. Clin Pharmacol Ther. 2014;95(2):234-240 4. Rothenberg ML, et al. J Clin Oncol. 2001;19(14):3801-3807 5. FDA Drug Safety Communication: New recommendations to reduce risk of severe neutropenia. 2014 6. Mathijssen RH, et al. Clin Cancer Res. 2001;7(8):2182-2194 7. Hoskins JM, et al. J Clin Oncol. 2007;25(24):3607-3614 8. Meyerhardt JA, et al. J Clin Oncol. 2006;24(21):3456-3461