O irinotecano e seu metabólito ativo (SN-38) ligam-se reversivelmente ao complexo topoisomerase I-DNA impedindo a religação da fita de DNA clivada. Isso resulta no acúmulo de complexos cliváveis e quebras de DNA de fita dupla. Como as células de mamífero não podem reparar eficientemente essas quebras, ocorre a morte celular consistente com a especificidade do ciclo celular da fase S, levando ao término da replicação celular.
Diarréia:
Formas precoces e tardias de diarréia podem ocorrer. A diarreia precoce pode ser acompanhada por sintomas colinérgicos que podem ser prevenidos ou melhorados pela atropina. A diarreia tardia pode ser fatal e deve ser tratada imediatamente com loperamida. Monitorar pacientes com diarreia e administrar líquidos e eletrólitos conforme necessário. Instituir antibioticoterapia se os pacientes desenvolverem íleo paralítico, febre ou neutropenia grave. Interrompa o irinotecano e reduza as doses subsequentes se ocorrer diarreia grave.
Supressão da medula óssea:
Pode ocorrer mielossupressão grave.
Insuficiência renal: Não há ajustes de dosagem previstos na bula do fabricante (não foi estudado); Use com cuidado.
Diálise: O uso em pacientes em diálise não é recomendado pelo fabricante; no entanto, a literatura sugere reduzir a dose semanal de 125 mg/m2 para 50 mg/m2 e administrar após hemodiálise ou em dias sem diálise (Janus 2010).
Rotulagem do fabricante:
Metástases hepáticas com função hepática normal: Não é necessário ajuste de dose.
Bilirrubina >ULN para ≤2 mg/dL: Considere reduzir a dose inicial em um nível de dose
Bilirrubina >2 mg/dL: o uso não é recomendado
Recomendações alternativas: Os seguintes ajustes também foram recomendados:
Bilirrubina 1,5 a 3 mg/dL: Administrar 75% da dose (Floyd 2006)
Bilirrubina 1,51 a 3 vezes o LSN: Reduzir a dose de 350 mg/m2 a cada 3 semanas para 200 mg/m2 a cada 3 semanas (Raymond 2002)
• Bone marrow suppression: [US Boxed Warning]: May cause severe myelosuppression. Deaths due to sepsis following severe neutropenia have been reported. Complications due to neutropenia should be promptly managed with antibiotics. Therapy should be temporarily withheld if neutropenic fever occurs or if the absolute neutrophil count is <1,000/mm3; reduce the dose upon recovery to an absolute neutrophil count ≥1,000/mm3. Patients who have previously received pelvic/abdominal radiation therapy have an increased risk of severe bone marrow suppression; the incidence of grade 3 or 4 neutropenia was higher in patients receiving weekly irinotecan who have previously received pelvic/abdominal radiation therapy. Concurrent radiation therapy is not recommended with irinotecan (based on limited data).
• Diarrhea: [US Boxed Warning]: Severe diarrhea may be dose-limiting and potentially fatal; early-onset and late-onset diarrhea may occur. Early diarrhea occurs during or within 24 hours of receiving irinotecan and is characterized by cholinergic symptoms; may be prevented or treated with atropine. Late diarrhea may be life-threatening and should be promptly treated with loperamide. Antibiotics may be necessary if patient develops ileus, fever, or severe neutropenia. Interrupt treatment and reduce subsequent doses for severe diarrhea. Early diarrhea is generally transient and rarely severe; cholinergic symptoms may include increased salivation, rhinitis, miosis, diaphoresis, flushing, abdominal cramping, and lacrimation; bradycardia may also occur. Cholinergic symptoms may occur more frequently with higher irinotecan doses. Late diarrhea occurs more than 24 hours after treatment, which may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea may be complicated by colitis, ulceration, bleeding, ileus, obstruction, or infection; cases of megacolon and intestinal perforation have been reported. The median time to onset for late diarrhea is 5 days with every 3 week irinotecan dosing and 11 days with weekly dosing. Advise patients to have loperamide readily available for the treatment of late diarrhea. Patients with diarrhea should be carefully monitored and treated promptly; may require fluid and electrolyte therapy. Bowel function should be returned to baseline for at least 24 hours prior to resumption of weekly irinotecan dosing. Avoid diuretics and laxatives in patients experiencing diarrhea.
• Extravasation: Irinotecan is an irritant. Avoid extravasation; if extravasation occurs, the manufacturer recommends flushing the external site with sterile water and applying ice.
• Gastrointestinal toxicity: Irinotecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (POGO [Dupuis 2011]; ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]).
• Hepatitis B virus screening: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
• Hypersensitivity: Severe hypersensitivity reactions (including anaphylaxis) have occurred. Monitor closely; discontinue therapy if hypersensitivity occurs.
• Pulmonary toxicity: Fatal cases of interstitial pulmonary disease (IPD)-like events have been reported with single-agent and combination therapy. Risk factors for pulmonary toxicity include preexisting lung disease, use of pulmonary toxic medications, radiation therapy, and colony-stimulating factors. Patients with risk factors should be monitored for respiratory symptoms before and during irinotecan treatment. Promptly evaluate progressive changes in baseline pulmonary symptoms or any new-onset pulmonary symptoms (eg, dyspnea, cough, fever). Discontinue all chemotherapy if IPD is diagnosed.
• Renal toxicity: Renal impairment and acute renal failure have been reported, possibly due to dehydration secondary to diarrhea. Use with caution in patients with renal impairment; not recommended in patients on dialysis.
• Thromboembolism: Thromboembolic events have been reported.
Floyd J, Mirza I, Sachs B, et al, “Hepatotoxicity of Chemotherapy,” Semin Oncol, 2006, 33(1):50-67.
Raymond E, Boige V, Faivre S, et al, “Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic Dysfunction,” J Clin Oncol, 2002, 20(21):4303-12.