Irinotecan

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 3; 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).

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 re

Irinotecan is an irritant. Avoid extravasation; if extravasation occurs, the manufacturer recommends flushing the external site with sterile water and applying ice.

Irinotecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

Severe hypersensitivity reactions (including anaphylaxis) have occurred. Monitor closely; discontinue therapy if hypersensitivity occurs.

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 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.

Thromboembolic events have been reported. Disease-related concerns:

Patients with bowel obstruction should not be treated with irinotecan until resolution of obstruction.

Use with caution in patients with hepatic impairment; exposure to the active metabolite (SN-38) is increased; toxicities may be increased. Patients with even modest elevations in total serum bilirubin levels (1 to 2 mg/dL) have a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. CYP3A4 enzyme inducers may decrease exposure to irinotecan and SN-38 (active metabolite); enzyme inhibitors may increase exposure. For use in patients with CNS tumors (off-label use), selection of antiseizure medications that are not enzyme inducers is preferred. Special populations:

Patients >65 years of age are at greater risk for early and late diarrhea. A dose reduction is recommended for patients ≥70 years of age receiving the every-3-week regimen.

Patients homozygous for the UGT1A1*28 allele are at increased risk of neutropenia; consider reducing the initial dose by at least one dose level for both single-agent and combination regimens. Heterozygous carriers of the UGT1A1*28 allele may also be at increased neutropenic risk; however, most patients have tolerated normal starting doses. A test is available for clinical determination of UGT phenotype, although a dose reduction is already recommended in patients who have experienced toxicity.

Use with caution in patients who have previously received pelvic/abdominal radiation; may increase risk of severe myelosuppression.

Higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle discontinuation, and early mortality were observed in patients with a performance status of 2 than in patients with a performance status of 0 or 1. Dosage form specific issues:

Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.

Product contains sorbitol; do not use in patients with hereditary fructose intolerance. Other warnings/precautions:

Except as part of a clinical trial, use in combination with the fluorouracil and leucovorin administered for 4 or 5 consecutive days every 4 weeks (“Mayo Clinic” regimen) is not recommended due to increased toxicity.