Hypersensitivity reactions: Hypersensitivity reactions, including severe anaphylactic/anaphylactoid reactions, have been reported.
Administration: Irinotecan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Irinotecan will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks: in patients presenting a risk factor, particularly those with a WHO performance status = 2;
in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrheal treatment combined with high fluid intake at onset of delayed diarrhea). Strict hospital supervision is recommended for such patients.
Cholinergic symptoms: Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing (vasodilation), bradycardia, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea (i.e., diarrhea generally occurring during or within 8 hours of administration of irinotecan). These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher irinotecan doses. Therapeutic or prophylactic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing cholinergic symptoms.
Extravasation: While irinotecan is not a known vesicant, care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site, and application of ice is recommended.
Hepatic: In clinical studies, National Cancer Institute (NCI) Common Toxicity Criteria Grade 3 or 4 liver enzyme abnormalities have been observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases and are not clearly related to irinotecan.
Hematology: Irinotecan commonly causes neutropenia, leukopenia, and anemia, any of which may be severe and therefore, should not be used in patients with severe bone marrow failure. Serious thrombocytopenia is uncommon. In clinical studies, the frequency of NCI Grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also have had a significantly greater likelihood of experiencing first-cycle Grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL. There were no significant differences in the frequency of Grade 3 and 4 neutropenia by age or gender (see Dosage & Administration).
Neutropenic fever (concurrent NCI Grade 4 neutropenia and ≥Grade 2 fever) occurred in fewer than 10% of patients in clinical studies; however, deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan. Neutropenic complications should be managed promptly with antibiotic support. Therapy with irinotecan should be temporarily discontinued if neutropenic fever occurs or if the absolute neutrophil count drops below 1000/mm3. The dose of irinotecan should be reduced if clinically significant neutropenia occurs (see Dosage & Administration).
Patients with reduced UGT1A1 activity: The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 subsequently undergoes conjugation to form the inactive glucuronide metabolite SN-38G. This glucuronidation reaction is mediated primarily by uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is encoded by the UGT1A1 gene (see Pharmacology: Pharmacokinetics under Actions). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1 28 variant allele. This variant and other congenital deficiencies in UGT1A1 expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced enzyme activity and increased systemic exposure to SN-38. Higher plasma concentrations of SN-38 are observed in individuals who are homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype) versus patients who have one or two wild-type alleles.
Data from a meta-analysis of nine studies involving a total of 821 patients indicate that individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for the UGT1A1*28 allele (Gilbert's syndrome) are at increased risk of hematological toxicity (Grades 3 and 4) following administration of irinotecan at moderate or high doses (>150 mg/m2). A relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhea was not established.
Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated irinotecan starting dose. However, these patients should be monitored for hematologic toxicities. A reduced irinotecan starting dose should be considered for patients who have experienced prior hematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on individual patient tolerance to treatment.
Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Late diarrhea: Late diarrhea (generally occurring more than 8 hours after administration of irinotecan) can be prolonged, may lead to dehydration, electrolyte imbalance, or sepsis and may be life-threatening. In the clinical studies testing the every 3-week-dosage schedule, the median time to the onset of late diarrhea was 5 days after irinotecan infusion. In the clinical studies evaluating the weekly dosage schedule, the median time to onset of late diarrhea was 11 days following administration of irinotecan. For patients starting treatment at the 125 mg/m2 weekly dose, the median duration of any grade of late diarrhea was 3 days. Among those patients treated at the 125 mg/m2 weekly dose who experienced Grade 3 or 4 late diarrhea, the median duration of the entire episode of diarrhea was 7 days. Results from a prospective study of the weekly dosage schedule did not demonstrate any difference in the rate of late onset diarrhea in patients ≥65 yearsof age than patients <65 years of age. However, patients ≥65 years of age should be closely monitored due to a greater risk of early diarrhea observed in this population. Colonic ulceration, sometimes with bleeding, has been observed in association with irinotecan-induced diarrhea.
Late diarrhea should be treated promptly with loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. The recommended dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours. Premedication with loperamide is not recommended. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated and should be given antibiotic support if they develop ileus, fever, or severe neutropenia. In addition to the antibiotic treatment, hospitalization is recommended for management of the diarrhea, in the following cases: Diarrhea associated with fever.
Severe diarrhea (requiring intravenous hydration).
Patients with vomiting associated with delayed (i.e., late) diarrhea.
Diarrhea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.
After the first treatment, subsequent weekly chemotherapy treatments should be delayed in patients until return of pre-treatment bowel function for at least 24 hours without need for anti-diarrhea medication. If NCI Grade 2, 3, or 4 diarrhea occurs, subsequent doses of irinotecan should be reduced within the current cycle (see Dosage & Administration).
Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with irinotecan until resolution of the bowel obstruction.
Nausea & vomiting: Irinotecan is emetogenic. Nausea and vomiting can be severe and usually occurs during or shortly after infusion of irinotecan. It is recommended that patients receive premedication with antiemetic agents. Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan. Physicians should also consider providing patients with an antiemetic regimen for subsequent use as needed. Patients with vomiting associated with delayed (i.e., late) diarrhea should be hospitalized as soon as possible for treatment.
Neurologic: Dizziness has been observed and may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.
Renal: Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhea. Rare instances of renal dysfunction due to tumor lysis syndrome have also been reported.
Respiratory: NCI Grade 3 or 4 dyspnea has been observed. The extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea is unknown. A potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever, and a reticulonodular pattern on chest x-ray, was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan to these preliminary events was difficult to assess because these patients also had lung tumors and some had pre-existing non-malignant pulmonary disease.
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
Others: Since this product contains sorbitol, it is unsuitable in hereditary fructose intolerance.
Effects on ability to drive and use machines: The effect of irinotecan on the ability to drive or use machinery has not been evaluated. However, patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan, and advised not to drive or operate machinery if these symptoms occur (see Precautions).
Special populations: Irradiation therapy: Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation. Specific dosing recommendations may apply to this population depending upon the regimen used (see Dosage & Administration).
Performance status: Patients with poor performance status are at increased risk of irinotecan-related adverse events. Specific dosing recommendations for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 may apply depending upon the regimen used (see Dosage & Administration). Patients with performance status of 3 or 4 should not receive irinotecan. In patients receiving either irinotecan/5-FU/LVor 5-FU/LV in clinical trials comparing these agents, higher rates of hospitalisation, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.
Gastric cancer: Patients with gastric cancer appear to experience greater myelosuppression and other toxicities when given irinotecan. A lower starting dose should be considered in these patients (see Dosage & Administration).
Hepatic insufficiency: In patients with hyperbilirubinemia, the clearance of irinotecan is decreased (see Pharmacology: Pharmacokinetics under Actions) and therefore, the risk of hematotoxicity is increased. The use of irinotecan in patients with a serum total bilirubin concentration of >3.0 x institutional upper limit of normal (IULN) given as a single-agent on the once-every-3-weeks schedule has not been established (see Dosage & Administration). Liver function should be monitored before initiation of treatment and monthly, or as clinically indicated.
Use in Children: The effectiveness of irinotecan in pediatric patients has not been established (see Pharmacology: Pharmacokinetics under Actions). Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/m2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults.
In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3, and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant Grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalaemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition, Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship).
Use in Elderly: Specific dosing recommendations may apply to this population depending upon the regimen used (see Dosage & Administration).