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adverse reactions
ADVERSE REACTIONS Second-Line Single-Agent Therapy Weekly Dosage Schedule In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan Hydrochloride Injection. Seventeen of the patients died within 30 days of the administration of Irinotecan Hydrochloride Injection; in five cases (1.6%, 5/304), the deaths were potentially drug-related. These five patients experienced a constellation of medical events that included known effects of Irinotecan Hydrochloride Injection. One of these patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care. One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan Hydrochloride Injection. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%). Adjustments in the dose of Irinotecan Hydrochloride Injection were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The first dose of at least one cycle of Irinotecan Hydrochloride Injection was reduced for 67% of patients who began the studies at the 125-mg/m 2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan Hydrochloride Injection because of adverse events. The adverse events in Table 5 are based on the experience of the 304 patients enrolled in the three studies described in the CLINICAL STUDIES, Studies Evaluating the Weekly Dosage Schedule , section. Table 5. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum a Body System & Event % of Patients Reporting NCI Grades 1-4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) b 7-9 stools/day (grade 3) ≥10 stools/day (grade 4) Nausea Vomiting Anorexia Diarrhea (early) c Constipation Flatulence Stomatitis Dyspepsia 88 - - 86 67 55 51 30 12 12 10 31 (16) (14) 17 12 6 8 2 0 1 0 HEMATOLOGIC Leukopenia Anemia Neutropenia 500 to <1000/mm 3 (grade 3) <500/mm 3 (grade 4) 63 60 54 - - 28 7 26 (15) (12) BODY AS A WHOLE Asthenia Abdominal cramping/pain Fever Pain Headache Back pain Chills Minor infection d Edema Abdominal enlargement 76 57 45 24 17 14 14 14 10 10 12 16 1 2 1 2 0 0 1 0 METABOLIC & NUTRITIONAL ↓Body weight Dehydration ↑Alkaline phosphatase ↑SGOT 30 15 13 10 1 4 4 1 DERMATOLOGIC Alopecia Sweating Rash 60 16 13 NA e 0 1 RESPIRATORY Dyspnea ↑Coughing Rhinitis 22 17 16 4 0 0 NEUROLOGIC Insomnia Dizziness 19 15 0 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 a Severity of adverse events based on NCI CTC (version 1.0) b Occurring >24 hours after administration of Irinotecan Hydrochloride Injection c Occurring ≤24 hours after administration of Irinotecan Hydrochloride Injection d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2 Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea. Hospitalizations due to serious adverse events (whether or not related to study treatment) occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5- FU-based therapy discontinued treatment due to adverse events. Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 6 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in the CLINICAL STUDIES , Studies Evaluating the Once-Every-3-Week Dosage Schedule , section. Table 6. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy a Adverse Event Study 1 Study 2 Irinotecan N = 189 BSC b N = 90 Irinotecan N = 127 5-FU N = 129 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea Vomiting Nausea Abdominal pain Constipation Anorexia Mucositis 22 14 14 14 10 5 2 6 8 3 16 8 7 1 22 14 11 9 8 6 2 11 5 4 8 6 4 5 HEMATOLOGIC Leukopenia/Neutropenia Anemia Hemorrhage Thrombocytopenia Infection without grade 3/4 neutropenia with grade 3/4 neutropenia Fever without grade 3/4 neutropenia with grade 3/4 neutropenia 22 7 5 1 8 1 2 2 0 6 3 0 3 0 1 0 14 6 1 4 1 2 2 4 2 3 3 2 4 0 0 2 BODY AS A WHOLE Pain Asthenia 19 15 22 19 17 13 13 12 METABOLIC & NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand & foot syndrome Cutaneous signs d 0 2 0 0 0 1 5 3 RESPIRATORY e 10 8 5 7 NEUROLOGIC f 12 13 9 4 CARDIOVASCULAR g 9 3 4 2 OTHER h 32 28 12 14 a Severity of adverse events based on NCI CTC (version 1.0) b BSC = best supportive care c Hepatic includes events such as ascites and jaundice d Cutaneous signs include events such as rash e Respiratory includes events such as dyspnea and cough f Neurologic includes events such as somnolence g Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction h Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss Overview of Adverse Events Gastrointestinal Nausea, vomiting, and diarrhea are common adverse events following treatment with Irinotecan Hydrochloride Injection and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of Irinotecan Hydrochloride Injection. An increased incidence of late diarrhea was observed in two studies, one using a 3-week schedule and the other using a weekly schedule. 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 Hydrochloride Injection. For patients starting treatment at the 125-mg/m 2 weekly dose, the median duration of any grade of late diarrhea was 3 days. Among those patients treated at the 125-mg/m 2 weekly dose who experienced grade 3 or 4 late diarrhea, the median duration of the entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125 mg/m 2 than in patients given a 100-mg/m 2 weekly starting dose (34% [65/193] versus 23% [24/102]; p = 0.08). The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p = 0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92]. In one study of the weekly dosage treatment, the frequency of grade 3 and 4 late diarrhea was significantly greater in male than in female patients (43% [25/58] versus 16% [5/32]; p = 0.01), but there were no gender differences in the frequency of grade 3 and 4 late diarrhea in the other two studies of the weekly dosage treatment schedule. Colonic ulceration, sometimes with gastrointestinal bleeding, has been observed in association with administration of Irinotecan Hydrochloride Injection. Hematology Irinotecan Hydrochloride Injection commonly causes neutropenia, leukopenia (including lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p = 0.04). In these same studies, patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also 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 (50% [19/38] versus 18% [47/266]; p<0.001). There were no significant differences in the frequency of grade 3 and 4 neutropenia by age or gender. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 7% of the patients receiving weekly treatment; blood transfusions were given to 10% of the patients in these trials. Body as a Whole Asthenia, fever, and abdominal pain are generally the most common events of this type. Cholinergic Symptoms Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea. If these symptoms occur, they manifest during or shortly after drug infusion. They 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. Hepatic In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases. Dermatologic Alopecia has been reported during treatment with Irinotecan Hydrochloride Injection. Rashes have also been reported but did not result in discontinuation of treatment. Respiratory Severe pulmonary events are infrequent. In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in 4% of patients. Over half the patients with dyspnea had lung metastases; the extent to which malignant pulmonary involvement or other preexisting lung disease may have contributed to dyspnea in these patients is unknown. 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 (see WARNINGS ). Neurologic Insomnia and dizziness can occur, but are not usually considered to be directly related to the administration of Irinotecan Hydrochloride Injection. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration. Cardiovascular Vasodilation (flushing) may occur during administration of Irinotecan Hydrochloride Injection. Bradycardia may also occur, but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of Irinotecan Hydrochloride Injection. Thromboembolic events have been observed in patients receiving Irinotecan Hydrochloride Injection; the specific cause of these events has not been determined. Other Non-U.S. Clinical Trials Irinotecan has been studied in over 1,100 patients in Japan. Patients in these studies had a variety of tumor types, including cancer of the colon or rectum, and were treated with several different doses and schedules. In general, the types of toxicities observed were similar to those seen in U.S. trials with Irinotecan Hydrochloride Injection. There is some information from Japanese trials that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea. 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 preexisting nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the United States have enrolled few patients with compromised pulmonary function, significant ascites, or pleural effusions. Post-Marketing Experience The following events have been identified during postmarketing use of Irinotecan Hydrochloride Injection in clinical practice. Infrequent cases of ulcerative and ischemic colitis have been observed. This can be complicated by ulceration, bleeding, ileus, obstruction, and infection, including typhlitis. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS ). Cases of megacolon, intestinal perforation, symptomatic pancreatitis, and asymptomatic pancreatic enzyme elevation have been reported. Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have also been observed (see WARNINGS ). Cases of hyponatremia mostly related with diarrhea and vomiting have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis; transient increase of amylase and occasionally transient increase of lipase have been reported. Infrequent cases of renal insufficiency including acute renal failure, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see WARNINGS ). Early effects such as muscular contraction or cramps and paresthesia have been reported. Hiccups have been reported. Transient dysarthria has been reported in patients treated with Irinotecan Hydrochloride Injection; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.