FDA label 62202c5b-9276-403d-8b45-d06730293aa8

WARNING: DIARRHEA and MYELOSUPPRESSION Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt Irinotecan Hydrochloride Injection and reduce subsequent doses if severe diarrhea occurs [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)] . Severe myelosuppression may occur [see Warnings and Precautions (5.2)] . WARNING: DIARRHEA and MYELOSUPPRESSION See full prescribing information for complete boxed warning. Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt Irinotecan Hydrochloride Injection and reduce subsequent doses if severe diarrhea occurs. (2.2, 5.1) Severe myelosuppression may occur. (5.2)

5 WARNINGS AND PRECAUTIONS Diarrhea and Cholinergic Reactions: Early diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt Irinotecan Hydrochloride Injection and reduce subsequent doses if severe diarrhea occurs. (5.1) Myelosuppression: Manage promptly with antibiotic support. Interrupt Irinotecan Hydrochloride Injection and reduce subsequent doses if necessary. (5.2) Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of Irinotecan Hydrochloride Injection treatment. (5.3) Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue Irinotecan Hydrochloride Injection if this occurs. (5.4) Renal Impairment/Renal Failure: Rare cases of renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea. (5.5) Pulmonary Toxicity: Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred. Interrupt for new or progressive dyspnea, cough, and fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate treatment as needed. (5.6) Toxicity of the 5 Day Regimen: Irinotecan Hydrochloride Injection should not be used in combination with a regimen of 5-FU/LV administered for 4 to 5 consecutive days every 4 weeks outside of a clinical study. (5.7) Embryo-Fetal Toxicity: Irinotecan Hydrochloride Injection can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with female partners of reproductive potential to use condoms. (5.9, 8.1, 8.3) Patients with Hepatic Impairment: In clinical trials, Irinotecan Hydrochloride Injection has not been administered to patients with serum bilirubin greater than 2.0 mg/dL, or transaminases greater than 3 times ULN if no liver metastases, or transaminases greater than 5 times ULN if liver metastases. With the weekly dosage schedule, patients with total bilirubin levels 1.0 to 2.0 mg/dL had greater likelihood of grade 3 to 4 neutropenia. (5.10) 5.1 Diarrhea and Cholinergic Reactions Early diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses. Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3 to 4 late diarrhea occurred in 23 to 31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One 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. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of Irinotecan Hydrochloride Injection should be decreased [see Dosage and Administration ( 2 )]. Avoid diuretics or laxatives in patients with diarrhea. 5.2 Myelosuppression Irinotecan Hydrochloride Injection can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with Irinotecan Hydrochloride Injection. Deaths due to sepsis following severe neutropenia have been reported in patients treated with Irinotecan Hydrochloride Injection. 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. Manage febrile neutropenia promptly with antibiotic support [see Warnings and Precautions (5.2)]. Hold Irinotecan Hydrochloride Injection if neutropenic fever occurs or if the absolute neutrophil count drops less than 1000/mm 3 . After recovery to an absolute neutrophil count greater than or equal to 1000/mm 3 , subsequent doses of Irinotecan Hydrochloride Injection should be reduced [see Dosage and Administration ( 2 )]. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was 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). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of Irinotecan Hydrochloride Injection. Based on sparse available data, the concurrent administration of Irinotecan Hydrochloride Injection with irradiation is not recommended. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a 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). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with Irinotecan Hydrochloride Injection. 5.3 Patients With Reduced UGT1A1 Activity Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Irinotecan Hydrochloride Injection treatment. In a study of 66 patients who received single-agent Irinotecan Hydrochloride Injection (350 mg/m 2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype). In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with Irinotecan Hydrochloride Injection (180 mg/m 2 ) in combination with infusional 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele. In another study in which 109 patients were treated with Irinotecan Hydrochloride Injection (100 to 125 mg/m 2 ) in combination with bolus 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele. When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment [see Dosage and Administration ( 2 )]. UGT1A1 Testing A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes. 5.4 Hypersensitivity Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue Irinotecan Hydrochloride Injection if anaphylactic reaction occurs. 5.5 Renal Impairment/Renal Failure Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea. 5.6 Pulmonary Toxicity Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (in combination and as monotherapy). Risk factors 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. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, irinotecan and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see Adverse Reactions ( 6.1 )]. 5.7 Toxicity of the 5 Day Regimen Outside of a well-designed clinical study, Irinotecan Hydrochloride Injection should not be used in combination with a regimen of 5-FU/LV administered for 4 to 5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. Irinotecan Hydrochloride Injection should be used as recommended [see Dosage and Administration ( 2 )]. 5.8 Increased Toxicity in Patients with Performance Status 2 In the clinical trials, higher rates of hospitalization, 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. 5.9 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, Irinotecan Hydrochloride Injection can cause fetal harm when administered to a pregnant woman. In animal studies, intravenous administration of irinotecan during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 125 mg/m 2 . Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with Irinotecan Hydrochloride Injection and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of Irinotecan Hydrochloride Injection [see Use in Specific Populations ( 8.1 ), ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] . 5.10 Patients with Hepatic Impairment The use of Irinotecan Hydrochloride Injection in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin greater than 2.0 mg/dL, or transaminase greater than 3 times the upper limit of normal if no liver metastasis, or transaminase greater than 5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) 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% [47/226]; p<0.001) [see Dosage and Administration ( 2 ), Use in Specific Populations (8.7) and Clinical Pharmacology ( 12.3 )].

6 ADVERSE REACTIONS Common adverse reactions (greater than or equal to 30%) observed in single-agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (greater than or equal to 30%) observed in single-agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. 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. One of the 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 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%). 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 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1) . Table 7. Adverse Events Occurring in Greater Than 10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum a % of Patients Reporting Body System & Event NCI Grades 1 to 4 NCI Grades 3 & 4 a Severity of adverse events based on NCI CTC (version 1.0) b Occurring greater than 24 hours after administration of Irinotecan Hydrochloride Injection c Occurring less than or equal to 24 hours after administration of Irinotecan Hydrochloride Injection d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2 GASTROINTESTINAL Diarrhea (late) b 88 31 7 to 9 stools/day (grade 3) -- (16) ≥10 stools/day (grade 4) -- (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early) c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm 3 (grade 3) -- (15) <500/mm 3 (grade 4) -- (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infection d 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NA e Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Coughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 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 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 to 4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies (14.1) . Table 8. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy a Study 1 Study 2 Irinotecan BSC b Irinotecan 5-FU Adverse Event N=189 N=90 N=127 N=129 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 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea 22 6 22 11 Vomiting 14 8 14 5 Nausea 14 3 11 4 Abdominal pain 14 16 9 8 Constipation 10 8 8 6 Anorexia 5 7 6 4 Mucositis 2 1 2 5 HEMATOLOGIC Leukopenia/Neutropenia 22 0 14 2 Anemia 7 6 6 3 Hemorrhage 5 3 1 3 Thrombocytopenia 1 0 4 2 Infection without grade 3/4 neutropenia 8 3 1 4 with grade 3/4 neutropenia 1 0 2 0 Fever without grade 3/4 neutropenia 2 1 2 0 with grade 3/4 neutropenia 2 0 4 2 BODY AS A WHOLE Pain 19 22 17 13 Asthenia 15 19 13 12 METABOLIC AND NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand and foot syndrome 0 0 0 5 Cutaneous signs d 2 0 1 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 The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as Irinotecan Hydrochloride Injection than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Irinotecan Hydrochloride Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Myocardial ischemic events have been observed following irinotecan therapy. Thromboembolic events have been observed in patients receiving Irinotecan Hydrochloride Injection. Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed. Hyponatremia, mostly with diarrhea and vomiting, has 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. Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized. Infections: fungal and viral infections have been reported.

<table ID="LINK_8561509a-98ca-4895-a4ff-87d618dea922"><caption> Table 7. Adverse Events Occurring in Greater Than 10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum^a</caption><col/><col/><col/><thead><tr><td align="center" valign="bottom"> </td><td align="center" colspan="2"> <content styleCode="bold">% of Patients Reporting</content></td></tr><tr><td align="center" valign="bottom"> <content styleCode="bold">Body System &amp; Event</content></td><td align="center" valign="top"> <content styleCode="bold">NCI Grades 1 to 4</content></td><td align="center" valign="top"> <content styleCode="bold">NCI Grades 3 &amp; 4</content></td></tr></thead><tfoot><tr><td valign="top" colspan="3"> ^a Severity of adverse events based on NCI CTC (version 1.0) </td></tr><tr><td valign="top" colspan="3"> ^b Occurring greater than 24 hours after administration of Irinotecan Hydrochloride Injection </td></tr><tr><td valign="top" colspan="3"> ^c Occurring less than or equal to 24 hours after administration of Irinotecan Hydrochloride Injection </td></tr><tr><td valign="top" colspan="3"> ^d Primarily upper respiratory infections </td></tr><tr><td valign="top" colspan="3"> ^e Not applicable; complete hair loss = NCI grade 2 </td></tr></tfoot><tbody><tr><td> <content styleCode="bold">GASTROINTESTINAL </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> Diarrhea (late)^b</td><td align="center"> 88</td><td align="center"> 31</td></tr><tr><td> 7 to 9 stools/day (grade 3) </td><td align="center"> --</td><td align="center"> (16)</td></tr><tr><td> &#x2265;10 stools/day (grade 4) </td><td align="center"> --</td><td align="center"> (14)</td></tr><tr><td> Nausea </td><td align="center"> 86</td><td align="center"> 17</td></tr><tr><td> Vomiting </td><td align="center"> 67</td><td align="center"> 12</td></tr><tr><td> Anorexia </td><td align="center"> 55</td><td align="center"> 6</td></tr><tr><td> Diarrhea (early)^c</td><td align="center"> 51</td><td align="center"> 8</td></tr><tr><td> Constipation </td><td align="center"> 30</td><td align="center"> 2</td></tr><tr><td> Flatulence </td><td align="center"> 12</td><td align="center"> 0</td></tr><tr><td> Stomatitis </td><td align="center"> 12</td><td align="center"> 1</td></tr><tr><td> Dyspepsia </td><td align="center"> 10</td><td align="center"> 0</td></tr><tr><td> <content styleCode="bold">HEMATOLOGIC </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> Leukopenia </td><td align="center"> 63</td><td align="center"> 28</td></tr><tr><td> Anemia </td><td align="center"> 60</td><td align="center"> 7</td></tr><tr><td> Neutropenia </td><td align="center"> 54</td><td align="center"> 26</td></tr><tr><td valign="top"> 500 to &lt;1000/mm³ (grade 3) </td><td align="center" valign="bottom"> --</td><td align="center"> (15)</td></tr><tr><td valign="top"> &lt;500/mm³ (grade 4) </td><td align="center"> --</td><td align="center"> (12)</td></tr><tr><td> <content styleCode="bold">BODY AS A WHOLE </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> Asthenia </td><td align="center"> 76</td><td align="center"> 12</td></tr><tr><td> Abdominal cramping/pain </td><td align="center"> 57</td><td align="center"> 16</td></tr><tr><td> Fever </td><td align="center"> 45</td><td align="center"> 1</td></tr><tr><td> Pain </td><td align="center"> 24</td><td align="center"> 2</td></tr><tr><td> Headache </td><td align="center"> 17</td><td align="center"> 1</td></tr><tr><td> Back pain </td><td align="center"> 14</td><td align="center"> 2</td></tr><tr><td> Chills </td><td align="center"> 14</td><td align="center"> 0</td></tr><tr><td valign="top"> Minor infection^d</td><td align="center"> 14</td><td align="center"> 0</td></tr><tr><td> Edema </td><td align="center"> 10</td><td align="center"> 1</td></tr><tr><td> Abdominal enlargement </td><td align="center"> 10</td><td align="center"> 0</td></tr><tr><td> <content styleCode="bold">METABOLIC AND NUTRITIONAL </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> &#x2193; Body weight </td><td align="center"> 30</td><td align="center"> 1</td></tr><tr><td> Dehydration </td><td align="center"> 15</td><td align="center"> 4</td></tr><tr><td> &#x2191; Alkaline phosphatase </td><td align="center"> 13</td><td align="center"> 4</td></tr><tr><td> &#x2191; SGOT </td><td align="center"> 10</td><td align="center"> 1</td></tr><tr><td> <content styleCode="bold">DERMATOLOGIC</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> Alopecia </td><td align="center"> 60</td><td align="center"> NA^e</td></tr><tr><td> Sweating </td><td align="center"> 16</td><td align="center"> 0</td></tr><tr><td> Rash </td><td align="center"> 13</td><td align="center"> 1</td></tr><tr><td> <content styleCode="bold">RESPIRATORY </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td> Dyspnea </td><td align="center"> 22</td><td align="center"> 4</td></tr><tr><td> &#x2191; Coughing </td><td align="center"> 17</td><td align="center"> 0</td></tr><tr><td> Rhinitis </td><td align="center"> 16</td><td align="center"> 0</td></tr><tr><td valign="top"> <content styleCode="bold">NEUROLOGIC </content></td><td align="center" valign="bottom"> </td><td align="center" valign="bottom"> </td></tr><tr><td valign="top"> Insomnia </td><td align="center" valign="bottom"> 19 </td><td align="center" valign="bottom"> 0 </td></tr><tr><td valign="top"> Dizziness </td><td align="center" valign="bottom"> 15</td><td align="center" valign="bottom"> 0</td></tr><tr><td valign="top"> <content styleCode="bold">CARDIOVASCULAR </content></td><td align="center" valign="bottom"> </td><td align="center" valign="bottom"> </td></tr><tr><td valign="top"> Vasodilation (flushing) </td><td align="center" valign="bottom"> 11</td><td align="center" valign="bottom"> 0</td></tr></tbody></table>

<table ID="LINK_1d2352be-c152-44ea-8589-33e611492cd3"><caption> Table 8. Percent Of Patients Experiencing Grade 3 &amp; 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapy^a</caption><col/><col/><col/><col/><col/><thead><tr><td valign="top"> </td><td align="center" valign="top" colspan="2"> <content styleCode="bold">Study 1</content></td><td align="center" valign="top" colspan="2"> <content styleCode="bold">Study 2</content></td></tr><tr><td valign="top"> </td><td align="center" valign="top"> <content styleCode="bold">Irinotecan </content></td><td align="center" valign="top"> <content styleCode="bold">BSC</content><content styleCode="bold">^b</content></td><td align="center" valign="top"> <content styleCode="bold">Irinotecan </content></td><td align="center" valign="top"> <content styleCode="bold">5-FU </content></td></tr><tr><td valign="top"> <content styleCode="bold">Adverse Event </content></td><td align="center" valign="top"> <content styleCode="bold">N=189</content></td><td align="center" valign="top"> <content styleCode="bold">N=90</content></td><td align="center" valign="top"> <content styleCode="bold">N=127</content></td><td align="center" valign="top"> <content styleCode="bold">N=129</content></td></tr></thead><tfoot><tr><td> ^a Severity of adverse events based on NCI CTC (version 1.0) </td></tr><tr><td> ^b BSC = best supportive care </td></tr><tr><td> ^c Hepatic includes events such as ascites and jaundice </td></tr><tr><td> ^d Cutaneous signs include events such as rash </td></tr><tr><td> ^e Respiratory includes events such as dyspnea and cough </td></tr><tr><td> ^f Neurologic includes events such as somnolence </td></tr><tr><td> ^g Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction </td></tr><tr><td> ^h Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss </td></tr></tfoot><tbody><tr><td> TOTAL Grade 3/4 </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td> Adverse Events </td><td align="center"> 79</td><td align="center"> 67</td><td align="center"> 69</td><td align="center"> 54</td></tr><tr><td valign="top"> <content styleCode="bold">GASTROINTESTINAL </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Diarrhea </td><td align="center" valign="top"> 22</td><td align="center" valign="top"> 6</td><td align="center" valign="top"> 22</td><td align="center" valign="top"> 11</td></tr><tr><td valign="top"> Vomiting </td><td align="center" valign="top"> 14</td><td align="center" valign="top"> 8</td><td align="center" valign="top"> 14</td><td align="center" valign="top"> 5</td></tr><tr><td valign="top"> Nausea </td><td align="center" valign="top"> 14</td><td align="center" valign="top"> 3</td><td align="center" valign="top"> 11</td><td align="center" valign="top"> 4</td></tr><tr><td valign="top"> Abdominal pain </td><td align="center" valign="top"> 14</td><td align="center" valign="top"> 16</td><td align="center" valign="top"> 9</td><td align="center" valign="top"> 8</td></tr><tr><td valign="top"> Constipation </td><td align="center" valign="top"> 10</td><td align="center" valign="top"> 8</td><td align="center" valign="top"> 8</td><td align="center" valign="top"> 6</td></tr><tr><td valign="top"> Anorexia </td><td align="center" valign="top"> 5</td><td align="center" valign="top"> 7</td><td align="center" valign="top"> 6</td><td align="center" valign="top"> 4</td></tr><tr><td valign="top"> Mucositis </td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 5</td></tr><tr><td valign="top"> <content styleCode="bold">HEMATOLOGIC </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Leukopenia/Neutropenia</td><td align="center" valign="top"> 22</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 14</td><td align="center" valign="top"> 2</td></tr><tr><td valign="top"> Anemia </td><td align="center" valign="top"> 7</td><td align="center" valign="top"> 6</td><td align="center" valign="top"> 6</td><td align="center" valign="top"> 3</td></tr><tr><td valign="top"> Hemorrhage</td><td align="center" valign="top"> 5</td><td align="center" valign="top"> 3</td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 3</td></tr><tr><td valign="top"> Thrombocytopenia</td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 4</td><td align="center" valign="top"> 2</td></tr><tr><td valign="top"> <content styleCode="bold">Infection </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> without grade 3/4 neutropenia</td><td align="center" valign="top"> 8</td><td align="center" valign="top"> 3</td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 4</td></tr><tr><td valign="top"> with grade 3/4 neutropenia </td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top"> <content styleCode="bold">Fever </content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> without grade 3/4 neutropenia </td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 1</td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top"> with grade 3/4 neutropenia </td><td align="center" valign="top"> 2</td><td align="center" valign="top"> 0</td><td align="center" valign="top"> 4</td><td align="center" valign="top"> 2</td></tr><tr><td valign="top"> <content styleCode="bold">BODY AS A WHOLE </content></td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td valign="top"> Pain </td><td align="center"> 19</td><td align="center"> 22</td><td align="center"> 17</td><td align="center"> 13</td></tr><tr><td valign="top"> Asthenia </td><td align="center"> 15</td><td align="center"> 19</td><td align="center"> 13</td><td align="center"> 12</td></tr><tr><td valign="top"> <content styleCode="bold">METABOLIC AND NUTRITIONAL</content></td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td><td align="center" valign="top"> </td></tr><tr><td valign="top"> Hepatic ^c</td><td align="center" valign="top"> 9</td><td align="center" valign="top"> 7</td><td align="center" valign="top"> 9</td><td align="center" valign="top"> 6</td></tr><tr><td valign="top"> <content styleCode="bold">DERMATOLOGIC </content></td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td valign="top"> Hand and foot syndrome </td><td align="center"> 0</td><td align="center"> 0</td><td align="center"> 0</td><td align="center"> 5</td></tr><tr><td valign="top"> Cutaneous signs ^d</td><td align="center"> 2</td><td align="center"> 0</td><td align="center"> 1</td><td align="center"> 3</td></tr><tr><td> <content styleCode="bold">RESPIRATORY </content>^e</td><td align="center"> 10</td><td align="center"> 8</td><td align="center"> 5</td><td align="center"> 7</td></tr><tr><td> <content styleCode="bold">NEUROLOGIC </content>^f</td><td align="center"> 12</td><td align="center"> 13</td><td align="center"> 9</td><td align="center"> 4</td></tr><tr><td> <content styleCode="bold">CARDIOVASCULAR </content>^g</td><td align="center"> 9</td><td align="center"> 3</td><td align="center"> 4</td><td align="center"> 2</td></tr><tr><td> <content styleCode="bold">OTHER </content>^h</td><td align="center"> 32</td><td align="center"> 28</td><td align="center"> 12</td><td align="center"> 14</td></tr></tbody></table>