FDA label 54ffa1be-92db-498c-a315-fcf73f0989e1

WARNING: DIARRHEA and MYELOSUPPRESSION 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. Severe myelosuppression may occur. 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. Severe myelosuppression may occur.

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 dysnpnea, cough, and fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate treatment as needed. ( 5.6 ) Embryofetal Toxicity : Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. ( 5.9 ) 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 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 less than 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). When administered 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 (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 )] . 5.9 Embryofetal Toxicity Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m 2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m 2 dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m 2 dose).There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan hydrochloride injection. 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 less than 0.001) [see 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 Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) 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. Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia. 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 ). 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 % of Patients Reporting Body System & Event 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 AND 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 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 EventsIn Comparative Studies Of Once-Every-3-Week Irinotecan Therapy a 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 Study 1 Study 2 Adverse Event 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 22 7 5 1 0 6 3 0 14 6 1 4 2 3 3 2 Infection without grade 3/4 neutropenia with grade 3/4 neutropenia Fever without grade 3/4 neutropenia with grade 3/4 neutropenia 8 1 2 2 3 0 1 0 1 2 2 4 4 0 0 2 BODY AS A WHOLE Pain Asthenia 19 15 22 19 17 13 13 12 METABOLIC AND NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand and 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 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.

<table ID="ID422" width="91%"> <col width="53%"/> <col width="25%"/> <col width="21%"/> <tfoot> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> ^aSeverity of adverse events based on NCI CTC (version 1.0)</paragraph> </td> </tr> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> ^bOccurring greater than 24 hours after administration of irinotecan hydrochloride injection</paragraph> </td> </tr> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> ^cOccurring less than or equal to 24 hours after administration of irinotecan hydrochloride injection</paragraph> </td> </tr> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> ^dPrimarily upper respiratory infections </paragraph> </td> </tr> <tr> <td align="left" colspan="3"> <paragraph styleCode="Footnote"> ^eNot applicable; complete hair loss = NCI grade 2</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td valign="top" styleCode=" Toprule Lrule Rrule"/> <td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="left"> <content styleCode="bold"> % of Patients Reporting</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> Body System &amp; Event</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> <content styleCode="bold"> NCI Grades 1-4</content> </td> <td valign="top" styleCode=" Toprule Botrule Rrule" align="left"> <content styleCode="bold"> NCI Grades 3 &amp; 4</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> GASTROINTESTINAL</content> Diarrhea (late)^b 7-9 stools/day (grade 3) &#x2265;10 stools/day (grade 4) Nausea Vomiting Anorexia Diarrhea (early)^c Constipation Flatulence Stomatitis Dyspepsia </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 88 - - 86 67 55 51 30 12 12 10 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 31 (16) (14) 17 12 6 8 2 0 1 0 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> HEMATOLOGIC</content> Leukopenia Anemia Neutropenia 500 to &lt;1000/mm³(grade 3) &lt;500/mm³(grade 4) </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 63 60 54 - - </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 28 7 26 (15) (12) </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> BODY AS A WHOLE</content> Asthenia Abdominal cramping/pain Fever Pain Headache Back pain Chills Minor infection^d Edema Abdominal enlargement </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 76 57 45 24 17 14 14 14 10 10 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 12 16 1 2 1 2 0 0 1 0 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> METABOLIC AND</content> <content styleCode="bold"> NUTRITIONAL</content> &#x2193;Body weight Dehydration &#x2191;Alkaline phosphatase &#x2191;SGOT </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 30 15 13 10 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 1 4 4 1 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> DERMATOLOGIC</content> Alopecia Sweating Rash </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 60 16 13 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> NA^e 0 1 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> RESPIRATORY</content> Dyspnea &#x2191;Coughing Rhinitis </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 22 17 16 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 4 0 0 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> NEUROLOGIC</content> Insomnia Dizziness </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 19 15 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 0 0 </td> </tr> <tr> <td valign="top" styleCode=" Lrule Botrule Rrule" align="left"> <content styleCode="bold"> CARDIOVASCULAR</content> Vasodilation (flushing) </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 11 </td> <td valign="top" styleCode=" Botrule Rrule" align="left"> 0 </td> </tr> </tbody> </table>

<table ID="ID424" width="75%"> <caption> Table 8: Percent Of Patients Experiencing Grade 3 &amp; 4 Adverse EventsIn Comparative Studies Of Once-Every-3-Week Irinotecan Therapy^a </caption> <col width="54%"/> <col width="11%"/> <col width="12%"/> <col width="11%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^aSeverity of adverse events based on NCI CTC (version 1.0) </paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^bBSC = best supportive care </paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^cHepatic includes events such as ascites and jaundice </paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^dCutaneous signs include events such as rash </paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^eRespiratory includes events such as dyspnea and cough^fNeurologic includes events such as somnolence </paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^gCardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction</paragraph> </td> </tr> <tr> <td align="left" colspan="5"> <paragraph styleCode="Footnote"> ^hOther includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td valign="top" styleCode=" Toprule Lrule Rrule"/> <td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="center"> <content styleCode="bold"> Study 1</content> </td> <td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="center"> <content styleCode="bold"> Study 2</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> Adverse Event</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> Irinotecan N=189 </td> <td valign="top" styleCode=" Toprule Botrule Rrule" align="center"> <content styleCode="bold"> BSC^b </content> <content styleCode="bold"> N=90</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> Irinotecan</content> <content styleCode="bold"> N=127</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 5-FU</content> <content styleCode="bold"> N=129</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> TOTAL Grade 3/4 Adverse Events </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 79 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 67 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 69 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 54 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> GASTROINTESTINAL</content> Diarrhea Vomiting Nausea Abdominal pain Constipation Anorexia Mucositis </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 22 14 14 14 10 5 2 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 6 8 3 16 8 7 1 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 22 14 11 9 8 6 2 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 11 5 4 8 6 4 5 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> HEMATOLOGIC</content> Leukopenia/Neutropenia Anemia Hemorrhage Thrombocytopenia </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 22 7 5 1 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 0 6 3 0 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 14 6 1 4 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 2 3 3 2 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> Infection</content> <content styleCode="bold"> </content> without grade 3/4 neutropenia with grade 3/4 neutropenia <content styleCode="bold"> Fever</content> without grade 3/4 neutropenia with grade 3/4 neutropenia </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 8 1 2 2 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 3 0 1 0 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 1 2 2 4 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 4 0 0 2 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> BODY AS A WHOLE</content> Pain Asthenia </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 19 15 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 22 19 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 17 13 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 13 12 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> METABOLIC AND NUTRITIONAL</content> Hepatic^c </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> DERMATOLOGIC</content> Hand and foot syndrome Cutaneous signs^d </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 0 2 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 0 0 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 0 1 </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> 5 3 </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> RESPIRATORY^e </content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 10</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 8</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 5</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 7</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> NEUROLOGIC^f </content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 12</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 13</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 9</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 4</content> </td> </tr> <tr> <td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> CARDIOVASCULAR^g </content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 9</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 3</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 4</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 2</content> </td> </tr> <tr> <td valign="top" styleCode=" Lrule Botrule Rrule" align="left"> <content styleCode="bold"> OTHER^h </content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 32</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 28</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 12</content> </td> <td valign="top" styleCode=" Botrule Rrule" align="center"> <content styleCode="bold"> 14</content> </td> </tr> </tbody> </table>