Irinotecan hydrochloide

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. (2.2, 5.1) • Severe myelosuppression may occur. (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 [see Dosage and Administration ( 2.2) and Warnings and Precautions (5.1)]. Severe myelosuppression may occur [see Warnings and Precautions ( 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 ) • Increased Risk of Neutropenia in Patients with Reduced UGT1A1 Activity: Individuals with UGT1A1 *28/*28, or *6/*6, or *6/*28 genotypes are at increased risk for severe neutropenia during 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 4-5 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 > 2.0 mg/dL, or transaminases > 3 times ULN if no liver metastases, or transaminases > 5 times ULN if liver metastases. With the weekly dosage schedule, patients with total bilirubin levels 1.0-2.0 mg/dL had greater likelihood of grade 3-4 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 hydrochloride injection 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 <1000/mm 3 . After recovery to an absolute neutrophil count ≥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 [see Warnings and Precautions ( 5.3 )] . 5.3 Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity Published studies have shown that individuals who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during treatment with irinotecan hydrochloride injection. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 , 12.5 ) ]. Consider UGT1A1 genotype testing for the *28 and *6 alleles to determine UGT1A1 metabolizer status [see Clinical Pharmacology ( 12. 5 ) ]. When administering irinotecan hydrochloride injection, consider a reduction in the irinotecan hydrochloride injection starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A1*28 and/or *6 alleles (*28/*28, *6/*6, *6/*28). Closely monitor patients with UGT1A1*28 or *6 alleles for neutropenia during and after treatment with irinotecan hydrochloride injection. The precise dosage reduction in this patient population is not known. Subsequent dosage modifications may be required based on individual patient tolerance to treatment [see Dosage and Administration ( 2.1 , 2.2 ) ]. 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 hydrochloride injection 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 hydrochloride injection 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 in Table 2 [see Dosage and Administration (2) ]. 5.8 Increased Toxicity in Patients With Performance Status 2 In patients receiving either irinotecan/5-FU/LV or 5-FU/LV 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 pregnant women. 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 >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >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 (2.1) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, alopecia. ( 6.1 ) Common adverse reactions (≥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 Xiromed LLC at 844-XIROMED (1-844-947-6633) 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 (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. Common adverse reactions (≥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. First-Line Combination Therapy A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone [see Dosage and Administration (2) ] . In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan alone. In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%) patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%) patient who received 5-FU/LV alone. The most clinically significant adverse events for patients receiving irinotecan-based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically significant adverse events for patients receiving 5-FU/LV therapy were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV. Tables 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively. Table 5: Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies a Adverse Event Study 1 Irinotecan + Bolus 5- FU/LV weekly x 4 every 6 weeks N=225 Bolus 5-FU/LV daily x 5 every 4 weeks N=219 Irinotecan weekly x 4 every 6 weeks N=223 Grade 1 to 4 Grade 3&4 Grade 1 to 4 Grade 3&4 Grade 1 to 4 Grade 3&4 TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7 GASTROINTESTINAL Diarrhea Late grade 3 grade 4 Early Nausea Abdominal pain Vomiting Anorexia Constipation Mucositis 84.9 -- -- 45.8 79.1 63.1 60.4 34.2 41.3 32.4 22.7 15.1 7.6 4.9 15.6 14.6 9.7 5.8 3.1 2.2 69.4 -- -- 31.5 67.6 50.2 46.1 42.0 31.5 76.3 13.2 5.9 7.3 1.4 8.2 11.5 4.1 3.7 1.8 16.9 83.0 -- -- 43.0 81.6 67.7 62.8 43.9 32.3 29.6 31.0 18.4 12.6 6.7 16.1 13.0 12.1 7.2 0.4 2.2 HEMATOLOGIC Neutropenia grade 3 grade 4 Leukopenia Anemia Neutropenic fever Thrombocytopenia Neutropenic infection 96.9 -- -- 96.9 96.9 -- 96.0 -- 53.8 29.8 24.0 37.8 8.4 7.1 2.6 1.8 98.6 -- -- 98.6 98.6 -- 98.6 -- 66.7 23.7 42.5 23.3 5.5 14.6 2.7 0 96.4 -- --‑ 96.4 96.9 -- 96.0 -- 31.4 19.3 12.1 21.5 4.5 5.8 1.7 2.2 BODY AS A WHOLE Asthenia Pain Fever Infection 70.2 30.7 42.2 22.2 19.5 3.1 1.7 0 64.4 26.9 32.4 16.0 11.9 3.6 3.6 1.4 69.1 22.9 43.5 13.9 13.9 2.2 0.4 0.4 METABOLIC & NUTRITIONAL Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2 DERMATOLOGIC Exfoliative dermatitis Rash Alopecia b 0.9 19.1 43.1 0 0 -- 3.2 26.5 26.5 0.5 0.9 -- 0 14.3 46.1 0 0.4 -- RESPIRATORY Dyspnea Cough Pneumonia 27.6 26.7 6.2 6.3 1.3 2.7 16.0 18.3 1.4 0.5 0 1.0 22.0 20.2 3.6 2.2 0.4 1.3 NEUROLOGIC Dizziness Somnolence Confusion 23.1 12.4 7.1 1.3 1.8 1.8 16.4 4.6 4.1 0 1.8 0 21.1 9.4 2.7 1.8 1.3 0 CARDIOVASCULAR Vasodilatation Hypotension Thromboembolic events c 9.3 5.8 9.3 0.9 1.3 -- 5.0 2.3 11.4 0 0.5 -- 9.0 5.8 5.4 0 1.7 -- a Severity of adverse events based on NCI CTC (version 1.0) b Complete hair loss = Grade 2 c Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. Table 6: Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies a Adverse Event Study 2 Irinotecan + 5-FU/LV infusional days 1&2 every 2 weeks N= 145 5-FU/LV infusional days 1&2 every 2 weeks N= 143 Grades 1 to 4 Grades 3&4 Grades 1 to 4 Grades 3&4 TOTAL Adverse Events 100 72.4 100 39.2 GASTROINTESTINAL Diarrhea late grade 3 grade 4 Cholinergic syndrome b Nausea Abdominal pain Vomiting Anorexia Constipation Mucositis 72.4 -- -- 28.3 66.9 17.2 44.8 35.2 30.3 40.0 14.4 10.3 4.1 1.4 2.1 2.1 3.5 2.1 0.7 4.1 44.8 -- -- 0.7 55.2 16.8 32.2 18.9 25.2 28.7 6.3 4.2 2.1 0 3.5 0.7 2.8 0.7 1.4 2.8 HEMATOLOGIC Neutropenia grade 3 grade 4 Leukopenia Anemia Neutropenic fever Thrombocytopenia Neutropenic infection 82.5 -- -‑- 81.3 97.2 -‑- 32.6 -‑- 46.2 36.4 9.8 17.4 2.1 3.4 0 2.1 47.9 -- -‑- 42.0 90.9 -‑- 32.2 -‑- 13.4 12.7 0.7 3.5 2.1 0.7 0 0 BODY AS A WHOLE Asthenia Pain Fever Infection 57.9 64.1 22.1 35.9 9.0 9.7 0.7 7.6 48.3 61.5 25.9 33.6 4.2 8.4 0.7 3.5 METABOLIC AND NUTRITIONAL Bilirubin 19.1 3.5 35.9 10.6 DERMATOLOGIC Hand and foot syndrome Cutaneous signs Alopecia c 10.3 17.2 56.6 0.7 0.7 -- 12.6 20.3 16.8 0.7 0 -- RESPIRATORY Dyspnea 9.7 1.4 4.9 0 CARDIOVASCULAR Hypotension Thromboembolic events d 3.4 11.7 1.4 -- 0.7 5.6 0 -- a Severity of adverse events based on NCI CTC (version 1.0) b Includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan) c Complete hair loss = Grade 2 d Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder. 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 >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum a Body System & Event % of Patients Reporting NCI Grades 1 to 4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) b 7 to 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 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 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 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 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 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 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 hydrochloride injection 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 cellpadding="0pt" cellspacing="0pt" width="100%"><col width="22%"/><col width="22%"/><col width="11%"/><col width="11%"/><col width="11%"/><col width="11%"/><col width="13%"/><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule" valign="middle"><paragraph><content styleCode="bold">Adverse Event</content> </paragraph></td><td align="center" colspan="6" styleCode="Rrule Botrule Toprule" valign="top"><paragraph><content styleCode="bold">Study 1</content> </paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">Irinotecan + Bolus 5- FU/LV weekly x 4 every 6 weeks</content> <content styleCode="bold">N=225</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule" valign="top"><paragraph><content styleCode="bold">Bolus 5-FU/LV daily x 5 every 4 weeks</content> <content styleCode="bold">N=219</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule" valign="top"><paragraph><content styleCode="bold">Irinotecan weekly x 4</content> <content styleCode="bold">every 6 weeks</content> <content styleCode="bold">N=223</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule" valign="top"><paragraph>Grade 1 to 4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grade 3&amp;4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grade 1 to 4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grade 3&amp;4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grade 1 to 4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grade 3&amp;4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph>TOTAL Adverse Events </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>100 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>53.3 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>100 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>45.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>99.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>45.7 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">GASTROINTESTINAL</content> Diarrhea Late grade 3 grade 4 Early Nausea Abdominal pain Vomiting Anorexia Constipation Mucositis </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 84.9 -- -- 45.8 79.1 63.1 60.4 34.2 41.3 32.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 22.7 15.1 7.6 4.9 15.6 14.6 9.7 5.8 3.1 2.2 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 69.4 -- -- 31.5 67.6 50.2 46.1 42.0 31.5 76.3 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 13.2 5.9 7.3 1.4 8.2 11.5 4.1 3.7 1.8 16.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 83.0 -- -- 43.0 81.6 67.7 62.8 43.9 32.3 29.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 31.0 18.4 12.6 6.7 16.1 13.0 12.1 7.2 0.4 2.2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">HEMATOLOGIC</content> Neutropenia grade 3 grade 4 Leukopenia Anemia Neutropenic fever Thrombocytopenia Neutropenic infection </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 96.9 -- -- 96.9 96.9 -- 96.0 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 53.8 29.8 24.0 37.8 8.4 7.1 2.6 1.8 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 98.6 -- -- 98.6 98.6 -- 98.6 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 66.7 23.7 42.5 23.3 5.5 14.6 2.7 0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 96.4 -- --&#x2011; 96.4 96.9 -- 96.0 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 31.4 19.3 12.1 21.5 4.5 5.8 1.7 2.2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">BODY AS A WHOLE</content> Asthenia Pain Fever Infection </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 70.2 30.7 42.2 22.2 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 19.5 3.1 1.7 0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 64.4 26.9 32.4 16.0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 11.9 3.6 3.6 1.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 69.1 22.9 43.5 13.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 13.9 2.2 0.4 0.4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule" valign="top"><paragraph><content styleCode="bold">METABOLIC &amp; NUTRITIONAL</content> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td><td align="center" styleCode="Rrule" valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph> Bilirubin </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>87.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>7.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>92.2 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>8.2 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>83.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph>7.2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">DERMATOLOGIC</content> Exfoliative dermatitis Rash Alopecia ^b </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0.9 19.1 43.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0 0 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 3.2 26.5 26.5 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0.5 0.9 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0 14.3 46.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0 0.4 -- </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">RESPIRATORY</content> Dyspnea Cough Pneumonia </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 27.6 26.7 6.2 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 6.3 1.3 2.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 16.0 18.3 1.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 0.5 0 1.0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 22.0 20.2 3.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 2.2 0.4 1.3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">NEUROLOGIC</content> Dizziness Somnolence Confusion </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 23.1 12.4 7.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 1.3 1.8 1.8 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 16.4 4.6 4.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 0 1.8 0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 21.1 9.4 2.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 1.8 1.3 0 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule" valign="bottom"><paragraph><content styleCode="bold">CARDIOVASCULAR</content> Vasodilatation Hypotension Thromboembolic events ^c </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 9.3 5.8 9.3 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 0.9 1.3 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 5.0 2.3 11.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 0 0.5 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 9.0 5.8 5.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 0 1.7 -- </paragraph></td></tr></tbody></table>

<table cellpadding="0pt" cellspacing="0pt" width="100%"><col width="27%"/><col width="25%"/><col width="18%"/><col width="18%"/><col width="13%"/><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule" valign="top"><paragraph> </paragraph><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" colspan="4" styleCode="Rrule Botrule Toprule" valign="top"><paragraph><content styleCode="bold">Study 2</content> </paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">Irinotecan + 5-FU/LV infusional days 1&amp;2 every 2 weeks</content> <content styleCode="bold">N= 145</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule" valign="top"><paragraph><content styleCode="bold">5-FU/LV infusional days 1&amp;2 every 2 weeks</content> <content styleCode="bold">N= 143</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule" valign="top"><paragraph>Grades 1 to 4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grades 3&amp;4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grades 1 to 4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph>Grades 3&amp;4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="bottom"><paragraph>TOTAL Adverse Events </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>100 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>72.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>100 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>39.2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">GASTROINTESTINAL</content> Diarrhea late grade 3 grade 4 Cholinergic syndrome ^b Nausea Abdominal pain Vomiting Anorexia Constipation Mucositis </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 72.4 -- -- 28.3 66.9 17.2 44.8 35.2 30.3 40.0 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 14.4 10.3 4.1 1.4 2.1 2.1 3.5 2.1 0.7 4.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 44.8 -- -- 0.7 55.2 16.8 32.2 18.9 25.2 28.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 6.3 4.2 2.1 0 3.5 0.7 2.8 0.7 1.4 2.8 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">HEMATOLOGIC</content> Neutropenia grade 3 grade 4 Leukopenia Anemia Neutropenic fever Thrombocytopenia Neutropenic infection </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 82.5 -- -&#x2011;- 81.3 97.2 -&#x2011;- 32.6 -&#x2011;- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 46.2 36.4 9.8 17.4 2.1 3.4 0 2.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 47.9 -- -&#x2011;- 42.0 90.9 -&#x2011;- 32.2 -&#x2011;- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 13.4 12.7 0.7 3.5 2.1 0.7 0 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">BODY AS A WHOLE</content> Asthenia Pain Fever Infection </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 57.9 64.1 22.1 35.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 9.0 9.7 0.7 7.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 48.3 61.5 25.9 33.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 4.2 8.4 0.7 3.5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">METABOLIC AND NUTRITIONAL</content> Bilirubin </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 19.1 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 3.5 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 35.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="middle"><paragraph> 10.6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">DERMATOLOGIC</content> Hand and foot syndrome Cutaneous signs Alopecia ^c </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 10.3 17.2 56.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0.7 0.7 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 12.6 20.3 16.8 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0.7 0 -- </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">RESPIRATORY</content> Dyspnea </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph> 9.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph> 1.4 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph> 4.9 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph> 0 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule" valign="top"><paragraph><content styleCode="bold">CARDIOVASCULAR</content> <content styleCode="bold"> </content>Hypotension Thromboembolic events ^d </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>3.4 11.7 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>1.4 -- </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>0.7 5.6 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="bottom"><paragraph>0 -- </paragraph></td></tr></tbody></table>

<table cellpadding="0pt" cellspacing="0pt" width="100%"><col width="41%"/><col width="39%"/><col width="21%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule" valign="top"><paragraph><content styleCode="bold">Body System &amp; Event</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule" valign="top"><paragraph><content styleCode="bold">% of Patients Reporting</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">NCI Grades 1 to 4</content> </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph><content styleCode="bold">NCI Grades 3 &amp; 4</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">GASTROINTESTINAL</content> Diarrhea (late) ^b 7 to 9 stools/day (grade 3) &#x2265;10 stools/day (grade 4) Nausea Vomiting Anorexia Diarrhea (early) ^c Constipation Flatulence Stomatitis Dyspepsia </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 88 __ __ 86 67 55 51 30 12 12 10 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 31 (16) (14) 17 12 6 8 2 0 1 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">HEMATOLOGIC</content> Leukopenia Anemia Neutropenia 500 to &lt;1000/mm ³(grade 3) &lt;500/mm ³(grade 4) </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 63 60 54 __ __ </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 28 7 26 (15) (12) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">BODY AS A WHOLE</content> Asthenia Abdominal cramping/pain Fever Pain Headache Back pain Chills Minor infection ^d Edema Abdominal enlargement </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 76 57 45 24 17 14 14 14 10 10 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 12 16 1 2 1 2 0 0 1 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">METABOLIC AND NUTRITIONAL</content> &#x2193; Body weight Dehydration &#x2191; Alkaline phosphatase &#x2191; SGOT </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 30 15 13 10 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 1 4 4 1 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">DERMATOLOGIC</content> Alopecia Sweating Rash </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 60 16 13 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> NA ^e 0 1 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">RESPIRATORY</content> Dyspnea &#x2191; Coughing Rhinitis </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 22 17 16 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 4 0 0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">NEUROLOGIC</content> Insomnia Dizziness </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 19 15 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0 0 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule" valign="top"><paragraph><content styleCode="bold">CARDIOVASCULAR</content> Vasodilation (flushing) </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 11 </paragraph></td><td align="center" styleCode="Rrule Botrule" valign="top"><paragraph> 0 </paragraph></td></tr></tbody></table>