Irinotecan hydrochloide

1 INDICATIONS AND USAGE • Irinotecan hydrochloride injection is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum. • Irinotecan hydrochloride injection is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Irinotecan hydrochloride injection is a topoisomerase inhibitor indicated for: • First-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. (1) • Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy (1)

2 DOSAGE AND ADMINISTRATION • Colorectal cancer combination regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 with LV 20 mg/m 2 intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-FU intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks. ( 2.1 ) • Colorectal cancer combination regimen 2: Irinotecan hydrochloride injection 180 mg/m 2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m 2 intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m 2 intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m 2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. ( 2.1 ) • Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. ( 2.2 ) • Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m 2 intravenous infusion over 90 minutes on day 1 every 3 weeks. ( 2.2 ) 2.1 Colorectal Cancer Combination Regimens 1 and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1. A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. Table 1: Combination-Agent Dosage Regimens and Dose Modifications a Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) Irinotecan Hydrochloride Injection LV 5-FU 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m 2 intravenous injection bolus, days 1,8,15,22 500 mg/m 2 intravenous injection bolus, days 1,8,15,22 Starting Dose & Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 Irinotecan Hydrochloride Injection LV 5-FU 125 20 500 100 20 400 75 20 300 Regimen 2 6-wk cycle with infusional 5-FU/LV (next cycle begins on day 43) Irinotecan Hydrochloride Injection LV 5-FU Bolus 5-FU Infusion b 180 mg/m 2 intravenous infusion over 90 minutes, days 1,15,29 200 mg/m 2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 400 mg/m 2 intravenous injection bolus, days 1,2,15,16,29,30 600 mg/m 2 intravenous infusion over 22 hours, days 1,2,15,16,29,30 Starting Dose & Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 Irinotecan Hydrochloride Injection LV 5-FU Bolus 5-FU Infusion b 180 200 400 600 150 200 320 480 120 200 240 360 a Dose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. b Infusion follows bolus administration. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Dose Modifications Based on recommended dose levels described in Table 1, Combination Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Combination Regimens. All dose modifications should be based on the worst preceding toxicity. Table 2: Recommended Dose Modifications for Irinotecan Hydrochloride Injection/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3 , and the platelet count has recovered to ≥100,000/mm 3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy. Toxicity NCI CTC Grade a (Value) During a Cycle of Therapy At the Start of Subsequent Cycles of Therapy b No toxicity Maintain dose level Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) 2 (1000 to 1499/mm 3 ) 3 (500 to 999/mm 3 ) 4 (<500/mm 3 ) Maintain dose level ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels Maintain dose level Maintain dose level ↓ 1 dose level ↓ 2 dose levels Neutropenic fever Omit dose until resolved, then ↓ 2 dose levels Other hematologic toxicities Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2 to 3 stools/day > pretx c ) 2 (4 to 6 stools/day > pretx) 3 (7 to 9 stools/day > pretx) 4 (≥10 stools/day > pretx) Delay dose until resolved to baseline, then give same dose Omit dose until resolved to baseline, then ↓ 1 dose level Omit dose until resolved to baseline, then ↓ 1 dose level Omit dose until resolved to baseline, then ↓ 2 dose levels Maintain dose level Maintain dose level ↓ 1 dose level ↓ 2 dose levels Other nonhematologic toxicities d 1 2 3 4 Maintain dose level Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels For mucositis/stomatitis decrease only5-FU, not irinotecan hydrochloride injection Maintain dose level Maintain dose level ↓ 1 dose level ↓ 2 dose levels For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection. a National Cancer Institute Common Toxicity Criteria (version 1.0) b Relative to the starting dose used in the previous cycle c Pretreatment d Excludes alopecia, anorexia, asthenia 2.2 Colorectal Single Agent Regimens 1 and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3. A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. Table 3: Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications Regimen 1 (weekly) a 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels c (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Regimen 2 (every 3 weeks) b 350 mg/m 2 intravenous infusion over 90 minutes, once every 3 weeks c Starting Dose and Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 350 300 250 a Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m 2 in 50 mg/m 2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. Dose Modifications Based on recommended dose-levels described in Table 3, Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity. Table 4: Recommended Dose Modifications For Single-Agent Schedules a A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3 , and the platelet count has recovered to ≥100,000/mm 3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection. Worst Toxicity NCI Grade b (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle a Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m 2 up to a maximum dose of 150 mg/m 2 Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) 2 (1000 to 1499/mm 3 ) 3 (500 to 999/mm 3 ) 4 (<500/mm 3 ) Maintain dose level ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 Maintain dose level Maintain dose level ↓ 25 mg/m 2 ↓ 50 mg/m 2 Maintain dose level Maintain dose level ↓ 50 mg/m 2 ↓ 50 mg/m 2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m 2 when resolved ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2 to 3 stools/day > pretx c ) 2 (4 to 6 stools/day > pretx) 3 (7 to 9 stools/day > pretx) 4 (≥10 stools/day > pretx) Maintain dose level ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m 2 Maintain dose level Maintain dose level ↓ 25 mg/m 2 ↓ 50 mg/m 2 Maintain dose level Maintain dose level ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other nonhematologic d toxicities 1 2 3 4 Maintain dose level ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 Maintain dose level ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 Maintain dose level ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia 2.3 Dosage in Patients With Reduced UGT1A1 Activity When administered in combination with other agents , or as a single-agent, consider a reduction in the starting dose by at least one level of irinotecan hydrochloride injection for patients known to be homozygous for the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) [see Dosage and Administration ( 2.1 , 2.2 ), Warnings and Precautions ( 5.3 ), and Clinical Pharmacology ( 12.3 , 12.5 )] . Subsequent dosage modifications may be required based on individual patient tolerance to treatment [see Dosage and Administration( 2.1 , 2.2 )] . 2.4 Premedication It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT 3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. A similar antiemetic regimen should be used with irinotecan hydrochloride injection in combination therapy. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. 2.5 Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe. Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded. Irinotecan hydrochloride injection must be diluted prior to infusion using aseptic technique. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution. Prepare the infusion solution immediately prior to use and commence infusion as soon as possible after preparation. If visible particulates are present in the infusion solution discard. If it is not possible to use the infusion solution immediately, the infusion solution may be stored for up to 24 hours at 2 °C to 8 °C or discarded . 2.6 Safe Handling Irinotecan hydrochloride injection is a hazardous drug. Follow applicable special handling and diaposal procedures. 1 Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water. 2.7 Extravasation Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

4 CONTRAINDICATIONS • Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients. • Hypersensitivity to irinotecan hydrochloride injection or its excipients ( 4 )

Not available.

6 ADVERSE REACTIONS 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, 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 Gland Pharma at 864-879-9994 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 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 Therapya 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.