Irinotecan hydrochloide

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 intavenous 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 ( 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. 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. 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 table3 table4 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 antiemitic regiment 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 disposal 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.

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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.