Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE Irinotecan hydrochloride injection, USP 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) • Irinotecan hydrochloride injection, USP 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, USP is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Hereditary ATTR amyloidosis

Hereditary ATTR amyloidosis

Explore the pathophysiology, epidemiology and multi-system symptoms associated with hereditary ATTR amyloidosis, as well as how to achieve an early and accurate diagnosis.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Biosimilars Knowledge Centre

Biosimilars Knowledge Centre

What are biologics and how do they differ from small molecule medicines? Discover more about their development, as well as the manufacturing and regulatory processes in the Biosimilars in Oncology Knowledge Centre.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS •Hypersensitivity to irinotecan or its excipients (4) •Irinotecan hydrochloride injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
Adverse reactions
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 Cipla Limited, India at 1-866-604-3268 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. Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia. 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 5-FU/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 5-FU/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 Therapiesa 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. Adverse Event Study 1 Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 week N=225 Bolus 5-FU/LV daily × 5 every 4 weeks N=219 Irinotecan weekly × 4 every 6 weeks N=223 Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4 TOTAL Adverse Events 100 53.3 100 45.7 99.6 45.7 GASTROINTESTINAL Diarrhea late 84.9 22.7 69.4 13.2 83.0 31.0 grade 3 -- 15.1 -- 5.9 -- 18.4 grade 4 -- 7.6 -- 7.3 -- 12.6 early 45.8 4.9 31.5 1.4 43.0 6.7 Nausea 79.1 15.6 67.6 8.2 81.6 16.1 Abdominal pain 63.1 14.6 50.2 11.5 67.7 13.0 Vomiting 60.4 9.7 46.1 4.1 62.8 12.1 Anorexia 34.2 5.8 42.0 3.7 43.9 7.2 Constipation 41.3 3.1 31.5 1.8 32.3 0.4 Mucositis 32.4 2.2 76.3 16.9 29.6 2.2 HEMATOLOGIC Neutropenia 96.9 53.8 98.6 66.7 96.4 31.4 grade 3 -- 29.8 -- 23.7 -- 19.3 grade 4 -- 24.0 -- 42.5 -- 12.1 Leukopenia 96.9 37.8 98.6 23.3 96.4 21.5 Anemia 96.9 8.4 98.6 5.5 96.9 4.5 Neutropenic fever -- 7.1 -- 14.6 -- 5.8 Thrombocytopenia 96.0 2.6 98.6 2.7 96.0 1.7 Neutropenic infection -- 1.8 -- 0 -- 2.2 BODY AS A WHOLE Asthenia 70.2 19.5 64.4 11.9 69.1 13.9 Pain 30.7 3.1 26.9 3.6 22.9 2.2 Fever 42.2 1.7 32.4 3.6 43.5 0.4 Infection 22.2 0 16.0 1.4 13.9 0.4 METABOLIC & NUTRITIONAL Bilirubin 87.6 7.1 92.2 8.2 83.9 7.2 DERMATOLOGIC Exfoliative dermatitis 0.9 0 3.2 0.5 0 0 Rash 19.1 0 26.5 0.9 14.3 0.4 Alopeciab 43.1 -- 26.5 -- 46.1 -- RESPIRATORY Dyspnea 27.6 6.3 16.0 0.5 22.0 2.2 Cough 26.7 1.3 18.3 0 20.2 0.4 Pneumonia 6.2 2.7 1.4 1.0 3.6 1.3 NEUROLOGIC Dizziness 23.1 1.3 16.4 0 21.1 1.8 Somnolence 12.4 1.8 4.6 1.8 9.4 1.3 Confusion 7.1 1.8 4.1 0 2.7 0 CARDIOVASCULAR Vasodilatation 9.3 0.9 5.0 0 9.0 0 Hypotension 5.8 1.3 2.3 0.5 5.8 1.7 Thromboembolic eventsc 9.3 -- 11.4 -- 5.4 -- Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapiesa 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. 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 Adverse Event Grades 1-4 Grades 3&4 Grades 1-4 Grades 3&4 TOTAL Adverse Events 100 72.4 100 39.2 GASTROINTESTINAL Diarrhea late 72.4 14.4 44.8 6.3 grade 3 -- 10.3 -- 4.2 grade 4 -- 4.1 -- 2.1 Cholinergic syndromeb 28.3 1.4 0.7 0 Nausea 66.9 2.1 55.2 3.5 Abdominal pain 17.2 2.1 16.8 0.7 Vomiting 44.8 3.5 32.2 2.8 Anorexia 35.2 2.1 18.9 0.7 Constipation 30.3 0.7 25.2 1.4 Mucositis 40.0 4.1 28.7 2.8 HEMATOLOGIC Neutropenia 82.5 46.2 47.9 13.4 grade 3 -- 36.4 -- 12.7 grade 4 -- 9.8 -- 0.7 Leukopenia 81.3 17.4 42.0 3.5 Anemia 97.2 2.1 90.9 2.1 Neutropenic fever -- 3.4 -- 0.7 Thrombocytopenia 32.6 0 32.2 0 Neutropenic infection -- 2.1 -- 0 BODY AS A WHOLE Asthenia 57.9 9.0 48.3 4.2 Pain 64.1 9.7 61.5 8.4 Fever 22.1 0.7 25.9 0.7 Infection 35.9 7.6 33.6 3.5 METABOLIC AND NUTRITIONAL Bilirubin 19.1 3.5 35.9 10.6 DERMATOLOGIC Hand and foot syndrome 10.3 0.7 12.6 0.7 Cutaneous signs 17.2 0.7 20.3 0 Alopeciac 56.6 -- 16.8 -- RESPIRATORY Dyspnea 9.7 1.4 4.9 0 CARDIOVASCULAR Hypotension 3.4 1.4 0.7 0 Thromboembolic eventsd 11.7 -- 5.6 -- 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/m2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m2 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 Rectuma 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 Body System & Event % of Patients Reporting NCI Grades 1-4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late)b 88 31 7–9 stools/day (grade 3) — (16) ≥10 stools/day (grade 4) — (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early)c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm3 (grade 3) — (15) <500/mm3 (grade 4) — (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infectiond 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NAe Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Coughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 Once-Every-3-Week Dosage Schedule A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea. Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events. Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) 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 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 Adverse Event Study 1 Study 2 Irinotecan N=189 BSCb N=90 Irinotecan N=127 5-FU N=129 TOTAL Grade 3/4 Adverse Events 79 67 69 54 GASTROINTESTINAL Diarrhea 22 6 22 11 Vomiting 14 8 14 5 Nausea 14 3 11 4 Abdominal pain 14 16 9 8 Constipation 10 8 8 6 Anorexia 5 7 6 4 Mucositis 2 1 2 5 HEMATOLOGIC Leukopenia/Neutropenia 22 0 14 2 Anemia 7 6 6 3 Hemorrhage 5 3 1 3 Thrombocytopenia 1 0 4 2 Infection without grade 3/4 neutropenia 8 3 1 4 with grade 3/4 neutropenia 1 0 2 0 Fever without grade 3/4 neutropenia 2 1 2 0 with grade 3/4 neutropenia 2 0 4 2 BODY AS A WHOLE Pain 19 22 17 13 Asthenia 15 19 13 12 METABOLIC AND NUTRITIONAL Hepatic c 9 7 9 6 DERMATOLOGIC Hand and foot syndrome 0 0 0 5 Cutaneous signs d 2 0 1 3 RESPIRATORY e 10 8 5 7 NEUROLOGIC f 12 13 9 4 CARDIOVASCULAR g 9 3 4 2 OTHER h 32 28 12 14 The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as irinotecan 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 hydrochloride injection 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Colorectal cancer combination regimen 1: Irinotecan 125 mg/m2 intravenous infusion over 90 minutes on days 1, 8,15, 22 with LV 20 mg/m2 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 180 mg/m2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m2 intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m2 intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m2intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. (2.1) •Colorectal cancer single agent regimen 1: Irinotecan 125 mg/m2intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. (2.2) •Colorectal cancer single agent regimen 2: Irinotecan 350 mg/m2intravenous 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 Modificationsa 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. Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) Irinotecan hydrochloride injection LV 5-FU 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m2 intravenous injection bolus, days 1,8,15,22 500 mg/m2 intravenous injection bolus, days 1,8,15,22 Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 Irinotecan hydrochloride injection 125 100 75 LV 20 20 20 5-FU 500 400 300 Regimen 2 6-wk cycle with infusional 5-FU/LV Irinotecan hydrochloride injection 180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29 (next cycle begins on day 43) LV 200 mg/m2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 5-FU Bolus 400 mg/m2 intravenous injection bolus, days 1,2,15,16, 29,30 5-FU Infusionb 600 mg/m2 intravenous infusion over 22 hours, days 1,2, 15,16,29,30 Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 Irinotecan hydrochloride injection 180 150 120 LV 200 200 200 5-FU Bolus 400 320 240 5-FU Infusionb 600 480 360 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 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 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/mm3, and the platelet count has recovered to ≥100,000/mm3, 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 Gradea (Value) During a Cycle of Therapy At the Start of Subsequent Cycles of Therapyb No toxicity Maintain dose level Maintain dose level Neutropenia 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level 2 (1000 to 1499/mm3) ↓ 1 dose level Maintain dose level 3 (500 to 999/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level 4 (<500/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 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 (2–3 stools/day > pretxc) Delay dose until resolved to baseline, then give same dose Maintain dose level 2 (4–6 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level Maintain dose level 3 (7–9 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 1 dose level ↓ 1 dose level 4 (≥10 stools/day > pretx) Omit dose until resolved to baseline, then ↓ 2 dose levels ↓ 2 dose levels Other nonhematologic toxicitiesd 1 Maintain dose level Maintain dose level 2 Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Maintain dose level 3 Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓ 1 dose level 4 Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels For mucositis/stomatitis decrease only 5-FU, not Irinotecan hydrochloride injection For mucositis/stomatitis decrease only 5-FU, not Irinotecan hydrochloride injection. 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 a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 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. Regimen 1 (weekly)a 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels c (mg/m2) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Regimen 2 (every 3 weeks) b 350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeks c Starting Dose and Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level -2 350 300 250 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 Schedulesa 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 A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, 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/m2up to a maximum dose of 150 mg/m2 Maintain dose level Neutropenia 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm3) ↓ 25 mg/m2 Maintain dose level Maintain dose level 3 (500 to 999/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 4 (<500/mm3) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m2 when resolved ↓ 50 mg/m2 ↓ 50 mg/m2 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 (2–3 stools/day > pretx c) Maintain dose level Maintain dose level Maintain dose level 2 (4–6 stools/day > pretx) ↓ 25 mg/m2 Maintain dose level Maintain dose level 3 (7–9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 Other nonhematologicd toxicities 1 2 3 4 Maintain dose level ↓ 25 mg/m2 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 Maintain dose level ↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 Maintain dose level ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2 2.3 Dosage in Patients with Reduced UGT1A1 Activity When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele [see Dosage and Administration (2.1 and 2.2) and Warnings and Precautions (5.3)]. However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 1-4). 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-HT3 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 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. 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. The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided. The irinotecan hydrochloride injection solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), irinotecan hydrochloride injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F). 2.6 Safe Handling 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 contacts the skin, wash the skin immediately and thoroughly with soap and water. If Irinotecan contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available. 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Discontinue nursing when receiving therapy with irinotecan hydrochloride injection. (8.3) • Geriatric Use: Closely monitor patients greater than 65 years of age because of a greater risk of early and late diarrhea in this population. (8.5) • Patients with Renal Impairment: Use caution and do not use in patients on dialysis. (8.6) • Patients with Hepatic Impairment: Use caution. (2.1, 5.10, 8.7, 12.3) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m2). Intravenous administration of irinotecan 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose produced an Irinotecan Cmax and AUC of about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m2. In rabbits, the embryotoxic dose was about one-half the recommended human weekly starting dose on a mg/m2basis. Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day and in rabbits at 6.0 mg/kg/day. In separate studies in rats, this dose produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the corresponding values in patients administered 125 mg/m2. In rabbits, the teratogenic dose was about one-half the recommended human weekly starting dose on a mg/m2basis. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring. There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan hydrochloride injection. 8.3 Nursing Mothers Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from irinotecan hydrochloride injection, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/ m2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship). Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48) and 125 mg/m2 (90-min infusion, n=6). Irinotecan clearance (mean + S.D.) was 17.3 + 6.7 L/h/m2 for the 50mg/m2 dose and 16.2 + 4.6 L/h/m2 for the 125 mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks]. 8.5 Geriatric Use Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population [see Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. The starting dose of irinotecan hydrochloride injection in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m2 [see Clinical Pharmacology (12.3) and Dosage and Administration (2)]. The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients >65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92]. 8.6 Renal Impairment The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. Irinotecan hydrochloride injection is not recommended for use in patients on dialysis. 8.7 Hepatic Impairment Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. Therefore, use caution when administering irinotecan hydrochloride injection patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made [see Dosage and Administration (2.1), Warnings and Precautions (5.10) and Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from irinotecan hydrochloride injection, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS •Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection. (7.2) •Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with irinotecan hydrochloride injection. (7.3) 7.1 5-Fluorouracil (5-FU) and Leucovorin (LV) In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered when the drugs were co-administered. Although the Cmax and AUC0-24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed by 5-FU and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended [see Dosage and Administration (2)]. Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted. 7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives 7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ]. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride injection with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.

More information

Category Value
Authorisation number ANDA077219
Agency product number 042LAQ1IIS
Orphan designation No
Product NDC 68001-284
Date Last Revised 22-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1726319
Marketing authorisation holder BluePoint Laboratories
Warnings WARNING: DIARRHEA and MYELOSUPPRESSION WARNING: DIARRHEA and MYELOSUPPRESSION See full prescribing information for complete boxed warning. • Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan and reduce subsequent doses if severe diarrhea occurs. • Severe myelosuppression may occur. • Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan and reduce subsequent doses if severe diarrhea occurs. • Severe myelosuppression may occur.