DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 40 mg/2 mL (20 mg/mL), 100 mg/5 mL (20 mg/mL), and 300 mg/15 mL (20 mg/mL) sterile, pale yellow, clear, aqueous solution in single-dose vial.. Injection: 40 mg/2 mL (20 mg/mL), 100 mg/5 mL (20 mg/mL), and 300 mg/15 mL (20 mg/mL) solution in single-dose vial. (3).

DESCRIPTION SECTION.

11 DESCRIPTION. CAMPTOSAR Injection (irinotecan hydrochloride injection) is an antineoplastic agent of the topoisomerase inhibitor class.CAMPTOSAR is supplied as sterile, pale yellow, clear, aqueous solution. Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. CAMPTOSAR is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP.Irinotecan hydrochloride is semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized. The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3, 4:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4bipiperidine]-1-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C33H38N4O6 HCl3H2O and molecular weight is 677.19. It is slightly soluble in water and organic solvents. Its structural formula is as follows:. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Colorectal cancer combination regimen 1: CAMPTOSAR 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 weeks. (2.1)Colorectal cancer combination regimen 2: CAMPTOSAR 180 mg/m2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m2 intravenous infusion over 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/m2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. (2.1)Colorectal cancer single agent regimen 1: CAMPTOSAR 125 mg/m2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. (2.2)Colorectal cancer single agent regimen 2: CAMPTOSAR 350 mg/m2 intravenous infusion over 90 minutes on day every weeks. (2.2). Colorectal cancer combination regimen 1: CAMPTOSAR 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 weeks. (2.1). Colorectal cancer combination regimen 2: CAMPTOSAR 180 mg/m2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m2 intravenous infusion over 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/m2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. (2.1). Colorectal cancer single agent regimen 1: CAMPTOSAR 125 mg/m2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. (2.2). Colorectal cancer single agent regimen 2: CAMPTOSAR 350 mg/m2 intravenous infusion over 90 minutes on day every weeks. (2.2). 2.1Colorectal Cancer Combination Regimens and 2. Administer CAMPTOSAR as 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 CAMPTOSAR 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 dose in these patients.Table 1. Combination-Agent Dosage Regimens and Dose ModificationsDose 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. Regimen 16-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)CAMPTOSAR LV5-FU125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,2220 mg/m2 intravenous injection bolus, days 1,8,15,22500 mg/m2 intravenous injection bolus, days 1,8,15,22Starting Dose Modified Dose Levels (mg/m2)Starting DoseDose Level -1Dose Level -2CAMPTOSAR12510075LV2020205-FU500400300Regimen 26-wk cycle with infusional 5-FU/LV(next cycle begins on day 43)CAMPTOSAR180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29LV200 mg/m2 intravenous infusion over hours, days 1,2,15,16,29,305-FU Bolus400 mg/m2 intravenous injection bolus, days 1,2,15,16,29,305-FU InfusionInfusion follows bolus administration. 600 mg/m2 intravenous infusion over 22 hours, days 1,2,15,16,29,30Starting Dose Modified Dose Levels (mg/m2)Starting DoseDose Level -1Dose Level -2CAMPTOSAR180150120LV2002002005-FU Bolus4003202405-FU Infusion 600480360Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend dose in these patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. Dose ModificationsBased on recommended dose levels described in Table 1, Combination Regimens of CAMPTOSAR 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 CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination SchedulesPatients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. 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 to weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after 2-week delay, consideration should be given to discontinuing therapy.ToxicityNCI CTC GradeNational Cancer Institute Common Toxicity Criteria (version 1.0) (Value) During Cycle of TherapyAt the Start of Subsequent Cycles of TherapyRelative to the starting dose used in the previous cycle No toxicityMaintain dose levelMaintain dose levelNeutropenia1 (1500 to 1999/mm3)Maintain dose levelMaintain dose level2 (1000 to 1499/mm3) dose levelMaintain dose level3 (500 to 999/mm3)Omit dose until resolved to <= grade 2, then dose level dose level4 (<500/mm3)Omit dose until resolved to <= grade 2, then dose levels dose levelsNeutropenic feverOmit dose until resolved, then dose levelsOther hematologic toxicitiesDose modifications for leukopenia or thrombocytopenia during 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.Diarrhea1 (2-3 stools/day pretxPretreatment) Delay dose until resolved to baseline, then give same doseMaintain dose level2 (4-6 stools/day pretx)Omit dose until resolved to baseline, then dose levelMaintain dose level3 (7-9 stools/day pretx)Omit dose until resolved to baseline, then dose level dose level4 (>=10 stools/day pretx)Omit dose until resolved to baseline, then dose levels dose levelsOther nonhematologic toxicitiesExcludes alopecia, anorexia, asthenia 1Maintain dose levelMaintain dose level2Omit dose until resolved to <= grade 1, then dose levelMaintain dose level3Omit dose until resolved to <= grade 2, then dose level dose level4Omit dose until resolved to <= grade 2, then dose levels dose levelsFor mucositis/stomatitis decrease only 5-FU, not CAMPTOSARFor mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR.. 2.2Colorectal Single Agent Regimens and 2. Administer CAMPTOSAR as 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.A reduction in the starting dose by one dose level of CAMPTOSAR 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 dose in these patients.Table 3. Single-Agent Regimens of CAMPTOSAR and Dose Modifications Regimen (weekly)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. 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. (mg/m2) Starting DoseDose Level -1Dose Level -212510075Regimen (every weeks)Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. 350 mg/m2 intravenous infusion over 90 minutes, once every weeks Starting Dose and Modified Dose Levels (mg/m2) Starting DoseDose Level -1Dose Level -2350300250. Dose ModificationsBased on recommended dose-levels described in Table 3, Single-Agent Regimens of CAMPTOSAR 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 SchedulesAll dose modifications should be based on the worst preceding toxicity 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 to weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after 2-week delay, consideration should be given to discontinuing CAMPTOSAR.Worst ToxicityNCI GradeNational Cancer Institute Common Toxicity Criteria (version 1.0) (Value)During Cycle of TherapyAt the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle WeeklyWeeklyOnce Every WeeksNo toxicityMaintain dose level 25 mg/m2 up to maximum dose of 150 mg/m2 Maintain dose levelNeutropenia1 (1500 to 1999/mm3)Maintain dose levelMaintain dose levelMaintain dose level2 (1000 to 1499/mm3) 25 mg/m2 Maintain dose levelMaintain dose level3 (500 to 999/mm3)Omit dose until resolved to <= grade 2, then 25 mg/m2 25 mg/m2 50 mg/m2 (<500/mm3)Omit dose until resolved to <= grade 2, then 50 mg/m2 50 mg/m2 50 mg/m2 Neutropenic feverOmit dose until resolved, then 50 mg/m2 when resolved 50 mg/m2 50 mg/m2 Other hematologic toxicitiesDose modifications for leukopenia, thrombocytopenia, and anemia during 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.Diarrhea1 (2-3 stools/day pretxPretreatment)Maintain dose levelMaintain dose levelMaintain dose level2 (4-6 stools/day pretx) 25 mg/m2 Maintain dose levelMaintain dose level3 (7-9 stools/day pretx)Omit dose until resolved to <= grade 2, then 25 mg/m2 25 mg/m2 50 mg/m2 (>=10 stools/day pretx)Omit dose until resolved to <= grade then 50 mg/m2 50 mg/m2 50 mg/m2 Other nonhematologicExcludes alopecia, anorexia, asthenia toxicities1Maintain dose levelMaintain dose levelMaintain dose level2 25 mg/m2 25 mg/m2 50 mg/m2 3Omit dose until resolved to <= grade 2, then 25 mg/m2 25 mg/m2 50 mg/m2 4Omit dose until resolved to <= grade 2, then 50 mg/m2 50 mg/m2 50 mg/m2 2.3Dosage in Patients With Reduced UGT1A1 Activity. When administered in combination with other agents, or as single-agent, consider reduction in the starting dose by at least one level of CAMPTOSAR for patients known to be homozygous for the UGT1A128 or alleles (28/28, 6/6) or compound heterozygous for the UGT1A128 and 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)].. 2.4Premedication. 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 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 CAMPTOSAR. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. similar antiemetic regimen should be used with CAMPTOSAR in combination therapy.Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.. 2.5Preparation of Infusion Solution. Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.CAMPTOSAR Injection 20 mg/mL is intended for single use only and any unused portion should be discarded.CAMPTOSAR Injection must be diluted prior to infusion using aseptic technique. CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to 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 C to C or discarded.. 2.6Safe Handling. CAMPTOSAR is hazardous drug. Follow applicable special handling and disposal procedures.1 Care should be exercised in the handling and preparation of infusion solutions prepared from CAMPTOSAR Injection. The use of gloves is recommended. If solution of CAMPTOSAR contacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water.. 2.7Extravasation. 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.

ADVERSE REACTIONS SECTION.

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 Pfizer Inc, at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 TherapyA 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 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 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, CNS bleeding during thrombocytopenia, unknown) and (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: (4.1%) received irinotecan in combination with 5-FU/LV and (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in 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 (2.1%) patients who received irinotecan in combination with 5-FU/LV and (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for (6.2%) patients who received irinotecan in combination with 5FU/LV and (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 neutropenia, neutropenic fever (defined as grade fever and grade neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV.Tables and list the clinically relevant adverse events reported in Studies and 2, respectively.Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination TherapiesSeverity of adverse events based on NCI CTC (version 1.0) Adverse EventStudy 1Irinotecan Bolus 5-FU/LV weekly 4 every weeksN=225Bolus 5-FU/LV daily 5 every weeksN=219Irinotecan weekly 4 every weeksN=223Grade 1-4Grade 3&4Grade 1-4Grade 3&4Grade 1-4Grade 3&4TOTAL Adverse Events10053.310045.799.645.7GASTROINTESTINAL Diarrhea Late84.922.769.413.283.031.0 grade 3--15.1--5.9--18.4 grade 4--7.6--7.3--12.6 Early45.84.931.51.443.06.7 Nausea79.115.667.68.281.616.1 Abdominal pain63.114.650.211.567.713.0 Vomiting60.49.746.14.162.812.1 Anorexia34.25.842.03.743.97.2 Constipation41.33.131.51.832.30.4 Mucositis32.42.276.316.929.62.2HEMATOLOGIC Neutropenia96.953.898.666.796.431.4 grade 3--29.8--23.7--19.3 grade 4--24.0--42.5--12.1 Leukopenia96.937.898.623.396.421.5 Anemia96.98.498.65.596.94.5 Neutropenic fever--7.1--14.6--5.8 Thrombocytopenia96.02.698.62.796.01.7 Neutropenic infection--1.8--0--2.2BODY AS WHOLE Asthenia70.219.564.411.969.113.9 Pain30.73.126.93.622.92.2 Fever42.21.732.43.643.50.4 Infection22.2016.01.413.90.4METABOLIC NUTRITIONAL Bilirubin87.67.192.28.283.97.2DERMATOLOGIC Exfoliative dermatitis0.903.20.500 Rash19.1026.50.914.30.4 AlopeciaComplete hair loss Grade 43.1--26.5--46.1--RESPIRATORY Dyspnea27.66.316.00.522.02.2 Cough26.71.318.3020.20.4 Pneumonia6.22.71.41.03.61.3NEUROLOGIC Dizziness23.11.316.4021.11.8 Somnolence12.41.84.61.89.41.3 Confusion7.11.84.102.70CARDIOVASCULAR Vasodilatation9.30.95.009.00 Hypotension5.81.32.30.55.81.7 Thromboembolic eventsIncludes 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. 9.3--11.4--5.4--Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination TherapiesSeverity of adverse events based on NCI CTC (version 1.0) Adverse EventStudy 2Irinotecan 5-FU/LV infusional days 1&2 every weeksN= 1455-FU/LV infusional days 1&2 every weeksN=143Grades 1-4Grades 3&4Grades 1-4Grades 3&4TOTAL Adverse Events10072.410039.2GASTROINTESTINAL Diarrhea late72.414.444.86.3 grade 3--10.3--4.2 grade 4--4.1--2.1 Cholinergic syndromeIncludes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan) 28.31.40.70 Nausea66.92.155.23.5 Abdominal pain17.22.116.80.7 Vomiting44.83.532.22.8 Anorexia35.22.118.90.7 Constipation30.30.725.21.4 Mucositis40.04.128.72.8HEMATOLOGIC Neutropenia82.546.247.913.4 grade 3--36.4--12.7 grade 4--9.8--0.7 Leukopenia81.317.442.03.5 Anemia97.22.190.92.1 Neutropenic fever--3.4--0.7 Thrombocytopenia32.6032.20 Neutropenic infection--2.1--0BODY AS WHOLE Asthenia57.99.048.34.2 Pain64.19.761.58.4 Fever22.10.725.90.7 Infection35.97.633.63.5METABOLIC AND NUTRITIONAL Bilirubin19.13.535.910.6DERMATOLOGIC Hand and foot syndrome10.30.712.60.7 Cutaneous signs17.20.720.30 AlopeciaComplete hair loss Grade 56.6--16.8--RESPIRATORY Dyspnea9.71.44.90CARDIOVASCULAR Hypotension3.41.40.70 Thromboembolic eventsIncludes 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. 11.7--5.6--. Second-Line Single-Agent Therapy. Weekly Dosage ScheduleIn 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 CAMPTOSAR. Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; 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 CAMPTOSAR. 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 CAMPTOSAR 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 CAMPTOSAR because of adverse events. The adverse events in Table 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 RectumSeverity of adverse events based on NCI CTC (version 1.0) of Patients ReportingBody System EventNCI Grades 1-4NCI Grades & 4GASTROINTESTINAL Diarrhea (late)Occurring >24 hours after administration of CAMPTOSAR 8831 7-9 stools/day (grade 3)--(16) >=10 stools/day (grade 4)--(14) Nausea8617 Vomiting6712 Anorexia556 Diarrhea (early)Occurring <=24 hours after administration of CAMPTOSAR 518 Constipation302 Flatulence120 Stomatitis121 Dyspepsia100HEMATOLOGIC Leukopenia6328 Anemia607 Neutropenia5426 500 to <1000/mm3 (grade 3)--(15) <500/mm3 (grade 4)--(12)BODY AS WHOLE Asthenia7612 Abdominal cramping/pain5716 Fever451 Pain242 Headache171 Back pain142 Chills140 Minor infectionPrimarily upper respiratory infections 140 Edema101 Abdominal enlargement100METABOLIC AND NUTRITIONAL Body weight301 Dehydration154 Alkaline phosphatase134 SGOT101DERMATOLOGIC Alopecia60NANot applicable; complete hair loss NCI grade Sweating160 Rash131RESPIRATORY Dyspnea224 Coughing170 Rhinitis160NEUROLOGIC Insomnia190 Dizziness150CARDIOVASCULAR Vasodilation (flushing)110. Once-Every-3-Week Dosage ScheduleA total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 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 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 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 lists the grade and 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 & Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan TherapySeverity of adverse events based on NCI CTC (version 1.0) Study 1Study 2Adverse EventIrinotecanN=189BSC BSC best supportive care N=90IrinotecanN=1275-FUN=129TOTAL Grade 3/4 Adverse Events79676954GASTROINTESTINAL Diarrhea2262211 Vomiting148145 Nausea143114 Abdominal pain141698 Constipation10886 Anorexia5764 Mucositis2125HEMATOLOGIC Leukopenia/Neutropenia220142 Anemia7663 Hemorrhage5313 Thrombocytopenia1042Infection without grade 3/4 neutropenia8314 with grade 3/4 neutropenia1020Fever without grade 3/4 neutropenia2120 with grade 3/4 neutropenia2042BODY AS WHOLE Pain19221713 Asthenia15191312METABOLIC AND NUTRITIONALHepatic Hepatic includes events such as ascites and jaundice 9796DERMATOLOGIC Hand and foot syndrome0005 Cutaneous signs Cutaneous signs include events such as rash 2013RESPIRATORY Respiratory includes events such as dyspnea and cough10857NEUROLOGIC Neurologic includes events such as somnolence121394CARDIOVASCULAR Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction9342OTHER Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss32281214The 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 CAMPTOSAR 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 premedication for other chemotherapies.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of CAMPTOSAR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Myocardial ischemic events have been observed following CAMPTOSAR therapy. Thromboembolic events have been observed in patients receiving CAMPTOSAR.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 CAMPTOSAR; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.Interaction between CAMPTOSAR 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.

BOXED WARNING SECTION.

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 CAMPTOSAR 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)]. 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 CAMPTOSAR 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)]. WARNING: DIARRHEA and MYELOSUPPRESSIONSee 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 CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. (2.2, 5.1)Severe myelosuppression may occur. (5.2). 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 CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. (2.2, 5.1). Severe myelosuppression may occur. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m2 weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite SN-38 was mutagenic in the in vitro Ames assay.No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In separate studies in rodents, this dose produced an irinotecan Cmax and AUC about and times, respectively, of the corresponding values in patients administered 125 mg/m2 weekly. In dogs this dose produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, of the corresponding values in patients administered 125 mg/m2 weekly.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Irinotecan is derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.. 12.2 Pharmacodynamics. Irinotecan serves as water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan [see Clinical Pharmacology (12.3)]. The precise contribution of SN-38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while more basic pH favors the hydroxy acid anion form.Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.. 12.3 Pharmacokinetics. After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in multiexponential manner, with mean terminal elimination half-life of about to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within hour following the end of 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumors are summarized in Table 9:Table 9.Summary of Mean (+-Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients With Solid TumorsDose(mg/m2)IrinotecanSN-38Cmax (ng/mL)AUC0-24 (ngh/mL)t1/2 (h)Vz (L/m2)CL(L/h/m2)Cmax (ng/mL)AUC0-24 (ngh/mL)t1/2 (h)Cmax Maximum plasma concentrationAUC0-24 Area under the plasma concentration-time curve from time0 to 24 hours after the end of the 90-minute infusiont1/2 Terminal elimination half-lifeVz Volume of distribution of terminal elimination phaseCL Total systemic clearance125(N=64)1,660 +-79710,200 +-3,2705.8Plasma specimens collected for 24 hours following the end of the 90-minute infusion. +-0.7110+-48.513.3+-6.0126.3+-11.9229+-10810.4 +-3.1340(N=6)3,392+-87420,604+-6,02711.7Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38. +-1.0234+-69.613.9+-4.056.0+-28.2474+-24521.0 +-4.3. DistributionIrinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.. Elimination. MetabolismIrinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases that form an active metabolite SN-38, and UGT1A1 which mediates the glucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38. Patients who are homozygous for either the UGT1A128 or alleles, or who are compound heterozygous for these alleles, have higher SN-38 AUC than patients with the wild-type UGT1A1 alleles [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.5)].Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release the active metabolite SN-38.. ExcretionThe disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).. Specific Populations. Geriatric PatientsThe pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients >=65 years of age. In study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients >=65 years of age were observed. Although dose-normalized AUC0-24 for SN-38 in patients >=65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan [see Dosage and Administration (2)].. Male and Female PatientsThe pharmacokinetics of irinotecan do not appear to be influenced by gender.. Racial and Ethnic GroupsThe influence of race on the pharmacokinetics of irinotecan has not been evaluated.. Patients with Renal ImpairmentThe influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated.. Patients with Hepatic ImpairmentIrinotecan 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. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than mg/dl) has not been assessed sufficiently.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesDexamethasone, moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.. In Vitro StudiesIrinotecan and the metabolites SN-38 and aminopentane carboxylic acid (APC) do not inhibit cytochrome P-450 isozymes.. 12.5 Pharmacogenomics. The active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A128 [(TA)7] and alleles lead to reduced UGT1A1 enzyme expression or activity and decreased function to similar extent.Individuals who are homozygous or compound (double) heterozygous for these alleles (e.g., 28/28, 6/6, 6/28) are UGT1A1 poor metabolizers and are at increased risk for severe or life-threatening neutropenia from CAMPTOSAR due to elevated systemic exposure to SN-38. The UGT1A16/6 genotype should not be confused with 6/6 genotype, which is sometimes used to represent the genotype of individuals who are wild type for UGT1A128. Individuals who are heterozygous for either the UGT1A128 or alleles (1/6, 1/28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].Published studies have shown that individuals with UGT1A128 and alleles may be at an increased risk of severe diarrhea. The risk evidence appears greater in UGT1A128 and homozygous patients and in those taking irinotecan doses 125 mg/m2 [see Warnings and Precautions (5.1)]. UGT1A128 and alleles occur at various frequencies in different populations. Approximately 20% of Black or African American, 10% of White, and 2% of East Asian individuals are homozygous for the UGT1A128 allele. Approximately 2-6 of East Asian individuals are homozygous for the UGT1A16 allele. The UGT1A16 allele is uncommon in Black or African American or in White individuals. Decreased function alleles other than UGT1A128 and may be present in certain populations.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Irinotecan has been studied in clinical trials in combination with 5-fluorouracil (5-FU) and leucovorin (LV) and as single agent [see Dosage and Administration (2)]. When given as component of combination-agent treatment, irinotecan was either given with weekly schedule of bolus 5-FU/LV or with an every-2-week schedule of infusional 5-FU/LV. Weekly and once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies of combination and single-agent use are described below.. 14.1Metastatic Colorectal Cancer. First-Line Therapy in Combination with 5-FU/LV: Studies and 2Two phase 3, randomized, controlled, multinational clinical trials support the use of CAMPTOSAR Injection as first-line treatment of patients with metastatic carcinoma of the colon or rectum. In each study, combinations of irinotecan with 5-FU and LV were compared with 5-FU and LV alone. Study compared combination irinotecan/bolus 5-FU/LV therapy given weekly with standard bolus regimen of 5-FU/LV alone given daily for days every weeks; an irinotecan-alone treatment arm given on weekly schedule was also included. Study evaluated two different methods of administering infusional 5-FU/LV, with or without irinotecan. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In Study 2, 7-day course of fluoroquinolone antibiotic prophylaxis was given in patients whose diarrhea persisted for greater than 24 hours despite loperamide or if they developed fever in addition to diarrhea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) <500/mm3, even in the absence of fever or diarrhea. Patients in both studies also received treatment with intravenous antibiotics if they had persistent diarrhea or fever or if ileus developed.In both studies, the combination of irinotecan/5-FU/LV therapy resulted in significant improvements in objective tumor response rates, time to tumor progression, and survival when compared with 5-FU/LV alone. These differences in survival were observed in spite of second-line therapy in majority of patients on both arms, including crossover to irinotecan-containing regimens in the control arm. Patient characteristics and major efficacy results are shown in Table 10.Table 10. Combination Dosage Schedule: Study ResultsStudy 1Study 2Irinotecan Bolus 5-FU/LV weekly 4 every weeksBolus 5-FU/LV daily 5 every weeksIrinotecan weekly 4 every weeksIrinotecan Infusional 5-FU/LVInfusional 5-FU/LVNumber of patients231226226198187Demographics and treatment administrationFemale/Male (%)34/6545/5435/6433/6747/53Median age in years (range)62 (25-85)61 (19-85)61 (30-87)62 (27-75)59 (24-75)Performance status (%)039414651511464546424121513878Primary tumor (%)Colon8185845565Rectum1714154535Median time from diagnosis to randomization (months, range)1.9(0-161)1.7(0-203)1.8(0.1-185)4.5(0-88)2.7(0-104)Prior adjuvant 5-FU therapy (%)NoYes8911928901074267624Median duration of study treatmentStudy 1: N=225 (irinotecan/5-FU/LV),N=219 (5-FU/LV),N=223 (irinotecan)Study 2: N=199 (irinotecan/5-FU/LV),N=186 (5-FU/LV) (months)5.54.13.95.64.5Median Relative Dose Intensity (%) Irinotecan5-FU7271--8675--8786--93Efficacy ResultsConfirmed objective tumor response rateConfirmed >= to weeks after first evidence of objective response (%)3921183522(p<0.0001)Chi-square test (p<0.005) Median time to tumor progressionLog-rank test (months)7.04.34.26.74.4(p=0.004) (p<0.001) Median survival(months)14.812.612.017.414.1(p<0.05) (p<0.05) Improvement was noted with irinotecan-based combination therapy relative to 5-FU/LV when response rates and time to tumor progression were examined across the following demographic and disease-related subgroups (age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities). Figures and illustrate the Kaplan-Meier survival curves for the comparison of irinotecan/5-FU/LV versus 5-FU/LV in Studies and 2, respectively.. Figure 1. Figure 2. Second-Line Therapy After 5-FU-Based Treatment. Weekly Doses on 6-Week Cycle: Studies 3, 4, and 5Data from three open-label, single-agent, clinical studies, involving total of 304 patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. These studies were designed to evaluate tumor response rate and do not provide information on effects on survival and disease-related symptoms. In each study, CAMPTOSAR was administered in repeated 6-week cycles consisting of 90-minute intravenous infusion once weekly for weeks, followed by 2-week rest period. Starting doses of CAMPTOSAR in these trials were 100, 125, or 150 mg/m2, but the 150-mg/m2 dose was poorly tolerated (due to high rates of grade late diarrhea and febrile neutropenia). Study enrolled 48 patients and was conducted by single investigator at several regional hospitals. Study was multicenter study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study received starting dose of 125 mg/m2. Study was multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study was 125 mg/m2 but was reduced to 100 mg/m2 because the toxicity seen at the 125-mg/m2 dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table 11.Table 11.Weekly Dosage Schedule: Study ResultsStudy345Number of Patients489064102Starting Dose (mg/m2/week 4)125Nine patients received 150 mg/m2 as starting dose; two (22.2%) responded to CAMPTOSAR. 125125100Demographics and Treatment AdministrationFemale/Male (%)46/5436/6450/5051/49Median Age in years (range)63 (29-78)63 (32-81)61 (42-84)64 (25-84)Ethnic Origin (%) White79968191 African American124115 Hispanic8082 Oriental/Asian0002Performance Status (%) 060385944 138483351 221485Primary Tumor (%) Colon100718987 Rectum029118 Unknown0005Prior 5-FU Therapy (%) For Metastatic Disease81667368 <= months after Adjuvant1572728 6 months after Adjuvant21602 Classification Unknown21203Prior Pelvic/Abdominal Irradiation (%) Yes32900 Other0924 None97629896Duration of Treatment with CAMPTOSAR (median, months)5443Relative Dose IntensityRelative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3, and 66.7 mg/m2/wk corresponding with 150, 125, and 100 mg/m2 starting doses, respectively. (median %)74677381EfficacyConfirmed Objective Response Rate (%)Confirmed >= to weeks after first evidence of objective response. (95% CI)21(9.3 32.3)13(6.3 20.4)14(5.5 22.6)9(3.3 14.3)Time to Response (median, months)2.61.52.82.8Response Duration (median, months)6.45.95.66.4Survival (median, months)10.48.110.79.31-Year Survival (%)46314543In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m2. Among these 193 patients, complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. considerably lower response rate was seen with starting dose of 100 mg/m2. The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to CAMPTOSAR were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. The response rate was 18.5% in patients with performance status of and 8.2% in patients with performance status of or 2. Patients with performance status of or have not been studied. Over half of the patients responding to CAMPTOSAR had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to CAMPTOSAR at approximately the same rate as those who had not previously received irradiation.. Once-Every-3-Week Dosage Schedule. Single Arm Study: Study 6Data from an open-label, single-agent, single-arm, multicenter, clinical study involving total of 132 patients support once every-3-week dosage schedule of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received starting dose of 350 mg/m2 given by 30-minute intravenous infusion once every weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).. Randomized Studies: Studies and 8Two multicenter, randomized, clinical studies further support the use of irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, second-line irinotecan therapy plus best supportive care was compared with best supportive care alone. In Study 8, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. In both studies, irinotecan was administered intravenously at starting dose of 350 mg/m2 over 90 minutes once every weeks. The starting dose was 300 mg/m2 for patients who were 70 years and older or who had performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was provided to patients in both arms of Study and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study received one of the following 5-FU regimens: (1) LV, 200 mg/m2 IV over hours; followed by 5-FU, 400 mg/m2 IV bolus; followed by 5-FU, 600 mg/m2 continuous IV infusion over 22 hours on days and every weeks; (2) 5-FU, 250 to 300 mg/m2/day protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to g/m2 IV over 24 hours every week for weeks with or without LV, 20 to 500 mg/m2/day every week IV for weeks with 2-week rest between cycles. Patients were to be followed every to weeks for year.A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures and 4. In Study 7, median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. Multiple regression analyses determined that patients baseline characteristics also had significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with irinotecan remained significantly longer than in the control populations (p=0.001 for Study and p=0.017 for Study 8). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. When comparing irinotecan with best supportive care in Study 7, this analysis showed statistically significant advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to 5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with baseline performance status of or showed an improvement in performance status when treated with irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.Figure 3. Survival Second-Line Irinotecan vs Best Supportive Care (BSC)Study 7Figure 4. Survival Second-Line Irinotecan vs Infusion 5-FUStudy 8Table 12.Once-Every-3-Week Dosage Schedule: Study ResultsStudy 7Study 8IrinotecanBSCBSC best supportive care Irinotecan5-FUNumber of patients18990127129Demographics and treatment administrationFemale/Male (%)32/6842/5843/5735/65Median age in years (range)59 (22-75)62 (34-75)58 (30-75)58 (25-75)Performance status (%) 047315854 139463543 2142383Primary tumor (%) Colon55525762 Rectum45484338Prior 5-FU therapy (%) For metastatic disease70635868 As adjuvant treatment30374232Prior irradiation (%)26271820Duration of study treatment (median, months)(Log-rank test)4.1--4.2(p=0.02)2.8Relative dose intensity (median %)Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m2/wk corresponding with 350 and 300 mg/m2 starting doses, respectively. 94--9581-99SurvivalSurvival (median, months)9.26.510.88.5(Log-rank test)(p=0.0001)(p=0.035)In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, patients completed questionnaire consisting of 30 questions, such as Did pain interfere with daily activities (1 Not at All, to = Very Much) and Do you have any trouble taking long walk (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from to 100, and the global health status subscale that was derived from two questions about the patients sense of general well being in the past week. The results as summarized in Table 13 are based on patients worst post-baseline scores. In Study 7, multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 8, the multivariate analysis on all 15 subscales did not indicate statistically significant difference between irinotecan and infusional 5-FU.Table 13.EORTC QLQ-C30: Mean Worst Post-Baseline ScoreFor the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study. QLQ-C30 SubscaleStudy 7Study 8IrinotecanBSCp-valueIrinotecan5-FUp-valueGlobal health status47370.0353520.9Functional scalesCognitive77680.0779830.9Emotional68640.464680.9Social58470.0665670.9Physical60400.000366660.9Role53350.0254570.9Symptom ScalesFatigue51630.0347460.9Appetite loss37570.000735380.9Pain assessment41560.00938340.9Insomnia39470.339330.9Constipation28410.0325190.9Dyspnea31400.225240.9Nausea/Vomiting27290.525160.09Financial impact22260.524150.3Diarrhea32190.0132220.2. Figure 3. Figure 4.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 TherapyA 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 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 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, CNS bleeding during thrombocytopenia, unknown) and (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: (4.1%) received irinotecan in combination with 5-FU/LV and (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in 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 (2.1%) patients who received irinotecan in combination with 5-FU/LV and (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for (6.2%) patients who received irinotecan in combination with 5FU/LV and (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 neutropenia, neutropenic fever (defined as grade fever and grade neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV.Tables and list the clinically relevant adverse events reported in Studies and 2, respectively.Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination TherapiesSeverity of adverse events based on NCI CTC (version 1.0) Adverse EventStudy 1Irinotecan Bolus 5-FU/LV weekly 4 every weeksN=225Bolus 5-FU/LV daily 5 every weeksN=219Irinotecan weekly 4 every weeksN=223Grade 1-4Grade 3&4Grade 1-4Grade 3&4Grade 1-4Grade 3&4TOTAL Adverse Events10053.310045.799.645.7GASTROINTESTINAL Diarrhea Late84.922.769.413.283.031.0 grade 3--15.1--5.9--18.4 grade 4--7.6--7.3--12.6 Early45.84.931.51.443.06.7 Nausea79.115.667.68.281.616.1 Abdominal pain63.114.650.211.567.713.0 Vomiting60.49.746.14.162.812.1 Anorexia34.25.842.03.743.97.2 Constipation41.33.131.51.832.30.4 Mucositis32.42.276.316.929.62.2HEMATOLOGIC Neutropenia96.953.898.666.796.431.4 grade 3--29.8--23.7--19.3 grade 4--24.0--42.5--12.1 Leukopenia96.937.898.623.396.421.5 Anemia96.98.498.65.596.94.5 Neutropenic fever--7.1--14.6--5.8 Thrombocytopenia96.02.698.62.796.01.7 Neutropenic infection--1.8--0--2.2BODY AS WHOLE Asthenia70.219.564.411.969.113.9 Pain30.73.126.93.622.92.2 Fever42.21.732.43.643.50.4 Infection22.2016.01.413.90.4METABOLIC NUTRITIONAL Bilirubin87.67.192.28.283.97.2DERMATOLOGIC Exfoliative dermatitis0.903.20.500 Rash19.1026.50.914.30.4 AlopeciaComplete hair loss Grade 43.1--26.5--46.1--RESPIRATORY Dyspnea27.66.316.00.522.02.2 Cough26.71.318.3020.20.4 Pneumonia6.22.71.41.03.61.3NEUROLOGIC Dizziness23.11.316.4021.11.8 Somnolence12.41.84.61.89.41.3 Confusion7.11.84.102.70CARDIOVASCULAR Vasodilatation9.30.95.009.00 Hypotension5.81.32.30.55.81.7 Thromboembolic eventsIncludes 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. 9.3--11.4--5.4--Table 6. Study 2: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination TherapiesSeverity of adverse events based on NCI CTC (version 1.0) Adverse EventStudy 2Irinotecan 5-FU/LV infusional days 1&2 every weeksN= 1455-FU/LV infusional days 1&2 every weeksN=143Grades 1-4Grades 3&4Grades 1-4Grades 3&4TOTAL Adverse Events10072.410039.2GASTROINTESTINAL Diarrhea late72.414.444.86.3 grade 3--10.3--4.2 grade 4--4.1--2.1 Cholinergic syndromeIncludes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping or diarrhea (occurring during or shortly after infusion of irinotecan) 28.31.40.70 Nausea66.92.155.23.5 Abdominal pain17.22.116.80.7 Vomiting44.83.532.22.8 Anorexia35.22.118.90.7 Constipation30.30.725.21.4 Mucositis40.04.128.72.8HEMATOLOGIC Neutropenia82.546.247.913.4 grade 3--36.4--12.7 grade 4--9.8--0.7 Leukopenia81.317.442.03.5 Anemia97.22.190.92.1 Neutropenic fever--3.4--0.7 Thrombocytopenia32.6032.20 Neutropenic infection--2.1--0BODY AS WHOLE Asthenia57.99.048.34.2 Pain64.19.761.58.4 Fever22.10.725.90.7 Infection35.97.633.63.5METABOLIC AND NUTRITIONAL Bilirubin19.13.535.910.6DERMATOLOGIC Hand and foot syndrome10.30.712.60.7 Cutaneous signs17.20.720.30 AlopeciaComplete hair loss Grade 56.6--16.8--RESPIRATORY Dyspnea9.71.44.90CARDIOVASCULAR Hypotension3.41.40.70 Thromboembolic eventsIncludes 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. 11.7--5.6--. Second-Line Single-Agent Therapy. Weekly Dosage ScheduleIn 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 CAMPTOSAR. Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; 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 CAMPTOSAR. 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 CAMPTOSAR 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 CAMPTOSAR because of adverse events. The adverse events in Table 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 RectumSeverity of adverse events based on NCI CTC (version 1.0) of Patients ReportingBody System EventNCI Grades 1-4NCI Grades & 4GASTROINTESTINAL Diarrhea (late)Occurring >24 hours after administration of CAMPTOSAR 8831 7-9 stools/day (grade 3)--(16) >=10 stools/day (grade 4)--(14) Nausea8617 Vomiting6712 Anorexia556 Diarrhea (early)Occurring <=24 hours after administration of CAMPTOSAR 518 Constipation302 Flatulence120 Stomatitis121 Dyspepsia100HEMATOLOGIC Leukopenia6328 Anemia607 Neutropenia5426 500 to <1000/mm3 (grade 3)--(15) <500/mm3 (grade 4)--(12)BODY AS WHOLE Asthenia7612 Abdominal cramping/pain5716 Fever451 Pain242 Headache171 Back pain142 Chills140 Minor infectionPrimarily upper respiratory infections 140 Edema101 Abdominal enlargement100METABOLIC AND NUTRITIONAL Body weight301 Dehydration154 Alkaline phosphatase134 SGOT101DERMATOLOGIC Alopecia60NANot applicable; complete hair loss NCI grade Sweating160 Rash131RESPIRATORY Dyspnea224 Coughing170 Rhinitis160NEUROLOGIC Insomnia190 Dizziness150CARDIOVASCULAR Vasodilation (flushing)110. Once-Every-3-Week Dosage ScheduleA total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 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 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 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 lists the grade and 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 & Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan TherapySeverity of adverse events based on NCI CTC (version 1.0) Study 1Study 2Adverse EventIrinotecanN=189BSC BSC best supportive care N=90IrinotecanN=1275-FUN=129TOTAL Grade 3/4 Adverse Events79676954GASTROINTESTINAL Diarrhea2262211 Vomiting148145 Nausea143114 Abdominal pain141698 Constipation10886 Anorexia5764 Mucositis2125HEMATOLOGIC Leukopenia/Neutropenia220142 Anemia7663 Hemorrhage5313 Thrombocytopenia1042Infection without grade 3/4 neutropenia8314 with grade 3/4 neutropenia1020Fever without grade 3/4 neutropenia2120 with grade 3/4 neutropenia2042BODY AS WHOLE Pain19221713 Asthenia15191312METABOLIC AND NUTRITIONALHepatic Hepatic includes events such as ascites and jaundice 9796DERMATOLOGIC Hand and foot syndrome0005 Cutaneous signs Cutaneous signs include events such as rash 2013RESPIRATORY Respiratory includes events such as dyspnea and cough10857NEUROLOGIC Neurologic includes events such as somnolence121394CARDIOVASCULAR Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction9342OTHER Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss32281214The 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 CAMPTOSAR 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 premedication for other chemotherapies.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. CAMPTOSAR Injection is contraindicated in patients with known hypersensitivity to the drug or its excipients.. CAMPTOSAR Injection is contraindicated in patients with known hypersensitivity to the drug or its excipients.. Hypersensitivity to CAMPTOSAR or its excipients (4). Hypersensitivity to CAMPTOSAR or its excipients (4).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with CAMPTOSAR. (7.2)Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with CAMPTOSAR. (7.3). Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with CAMPTOSAR. (7.2). Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with CAMPTOSAR. (7.3). 7.15-Fluorouracil (5-FU) and Leucovorin (LV). In phase 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.. 7.2Strong 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. Johns 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 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with CAMPTOSAR unless there are no therapeutic alternatives.. 7.3Strong 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, CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of CAMPTOSAR 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 week prior to starting CAMPTOSAR therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with CAMPTOSAR unless there are no therapeutic alternatives.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status in female patients of reproductive potential prior to initiating CAMPTOSAR.. ContraceptionCAMPTOSAR can cause fetal harm when administered to pregnant woman.. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment and for months after the final dose of CAMPTOSAR [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].. MalesDue to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR [see Nonclinical Toxicology (13.1)]. Infertility. FemalesBased on postmarketing reports, female fertility may be impaired by treatment with CAMPTOSAR. Menstrual dysfunction has been reported following CAMPTOSAR administration.. MalesBased on findings from animal studies, male fertility may be impaired by treatment with CAMPTOSAR [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Patients greater than 65 years of age should be closely monitored because of greater risk of early and late diarrhea in this population [see Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. The starting dose of CAMPTOSAR 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 and 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 or 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].

HEPATIC IMPAIRMENT SUBSECTION.

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 CAMPTOSAR to patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. CAMPTOSAR (irinotecan hydrochloride) Injection is available as sterile, pale yellow, clear, aqueous solution in vial packaged within carton in the following packaging configurations:Single-dose amber colored polypropylene CYTOSAFE(R) vial presentations:40 mg/2 mL (20 mg/mL)NDC 0009-7529-04100 mg/5 mL (20 mg/mL)NDC 0009-7529-03300 mg/15 mL (20 mg/mL)NDC 0009-7529-05 Single-dose amber colored polypropylene CYTOSAFE(R) vial presentations:40 mg/2 mL (20 mg/mL)NDC 0009-7529-04100 mg/5 mL (20 mg/mL)NDC 0009-7529-03300 mg/15 mL (20 mg/mL)NDC 0009-7529-05 40 mg/2 mL (20 mg/mL)NDC 0009-7529-04. 100 mg/5 mL (20 mg/mL)NDC 0009-7529-03. 300 mg/15 mL (20 mg/mL)NDC 0009-7529-05. Store at controlled room temperature 15C to 30C (59 to 86F). Protect from light. Keep the vial in the carton until the time of use.Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.CAMPTOSAR is hazardous drug. Follow special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CAMPTOSAR is indicated as 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.CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.. CAMPTOSAR is indicated as 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.. CAMPTOSAR is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.. CAMPTOSAR is 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). 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR). 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 mg at the first onset of late diarrhea and then mg every 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 mg of loperamide every hours. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of CAMPTOSAR.Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.Embryo-Fetal Toxicity [see Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] Advise pregnant women and females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy.Advise females of reproductive potential to use effective contraception during treatment with CAMPTOSAR and for months after the final dose.Advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR. LactationAdvise women not to breastfeed during treatment with CAMPTOSAR and for at least days after the final dose [see Use in Specific Populations (8.2)]. InfertilityAdvise females and males of reproductive potential that CAMPTOSAR may impair fertility [see Use in Specific Populations (8.3)]. Patients should be alerted to the possibility of alopecia.Contains sorbitol.. Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR). 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 mg at the first onset of late diarrhea and then mg every 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 mg of loperamide every hours. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.. Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of CAMPTOSAR.. Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.. Embryo-Fetal Toxicity [see Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] Advise pregnant women and females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy.Advise females of reproductive potential to use effective contraception during treatment with CAMPTOSAR and for months after the final dose.Advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR. Advise pregnant women and females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy.. Advise females of reproductive potential to use effective contraception during treatment with CAMPTOSAR and for months after the final dose.. Advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR.. LactationAdvise women not to breastfeed during treatment with CAMPTOSAR and for at least days after the final dose [see Use in Specific Populations (8.2)]. Advise women not to breastfeed during treatment with CAMPTOSAR and for at least days after the final dose [see Use in Specific Populations (8.2)].. InfertilityAdvise females and males of reproductive potential that CAMPTOSAR may impair fertility [see Use in Specific Populations (8.3)]. Advise females and males of reproductive potential that CAMPTOSAR may impair fertility [see Use in Specific Populations (8.3)]. Patients should be alerted to the possibility of alopecia.. Contains sorbitol.

LACTATION SECTION.

8.2 Lactation. Risk SummaryIrinotecan and its metabolites are present in human milk. There is no information regarding the effects of irinotecan on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from CAMPTOSAR in the breastfed child, advise lactating women not to breastfeed during treatment with CAMPTOSAR and for days after the final dose.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Irinotecan is derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m2 weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite SN-38 was mutagenic in the in vitro Ames assay.No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In separate studies in rodents, this dose produced an irinotecan Cmax and AUC about and times, respectively, of the corresponding values in patients administered 125 mg/m2 weekly. In dogs this dose produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, of the corresponding values in patients administered 125 mg/m2 weekly.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In U.S. phase trials, single doses of up to 345 mg/m2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg/5 mL Vial LabelNDC 0009-7529-03Single Use: Discard unused portionCamptosar(R) irinotecan HCl injection100 mg/5 mL(20 mg/mL)For Intravenous Use OnlyCytosafe(R) Vial Caution: Cytotoxic Agent PRINCIPAL DISPLAY PANEL 100 mg/5 mL Vial Label.

PEDIATRIC USE SECTION.

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 trial in which 50 mg/ m2 of irinotecan was infused for consecutive days every 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 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for consecutive days on weeks 0, 1, 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 or adverse events were dehydration experienced by patients (28.6%) associated with severe hypokalemia in patients (23.8%) and hyponatremia in patients (14.3%); in addition Grade 3-4 infection was reported in patients (23.8%) (across all courses of therapy and irrespective of causal relationship).Pharmacokinetic parameters for irinotecan and SN-38 were determined in 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 5 every weeks or (daily 5) 2 weeks every weeks].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Irinotecan serves as water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan [see Clinical Pharmacology (12.3)]. The precise contribution of SN-38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while more basic pH favors the hydroxy acid anion form.Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.

PHARMACOGENOMICS SECTION.

12.5 Pharmacogenomics. The active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A128 [(TA)7] and alleles lead to reduced UGT1A1 enzyme expression or activity and decreased function to similar extent.Individuals who are homozygous or compound (double) heterozygous for these alleles (e.g., 28/28, 6/6, 6/28) are UGT1A1 poor metabolizers and are at increased risk for severe or life-threatening neutropenia from CAMPTOSAR due to elevated systemic exposure to SN-38. The UGT1A16/6 genotype should not be confused with 6/6 genotype, which is sometimes used to represent the genotype of individuals who are wild type for UGT1A128. Individuals who are heterozygous for either the UGT1A128 or alleles (1/6, 1/28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].Published studies have shown that individuals with UGT1A128 and alleles may be at an increased risk of severe diarrhea. The risk evidence appears greater in UGT1A128 and homozygous patients and in those taking irinotecan doses 125 mg/m2 [see Warnings and Precautions (5.1)]. UGT1A128 and alleles occur at various frequencies in different populations. Approximately 20% of Black or African American, 10% of White, and 2% of East Asian individuals are homozygous for the UGT1A128 allele. Approximately 2-6 of East Asian individuals are homozygous for the UGT1A16 allele. The UGT1A16 allele is uncommon in Black or African American or in White individuals. Decreased function alleles other than UGT1A128 and may be present in certain populations.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in multiexponential manner, with mean terminal elimination half-life of about to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within hour following the end of 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumors are summarized in Table 9:Table 9.Summary of Mean (+-Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients With Solid TumorsDose(mg/m2)IrinotecanSN-38Cmax (ng/mL)AUC0-24 (ngh/mL)t1/2 (h)Vz (L/m2)CL(L/h/m2)Cmax (ng/mL)AUC0-24 (ngh/mL)t1/2 (h)Cmax Maximum plasma concentrationAUC0-24 Area under the plasma concentration-time curve from time0 to 24 hours after the end of the 90-minute infusiont1/2 Terminal elimination half-lifeVz Volume of distribution of terminal elimination phaseCL Total systemic clearance125(N=64)1,660 +-79710,200 +-3,2705.8Plasma specimens collected for 24 hours following the end of the 90-minute infusion. +-0.7110+-48.513.3+-6.0126.3+-11.9229+-10810.4 +-3.1340(N=6)3,392+-87420,604+-6,02711.7Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38. +-1.0234+-69.613.9+-4.056.0+-28.2474+-24521.0 +-4.3. DistributionIrinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.. Elimination. MetabolismIrinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases that form an active metabolite SN-38, and UGT1A1 which mediates the glucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38. Patients who are homozygous for either the UGT1A128 or alleles, or who are compound heterozygous for these alleles, have higher SN-38 AUC than patients with the wild-type UGT1A1 alleles [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.5)].Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release the active metabolite SN-38.. ExcretionThe disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).. Specific Populations. Geriatric PatientsThe pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients >=65 years of age. In study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients >=65 years of age were observed. Although dose-normalized AUC0-24 for SN-38 in patients >=65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan [see Dosage and Administration (2)].. Male and Female PatientsThe pharmacokinetics of irinotecan do not appear to be influenced by gender.. Racial and Ethnic GroupsThe influence of race on the pharmacokinetics of irinotecan has not been evaluated.. Patients with Renal ImpairmentThe influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated.. Patients with Hepatic ImpairmentIrinotecan 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. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than mg/dl) has not been assessed sufficiently.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesDexamethasone, moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.. In Vitro StudiesIrinotecan and the metabolites SN-38 and aminopentane carboxylic acid (APC) do not inhibit cytochrome P-450 isozymes.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of CAMPTOSAR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Myocardial ischemic events have been observed following CAMPTOSAR therapy. Thromboembolic events have been observed in patients receiving CAMPTOSAR.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 CAMPTOSAR; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.Interaction between CAMPTOSAR 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m2 (see Data ). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataRadioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan to rats at dose of mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses >= 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from separate rat study) there were increases in variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at dose of mg/kg (approximately half of the clinical dose of 125 mg/m2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased external, visceral, and skeletal abnormalities.Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Dosage in Patients With Reduced UGT1A1 Activity (2.3)1/2022Dosage and Administration, Preparation of Infusion Solution (2.5)1/2022Dosage and Administration, Safe Handling (2.6)1/2022Warnings and Precautions, Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity (5.3)1/2022.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

RENAL IMPAIRMENT SUBSECTION.

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. CAMPTOSAR is not recommended for use in patients on dialysis.

SPL UNCLASSIFIED SECTION.

2.1Colorectal Cancer Combination Regimens and 2. Administer CAMPTOSAR as 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 CAMPTOSAR 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 dose in these patients.Table 1. Combination-Agent Dosage Regimens and Dose ModificationsDose 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. Regimen 16-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)CAMPTOSAR LV5-FU125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,2220 mg/m2 intravenous injection bolus, days 1,8,15,22500 mg/m2 intravenous injection bolus, days 1,8,15,22Starting Dose Modified Dose Levels (mg/m2)Starting DoseDose Level -1Dose Level -2CAMPTOSAR12510075LV2020205-FU500400300Regimen 26-wk cycle with infusional 5-FU/LV(next cycle begins on day 43)CAMPTOSAR180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29LV200 mg/m2 intravenous infusion over hours, days 1,2,15,16,29,305-FU Bolus400 mg/m2 intravenous injection bolus, days 1,2,15,16,29,305-FU InfusionInfusion follows bolus administration. 600 mg/m2 intravenous infusion over 22 hours, days 1,2,15,16,29,30Starting Dose Modified Dose Levels (mg/m2)Starting DoseDose Level -1Dose Level -2CAMPTOSAR180150120LV2002002005-FU Bolus4003202405-FU Infusion 600480360Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend dose in these patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. Dose ModificationsBased on recommended dose levels described in Table 1, Combination Regimens of CAMPTOSAR 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 CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination SchedulesPatients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. 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 to weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after 2-week delay, consideration should be given to discontinuing therapy.ToxicityNCI CTC GradeNational Cancer Institute Common Toxicity Criteria (version 1.0) (Value) During Cycle of TherapyAt the Start of Subsequent Cycles of TherapyRelative to the starting dose used in the previous cycle No toxicityMaintain dose levelMaintain dose levelNeutropenia1 (1500 to 1999/mm3)Maintain dose levelMaintain dose level2 (1000 to 1499/mm3) dose levelMaintain dose level3 (500 to 999/mm3)Omit dose until resolved to <= grade 2, then dose level dose level4 (<500/mm3)Omit dose until resolved to <= grade 2, then dose levels dose levelsNeutropenic feverOmit dose until resolved, then dose levelsOther hematologic toxicitiesDose modifications for leukopenia or thrombocytopenia during 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.Diarrhea1 (2-3 stools/day pretxPretreatment) Delay dose until resolved to baseline, then give same doseMaintain dose level2 (4-6 stools/day pretx)Omit dose until resolved to baseline, then dose levelMaintain dose level3 (7-9 stools/day pretx)Omit dose until resolved to baseline, then dose level dose level4 (>=10 stools/day pretx)Omit dose until resolved to baseline, then dose levels dose levelsOther nonhematologic toxicitiesExcludes alopecia, anorexia, asthenia 1Maintain dose levelMaintain dose level2Omit dose until resolved to <= grade 1, then dose levelMaintain dose level3Omit dose until resolved to <= grade 2, then dose level dose level4Omit dose until resolved to <= grade 2, then dose levels dose levelsFor mucositis/stomatitis decrease only 5-FU, not CAMPTOSARFor mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR.

STORAGE AND HANDLING SECTION.

Store at controlled room temperature 15C to 30C (59 to 86F). Protect from light. Keep the vial in the carton until the time of use.Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.CAMPTOSAR is hazardous drug. Follow special handling and disposal procedures.1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Geriatric Use: Closely monitor patients greater than 65 years of age because of 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). Lactation: Advise not to breastfeed. (8.2). Geriatric Use: Closely monitor patients greater than 65 years of age because of 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. Risk SummaryBased on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m2 (see Data ). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataRadioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan to rats at dose of mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses >= 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m2 dose based on exposure data from separate rat study) there were increases in variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at dose of mg/kg (approximately half of the clinical dose of 125 mg/m2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased external, visceral, and skeletal abnormalities.Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.. 8.2 Lactation. Risk SummaryIrinotecan and its metabolites are present in human milk. There is no information regarding the effects of irinotecan on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from CAMPTOSAR in the breastfed child, advise lactating women not to breastfeed during treatment with CAMPTOSAR and for days after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status in female patients of reproductive potential prior to initiating CAMPTOSAR.. ContraceptionCAMPTOSAR can cause fetal harm when administered to pregnant woman.. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment and for months after the final dose of CAMPTOSAR [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].. MalesDue to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR [see Nonclinical Toxicology (13.1)]. Infertility. FemalesBased on postmarketing reports, female fertility may be impaired by treatment with CAMPTOSAR. Menstrual dysfunction has been reported following CAMPTOSAR administration.. MalesBased on findings from animal studies, male fertility may be impaired by treatment with CAMPTOSAR [see Nonclinical Toxicology (13.1)]. 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 trial in which 50 mg/ m2 of irinotecan was infused for consecutive days every 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 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for consecutive days on weeks 0, 1, 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 or adverse events were dehydration experienced by patients (28.6%) associated with severe hypokalemia in patients (23.8%) and hyponatremia in patients (14.3%); in addition Grade 3-4 infection was reported in patients (23.8%) (across all courses of therapy and irrespective of causal relationship).Pharmacokinetic parameters for irinotecan and SN-38 were determined in 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 5 every weeks or (daily 5) 2 weeks every weeks].. 8.5 Geriatric Use. Patients greater than 65 years of age should be closely monitored because of greater risk of early and late diarrhea in this population [see Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. The starting dose of CAMPTOSAR 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 and 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 or 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. CAMPTOSAR 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 CAMPTOSAR to patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Diarrhea and Cholinergic Reactions: Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. (5.1)Myelosuppression: Manage promptly with antibiotic support. Interrupt CAMPTOSAR and reduce subsequent doses if necessary. (5.2)Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity: Individuals with UGT1A128/28, or 6/6, or 6/28 genotypes are at increased risk for severe neutropenia during CAMPTOSAR treatment. (5.3)Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR 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 Day Regimen: CAMPTOSAR should not be used in combination with regimen of 5-FU/LV administered for 4-5 consecutive days every weeks outside of clinical study. (5.7)Embryo-Fetal Toxicity: CAMPTOSAR can cause fetal harm. Advise females of reproductive potential of the potential risk to 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, CAMPTOSAR 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). Diarrhea and Cholinergic Reactions: Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. (5.1). Myelosuppression: Manage promptly with antibiotic support. Interrupt CAMPTOSAR and reduce subsequent doses if necessary. (5.2). Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity: Individuals with UGT1A128/28, or 6/6, or 6/28 genotypes are at increased risk for severe neutropenia during CAMPTOSAR treatment. (5.3). Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR 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 Day Regimen: CAMPTOSAR should not be used in combination with regimen of 5-FU/LV administered for 4-5 consecutive days every weeks outside of clinical study. (5.7). Embryo-Fetal Toxicity: CAMPTOSAR can cause fetal harm. Advise females of reproductive potential of the potential risk to 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, CAMPTOSAR 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). 5.1Diarrhea and Cholinergic Reactions. Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) 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 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 CAMPTOSAR) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3-4 late diarrhea occurred in 23-31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 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 mg at the first onset of late diarrhea and then mg every 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 mg of loperamide every 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 CAMPTOSAR until resolution of the bowel obstruction. If grade 2, 3, or late diarrhea recurs, subsequent doses of CAMPTOSAR should be decreased [see Dosage and Administration (2)].Avoid diuretics or laxatives in patients with diarrhea.. 5.2Myelosuppression. CAMPTOSAR can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with CAMPTOSAR.Deaths due to sepsis following severe neutropenia have been reported in patients treated with CAMPTOSAR. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade neutropenia and fever of grade 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 CAMPTOSAR if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After recovery to an absolute neutrophil count >=1000/mm3, subsequent doses of CAMPTOSAR should be reduced [see Dosage and Administration (2)].When evaluated in the trials of weekly administration, the frequency of grade and 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 CAMPTOSAR. Based on sparse available data, the concurrent administration of CAMPTOSAR with irradiation is not recommended.Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had greater likelihood of experiencing first-cycle grade or 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 Gilberts syndrome, may be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR [see Warnings and Precautions (5.3)].. 5.3Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity. Published studies have shown that individuals who are homozygous for either the UGT1A128 or alleles (28/28, 6/6) or who are compound or double heterozygous for the UGT1A128 and alleles (6/28) are at increased risk for severe or life-threatening neutropenia during treatment with CAMPTOSAR. 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 UGT1A128 or 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 alleles to determine UGT1A1 metabolizer status [see Clinical Pharmacology (12.5)].When administering CAMPTOSAR, consider reduction in the CAMPTOSAR starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A128 and/or alleles (28/28, 6/6, 6/28).Closely monitor patients with UGT1A1 28 or alleles for neutropenia during and after treatment with CAMPTOSAR. 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)].. 5.4Hypersensitivity. Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue CAMPTOSAR if anaphylactic reaction occurs.. 5.5Renal 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.. 5.6Pulmonary 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 CAMPTOSAR therapy. In Japanese studies, reticulonodular pattern on chest x-ray was observed in small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, CAMPTOSAR and other chemotherapy should be discontinued and appropriate treatment instituted as needed [see Adverse Reactions (6.1)].. 5.7Toxicity of the Day Regimen. Outside of well-designed clinical study, CAMPTOSAR Injection should not be used in combination with regimen of 5-FU/LV administered for 4-5 consecutive days every weeks because of reports of increased toxicity, including toxic deaths. CAMPTOSAR should be used as recommended in Table [see Dosage and Administration (2)].. 5.8Increased 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 baseline performance status of than in patients with baseline performance status of or 1.. 5.9Embryo-Fetal Toxicity. Based on its mechanism of action and findings in animals, CAMPTOSAR can cause fetal harm when administered to pregnant woman. 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/m2. Advise pregnant women of the potential risk to fetus.Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with CAMPTOSAR and for months after the final dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of CAMPTOSAR [see Use in Specific Populations (8.1), (8.3) and Nonclinical Toxicology (13.1)].. 5.10Patients With Hepatic Impairment. The use of CAMPTOSAR 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 significantly greater likelihood of experiencing first-cycle, grade or 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)].