Irinotecan Hydrochloride

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

2 DOSAGE AND ADMINISTRATION Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. ( 2.2 ) Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m 2 intravenous infusion over 90 minutes on day 1 every 3 weeks. ( 2.2 ) 2.2 Colorectal Single Agent Regimens 1 and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3. A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients. Table 3. Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications a Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m 2 in 50 mg/m 2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. Regimen 1 (weekly) a 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest Starting Dose and Modified Dose Levels c (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Regimen 2 (every 3 weeks) b 350 mg/m 2 intravenous infusion over 90 minutes, once every 3 weeks c Starting Dose and Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 350 300 250 Dose Modifications Based on recommended dose-levels described in Table 3, Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity. Table 4: Recommended Dose Modifications For Single-Agent Schedules a a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3 , and the platelet count has recovered to ≥100,000/mm 3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection. Worst Toxicity NCI Grade b (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle a Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m 2 up to a maximum dose of 150 mg/m 2 Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm 3 ) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (500 to 999/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (<500/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m 2 when resolved ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Dia…

5 WARNINGS AND PRECAUTIONS Diarrhea and cholinergic reactions: Early diarrhea (occurring during or shortly after infusion of irinotecan hydrochloride injection) is usually transient and may be accompanied by cholinergic symptoms. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride injection) can occur. Monitor and replace fluid and electrolytes. Treat with loperamide. Use antibiotic support for ileus and fever. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if severe diarrhea occurs.( 5.1 ) Myelosuppression: Manage promptly with antibiotic support. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if necessary. ( 5.2 ) Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the UGT1A1 * 28 allele are at increased risk for neutropenia following initiation of irinotecan hydrochloride injection treatment. ( 5.3 ) Hypersensitivity: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue irinotecan hydrochloride injection if this occurs. ( 5.4 ) Renal Impairment/Renal Failure: Rare cases of renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea. ( 5.5 ) Pulmonary Toxicity: Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred. Interrupt for new or progressive dysnpnea, cough, and fever pending evaluation. If IPD diagnosed, discontinue and institute appropriate treatment as needed. ( 5.6 ) Toxicity of the 5 Day Regimen: Irinotecan hydrochloride injection should not be used in combination with a regimen of 5-FU/LV administered for 4-5 consecutive days every 4 weeks outside of a clinical study. ( 5.7 ) Embryofetal Toxicity: Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. ( 5.9 ) Patients with Hepatic Impairment: In clinical trials, irinotecan hydrochloride injection has not been administered to patients with serum bilirubin > 2.0 mg/dL, or transaminases > 3 times ULN if no liver metastases, or transaminases > 5 times ULN if liver metastases. With the weekly dosage schedule, patients with total bilirubin levels 1.0-2.0 mg/dL had greater likelihood of grade 3-4 neutropenia. ( 5.10 ) 5.1 Diarrhea and Cholinergic Reactions Early diarrhea (occurring during or shortly after infusion of Irinotecan hydrochloride) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses. Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride) 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 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movement…

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

7 DRUG INTERACTIONS Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with Irinotecan hydrochloride. ( 7.2 ) Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with Irinotecan hydrochloride. ( 7.3 ) 7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives. 7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [ see Clinical Pharmacology (12.3) ]. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.

8.3 Nursing Mothers Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from irinotecan hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6 ADVERSE REACTIONS 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 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions ( > 30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia. Second-Line Single-Agent Therapy Weekly Dosage Schedule In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan hydrochloride. Seventeen of the patients died within 30 days of the administration of Irinotecan hydrochloride; in five cases (1.6%, 5/304), the deaths were potentially drug-related. One of the patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care. One hundred nineteen (39.1%) of the 304 patients were hospitalized because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan hydrochloride. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%). The first dose of at least one cycle of Irinotecan hydrochloride was reduced for 67% of patients who began the studies at the 125-mg/m 2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m 2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan hydrochloride because of adverse events. The adverse events in Table 7 are based on the experience of the 304 patients enrolled in the three studies described in Clinical Studies (14.1) . Table 7. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectum a a Severity of adverse events based on NCI CTC (version 1.0) b Occurring >24 hours after administration of Irinotecan hydrochloride c Occurring ≤24 hours after administration of Irinotecan hydrochloride d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2 Body System & Event % of Patients Reporting NCI Grades 1-4 NCI Grades 3 & 4 GASTROINTESTINAL Diarrhea (late) b 88 31 7–9 stools/day (grade 3) — (16) ≥10 stools/day (grade 4) — (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early) c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC Leukopenia 63 28 Anemia 60 7 Neutropenia 54 26 500 to <1000/mm 3 (grade 3) — (15) <500/mm 3 (grade 4) — (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infection d 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC AND NUTRITIONAL ↓ Body weight 30 1 Dehydration 15 4 ↑ Alkaline phosphatase 13 4 ↑ SGOT 10 1 DERMATOLOGIC Alopecia 60 NA e Sweating 16 0 Rash 13 1 RESPIRATORY Dyspnea 22 4 ↑ Cou…