Irinotecan Hydrochloride

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

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

2 DOSAGE AND ADMINISTRATION Colorectal cancer combination regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8,15, 22 with LV 20 mg/m 2 intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-FU intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks. ( 2.1 ) Colorectal cancer combination regimen 2: Irinotecan hydrochloride injection 180 mg/m 2 intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m 2 intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m 2 intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m 2 intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. ( 2.1 ) Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m 2 intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. ( 2.2 ) Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m 2 intravenous infusion over 90 minutes on day 1 every 3 weeks. ( 2.2 ) 2.1 Colorectal Cancer Combination Regimens 1 and 2 Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1. A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients . Table 1. Combination-Agent Dosage Regimens and Dose Modifications a a Dose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. b Infusion follows bolus administration. Irinotecan hydrochloride injection LV 5-FU 125 mg/m 2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m 2 intravenous injection bolus, days 1,8,15,22 500 mg/m 2 intravenous injection bolus, days 1,8,15,22 Starting Dose & Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 Irinotecan hydrochloride injection 125 100 75 LV 20 20 20 5-FU 500 400 300 Irinotecan hydrochloride injection 180 mg/m 2 intravenous infusion over 90 minutes, days 1,15,29 Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) LV 200 mg/m 2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 5-FU Bolus 400 mg/m 2 intravenous injection bolus, days 1,2,15,16,29,30 5-FU Infusion b 600 mg/m 2 intravenous infusion over 22 hours, days 1,2,15,16,29,30 Starting Dose & Modified Dose Levels (mg/m 2 ) Starting Dose Dose Level -1 Dose Level -2 Irinotecan hydrochloride injection 180 150 120 LV 200 200 200 5-FU Bolus 400 320 240 5-FU Infusion b 600 480 360 Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients [see Warnings and Precautions (5.10) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Dose Modifications Based on recommended dose levels described in Table 1, Combination Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Combination Regimens. All dose modifications should be based on the worst preceding toxicity. Table 2. Recommended Dose Modifications for Irinotecan Hydrochloride Injection/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules a National Cancer Institute Common Toxicity Criteria (version 1.0) b Relative to the starting dose used in the previous cycle c Pretreatment d Excludes alopecia, anorexia, asthenia Patients should return t …

3 DOSAGE FORMS AND STRENGTHS Irinotecan hydrochloride injection is available in two single-dose sizes: 2 mL-fill vial containing 40 mg irinotecan hydrochloride 5 mL-fill vial containing 100 mg irinotecan hydrochloride Irinotecan hydrochloride injection is available in two single-dose sizes: ( 3) 2 mL-fill vial containing 40 mg irinotecan hydrochloride injection 5 mL-fill vial containing 100 mg irinotecan hydrochloride injection

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

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 Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (≥30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. Common adverse reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia. First-Line Combination Therapy A total of 955 patients with metastatic colorectal cancer received the recommended regimens of irinotecan in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan alone. In the two phase 3 studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan alone [see Dosage and Administration (2) ]. In Study 1, 49 (7.3%) patients died within 30 days of last study treatment: 21 (9.3%) received irinotecan in combination with 5-FU/LV, 15 (6.8%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan alone. Deaths potentially related to treatment occurred in 2 (0.9%) patients who received irinotecan in combination with 5-FU/LV (2 neutropenic fever/sepsis), 3 (1.4%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan alone (2 neutropenic fever). Deaths from any cause within 60 days of first study treatment were reported for 15 (6.7%) patients who received irinotecan in combination with 5-FU/LV, 16 (7.3%) patients who received 5-FU/LV alone, and 15 (6.7%) patients who received irinotecan alone. Discontinuations due to adverse events were reported for 17 (7.6%) patients who received irinotecan in combination with 5FU/LV, 14 (6.4%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan alone. In Study 2, 10 (3.5%) patients died within 30 days of last study treatment: 6 (4.1%) received irinotecan in combination with 5-FU/LV and 4 (2.8%) received 5-FU/LV alone. There was one potentially treatment-related death, which occurred in a patient who received irinotecan in combination with 5-FU/LV (0.7%, neutropenic sepsis). Deaths from any cause within 60 days of first study treatment were reported for 3 (2.1%) patients who received irinotecan in combination with 5-FU/LV and 2 (1.4%) patients who received 5-FU/LV alone. Discontinuations due to adverse events were reported for 9 (6.2%) patients who received irinotecan in combination with 5FU/LV and 1 (0.7%) patient who received 5-FU/LV alone. The most clinically significant adverse events for patients receiving irinotecan-based therapy were diarrhea, nausea, vomiting, neutropenia, and alopecia. The most clinically significant adverse even …

7 DRUG INTERACTIONS • Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection. ( 7.2 ) • Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with irinotecan hydrochloride injection. ( 7.3 ) 7.1 5-Fluorouracil (5-FU) and Leucovorin (LV) In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered when the drugs were co-administered. Although the C max and AUC 0-24 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 i n vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted 7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives. 7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ]. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride injection with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.

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 a greater risk of early and late diarrhea in this population. ( 8.5 ) Patients with Renal Impairment: Use caution and do not use in patients on dialysis. ( 8.6 ) Patients with Hepatic Impairment : Use caution. ( 5.10 , 8.7 , 12.3 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Available postmarketing and published data reporting the use of irinotecan hydrochloride injection 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/m 2 (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan to rats at a dose of 6 mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a 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 a separate rat study) there were increases in a variety of external, visceral, and skeletal abnormalities. Administration of irinotecan to pregnant rabbits at a dose of 6 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 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring. 8.2 Lactation Risk Summary Irinotecan 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 irinotecan hydrochloride injection in the breastfed child, advise lactating women not to breastfeed during treatment with irinotecan hydrochloride injection and for 7 days after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status in female patients of reproductive potential prior to initiating irinotecan hydrochloride injection. Contraception Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. Females Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the final dose of irinotecan hydrochloride injection [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ] . Males Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of irinotecan hydrochloride injection [see Nonclinical Toxicology (13.1) ] . Infertility Females Based on postmarketing reports, female fertility may be impaired …

12.1 Mechanism of Action Irinotecan is a 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.

11 DESCRIPTION Irinotecan hydrochloride injection, USP is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride injection, USP is supplied as a sterile, pale yellow, clear, aqueous solution free from visible particles. 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. Irinotecan hydrochloride injection, USP 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, USP is a 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-dioxo1 H -pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C 33 H 38 N 4 O 6 •HCl•3H 2 O and molecular weight is 677.19. It is slightly soluble in water and organic solvents. Its structural formula is as follows: Irinotecan Hydrochloride Structural formulla

10 OVERDOSAGE In U.S. phase 1 trials, single doses of up to 345 mg/m 2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m 2 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 irinotecan hydrochloride injection. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

16 HOW SUPPLIED/STORAGE AND HANDLING Irinotecan hydrochloride injection, USP is supplied as a sterile, pale yellow, clear, aqueous solution and is available in single-dose brown glass vials in the following package sizes: PRESENTATION NDC CODE 2 mL-fill vial containing 40 mg/2 mL (20 mg/mL) irinotecan hydrochloride injection NDC 16714-027-01 5 mL- fill vial containing 100 mg/5 mL(20 mg/mL) irinotecan hydrochloride injection NDC 16714-131-01 Store at 20° to25°C (68° to 77°F) [see USP Controlled Room Temperature].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. Irinotecan hydrochloride is a hazardous drug. Follow special handling and disposal procedures. 1