Irinotecan Hydrochloride
Injection, Solution · Intravenous
Uses
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 ) 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.
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 to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm 3 , and the platelet count has recovered to ≥100,000/mm 3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy. Toxicity NCI CTC Grade a (Value) During a Cycle of Therapy At the Start of Subsequent Cycles of Therapy b No toxicity Maintain dose level Maintain dose level Neutropenia 1 (1500 to 1999/mm 3 ) Maintain dose level Maintain dose level 2 (1000 to 1499/mm 3 ) ↓1 dose level Maintain dose level 3 (500 to 999/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level ↓1 dose level 4 (<500/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels ↓ 2 dose levels Neutropenic fever Omit dose until resolved, then ↓ 2 dose levels Other hematologic toxicities Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Dosage forms and strengths
Injection: 40 mg/2 mL (20 mg/mL) and 100 mg/5 mL (20 mg/mL) solution in a single-dose vial. ( 3 ) Injection: 40 mg/2 mL (20 mg/mL) and 100 mg/5 mL (20 mg/mL) sterile, pale yellow, clear, aqueous solution in a single-dose vial.
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.
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 ) Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity: Individuals with UGT1A1*28/*28, or *6/*6, or *6/*28 genotypes are at increased risk for severe neutropenia during 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 dyspnea, 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 ) Embryo-Fetal Toxicity: Irinotecan hydrochloride injection can cause fetal harm. Advise females of reproductive potential of the potential risk to a 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, 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 injection) 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 injection) 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 movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 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 4 mg of loperamide every 4 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 irinotecan hydrochloride injection until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan hydrochloride injection should be decreased [see Dosage and Administration (2) ]. Avoid diuretics or laxatives in patients with diarrhea. 5.2 Myelosuppression Irinotecan hydrochloride injection can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with irinotecan hydrochloride injection. Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride injection. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 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 irinotecan hydrochloride injection if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm 3 .
Side effects
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 events for patients receiving 5-FU/LV therapy were diarrhea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with weekly irinotecan/5-FU/LV than with monthly administration of 5-FU/LV. Tables 5 and 6 list the clinically relevant adverse events reported in Studies 1 and 2, respectively. Table 5. Study 1: Percent (%) of Patients Experiencing Clinically Relevant Adverse Events in Combination Therapies a a Severity of adverse events based on NCI CTC (version 1.0) b Complete hair loss = Grade 2 c Includes angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis, vascular disorder.
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 in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted. 7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan hydrochloride injection therapy. Do not administer strong CYP3A4 inducers with irinotecan hydrochloride injection unless there are no therapeutic alternatives. 7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ] . Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of irinotecan hydrochloride injection with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan hydrochloride injection therapy. Do not administer strong CYP 3A4 or UGT1A1 inhibitors with irinotecan hydrochloride injection unless there are no therapeutic alternatives.
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.( 2.1 , 5.10 , 8.7 , 12.3 ) 8.1 Pregnancy Risk Summar y 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 14 C-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/m 2 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/m 2 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 by treatment with irinotecan hydrochloride injection. Menstrual dysfunction has been reported following irinotecan hydrochloride injection administration. Males Based on findings from animal studies, male fertility may be impaired by treatment with irinotecan hydrochloride injection [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 2 trial in which 50 mg/m 2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m 2 of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship). Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m 2 (60-min infusion, n=48) and 125 mg/m 2 (90-min infusion, n=6).
Pregnancy
5.9 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, irinotecan hydrochloride injection can cause fetal harm when administered to a 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/m 2 . Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with irinotecan hydrochloride injection and for 6 months after the final dose. 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 Use in Specific Populations (8.1) , (8.3) and Nonclinical Toxicology (13.1) ]. 8.1 Pregnancy Risk Summar y 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 14 C-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/m 2 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/m 2 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.
Pediatric use
8.4 Pediatric Use The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/m 2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m 2 of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship). Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m 2 (60-min infusion, n=48) and 125 mg/m 2 (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m 2 for the 50mg/m 2 dose and 16.2 ± 4.6 L/h/m 2 for the 125 mg/m 2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].
Geriatric use
8.5 Geriatric Use Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population [see Clinical Pharmacology (12.3) and Adverse Reactions (6.1) ] . The starting dose of irinotecan hydrochloride injection in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m 2 [see Clinical Pharmacology (12.3) and Dosage and Administration (2) ] . The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92].
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.
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
Mechanism of action
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.
How supplied
Irinotecan hydrochloride injection, USP is available as a sterile, pale yellow, clear, aqueous solution in single-dose amber glass vials in the following individual package sizes: ● 40 mg/2 mL (20 mg/mL) NDC 50742-401-02 ● 100 mg/5 mL (20 mg/mL) NDC 50742-402-05 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Protect from freezing. Keep the vials 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 injection is a hazardous drug. Follow special handling and disposal procedures. 1
Patient information
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 irinotecan hydrochloride injection). 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 4 mg at the first onset of late diarrhea and then 2 mg every 2 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 4 mg of loperamide every 4 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 irinotecan hydrochloride injection. ● 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 and 8.3), Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ] ○ Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. ○ Advise females of reproductive potential to use effective contraception during treatment with irinotecan hydrochloride injection and for 6 months after the final dose. ○ 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. ● Lactation ○ Advise women not to breastfeed during treatment with irinotecan hydrochloride injection and for at least 7 days after the final dose [see Use in Specific Populations (8.2) ] . ● Infertility ○ Advise females and males of reproductive potential that irinotecan hydrochloride injection may impair fertility [see Use in Specific Populations (8.3) ]. ● Patients should be alerted to the possibility of alopecia. ● Contains sorbitol. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193 Made in Switzerland
Label text from the FDA structured product label by Ingenus Pharmaceuticals, LLC (revised Mar 7, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Irinotecan Hydrochloride in 22 products
Irinotecan Hydrochloride NDC products (22)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 45963-614 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Actavis Pharma, Inc. | ANDA |
| 60505-6272 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Apotex Corp. | ANDA |
| 60505-6128 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Apotex Corp. | ANDA |
| 55150-355 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Eugia US LLC | ANDA |
| 55150-354 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Eugia US LLC | ANDA |
| 55150-353 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Eugia US LLC | ANDA |
| 55150-352 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Eugia US LLC | ANDA |
| 63323-193 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Fresenius Kabi USA, LLC | ANDA |
| 68083-382 | Irinotecan Hydrochloride 20 mg/mL Injection | Gland Pharma Limited | ANDA |
| 0143-9701 | Irinotecan Hydrochloride 20 mg/mL Injection | Hikma Pharmaceuticals USA Inc. | ANDA |
| 0143-9702 | Irinotecan Hydrochloride 20 mg/mL Injection | Hikma Pharmaceuticals USA Inc. | ANDA |
| 0143-9583 | Irinotecan Hydrochloride 20 mg/mL Injection | Hikma Pharmaceuticals USA Inc. | ANDA |
| 61703-349 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Hospira, Inc. | ANDA |
| 50742-402 | Irinotecan Hydrochloride 100 mg/5mL Injection | Ingenus Pharmaceuticals, LLC | ANDA |
| 50742-401 | Irinotecan Hydrochloride 40 mg/2mL Injection | Ingenus Pharmaceuticals, LLC | ANDA |
| 16714-131 | Irinotecan Hydrochloride 20 mg/mL Injection | Northstar Rx LLC | ANDA |
| 16714-027 | Irinotecan Hydrochloride 20 mg/mL Injection | Northstar Rx LLC | ANDA |
| 67184-0511 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Qilu Pharmaceutical Co., Ltd. | ANDA |
| 67184-0512 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Qilu Pharmaceutical Co., Ltd. | ANDA |
| 67184-0513 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Qilu Pharmaceutical Co., Ltd. | ANDA |
| 25021-230 | Irinotecan Hydrochloride 20 mg/mL Injection, Solution | Sagent Pharmaceuticals | ANDA |
| 70700-170 | Irinotecan Hydrochloride 20 mg/mL Injection | Xiromed LLC | ANDA |
Irinotecan Hydrochloride recalls
- D-1308-2020 Jun 24, 2020 · Class II · Terminated
Defective Container: Customer complaints received of a crimp defect while removing the flip-cap during use. - D-1309-2020 Jun 24, 2020 · Class II · Terminated
Defective Container: Customer complaints received of a crimp defect while removing the flip-cap during use. - D-0890-2018 Jul 11, 2018 · Class II · Terminated
Superpotent Drug: High out of specification assay value results for potency. - D-0891-2018 Jul 11, 2018 · Class II · Terminated
Superpotent Drug: High out of specification assay value results for potency. - D-66447-001 Nov 13, 2013 · Class II · Terminated
Superpotent Drug: a recent review of the USP revealed that an incorrect calculation was used to determine the amount of irinotecan to use in formulation which will result in an assay higher than the labeled claim. - D-66447-002 Nov 13, 2013 · Class II · Terminated
Superpotent Drug: a recent review of the USP revealed that an incorrect calculation was used to determine the amount of irinotecan to use in formulation which will result in an assay higher than the labeled claim.
Frequently asked questions
What is Irinotecan Hydrochloride used for?
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 ) Irinotecan hydrochloride…
What are the side effects of Irinotecan Hydrochloride?
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… See the full label for the complete list.
Who makes Irinotecan Hydrochloride?
Irinotecan Hydrochloride is listed by 12 labelers in the FDA NDC directory, including Actavis Pharma, Inc., Apotex Corp., Eugia US LLC, Fresenius Kabi USA, LLC.
Has Irinotecan Hydrochloride been recalled?
The FDA enforcement database lists 6 recalls for Irinotecan Hydrochloride, most recently D-1308-2020 (class ii): Defective Container: Customer complaints received of a crimp defect while removing the flip-cap during use.