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 )
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 )
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 )
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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 )
5.1Diarrhea 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 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.
5.2Myelosuppression
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 . After recovery to an absolute neutrophil count ≥1000/mm 3 , subsequent doses of irinotecan hydrochloride injection should be reduced [ see Dosage and Administration (2) ]. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 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 irinotecan hydrochloride injection. Based on sparse available data, the concurrent administration of irinotecan hydrochloride injection with irradiation is not recommended. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 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 Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with irinotecan hydrochloride injection.
5.3Patients With Reduced UGT1A1 Activity
Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of irinotecan hydrochloride injection treatment. In a study of 66 patients who received single-agent irinotecan hydrochloride injection (350 mg/m 2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%.
No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype). In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with irinotecan hyd
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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.
7.2Strong 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. 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 therapy.
Do not administer strong CYP3A4 inducers with Irinotecan 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, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of Irinotecan 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 therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with Irinotecan unless there are no therapeutic alternatives.
Pregnancy and breastfeeding
8.1Pregnancy 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 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575, 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 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 Severity of adverse events based on NCI CTC (version 1.0) Adverse Event Study 1 Irinotecan + Bolus 5-FU/LV weekly × 4 every 6 weeks N=225 Bolus 5-FU/LV daily × 5 every 4 weeks N=219 Irinotecan weekly × 4 every 6 weeks N=223 Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4 Grade 1–4 Grade 3&4 TOTAL Adverse Events 100 53.3 100 45.7 99.6
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