irinotecan hydrochloride

Important safety information

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 to 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 to 2.0 mg/dL had greater likelihood of grade 3 to 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 to 4 late diarrhea occurred in 23 to 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. 5.2 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 . 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 [see Warnings and Precautions ( 5.3 )] . 5.3 Increased Risk of Neutropenia in Patients with Reduced UGT1A1 Activity Published studies have shown that individuals who are homozygous for either the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or who are compound or double heterozygous for the UGT1A1*28 and *6 alleles (*6/*28) are at increased risk for severe or life-threatening neutropenia during treatment with Irinotecan Hydrochloride Injection. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*28, *1/*6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage…