Irinotecan Hydrochloride

Contraindications

Conventional Irinotecan

• Known hypersensitivity to irinotecan or any ingredient in the formulation.1

Liposomal Irinotecan

• Severe hypersensitivity to liposomal or conventional irinotecan.65

Warnings/Precautions

Warnings

Early and late forms of diarrhea may occur; both may be severe.1 2 16 17 18 19 27 28 65

Early diarrhea (onset within 24 hours of administration) generally is transient and cholinergic in nature (possibly accompanied by diaphoresis, flushing, rhinitis, increased salivation, miosis, lacrimation, bradycardia, and abdominal cramping).1 27 28 65 Higher doses and more rapid infusion rates of conventional irinotecan may increase the likelihood of cholinergic symptoms.1 8 22 28

Late diarrhea (occurring >24 hours after administration) may be prolonged, life-threatening, and lead to dehydration, electrolyte imbalance, or sepsis.1 65 May be complicated by colitis, ulceration, bleeding, ileus, and infection; megacolon and intestinal perforation also reported.1

Early diarrhea may be prevented or ameliorated by administration of atropine.1 27 28 65 (See General under Dosage and Administration.)

Treat late diarrhea of any severity promptly with intensive oral loperamide hydrochloride therapy (e.g., 4 mg at the onset of diarrhea, then 2 mg every 2 hours [or 4 mg every 4 hours at night1 56 ] until patient is diarrhea-free for 12 hours).1 2 16 17 18 19 21 22 28 56 65 Do not use loperamide at these dosages for >48 consecutive hours; risk of paralytic ileus.1 63

Consider a 7-day course of oral fluoroquinolone therapy if diarrhea persists for >24 hours despite loperamide therapy, or if diarrhea occurs with fever.1 56 If diarrhea persists for >48 hours, some clinicians advise discontinuance of loperamide and hospitalization for parenteral hydration.56

Monitor patients with diarrhea carefully; give fluid and electrolyte replacement if patient becomes dehydrated or anti-infective therapy if ileus, fever, or severe neutropenia develops.1 22 Some clinicians recommend appropriate anti-infective therapy in any patient with prolonged diarrhea, regardless of neutrophil count (continued until resolution).56

Interruption of therapy and subsequent dosage reduction may be required.1 65 (See Dosage Modification for Toxicity sections under Dosage and Administration.)

Do not administer irinotecan until bowel obstruction has resolved.1 65

Severe myelosuppression, particularly neutropenia,1 16 17 18 19 27 65 and deaths caused by sepsis have been reported.1 18 19 28 65

Possible increased risk of severe myelosuppression in patients receiving conventional irinotecan who have previously received pelvic or abdominal radiation therapy.1 Consider reducing initial dosage of conventional irinotecan.1 (See Prior Pelvic or Abdominal Radiation Therapy under Dosage and Administration.)

Increased risk of grade 3 or 4 neutropenia observed in conventional irinotecan-treated patients with modestly elevated (i.e., 1–2 mg/dL) total serum bilirubin concentrations.1 Possible increased risk of myelosuppression in patients with abnormal glucuronidation of bilirubin (e.g., Gilbert’s syndrome).1

Prompt anti-infective therapy recommended for complications of neutropenia.1

Interruption of therapy and subsequent dosage reduction may be required if neutropenia occurs.1 65 (See Dosage Modification for Toxicity sections under Dosage and Administration.)

Obtain blood tests no sooner than 48 hours before scheduled treatment; consider trends in the ANC as well as absolute values.56

Manufacturer recommends monitoring CBC on days 1 and 8 of each cycle of liposomal irinotecan therapy for pancreatic cancer and more frequently as clinically indicated.65

Do not use in patients with severe bone marrow failure; causes neutropenia, leukopenia, and anemia, any of which may be severe.63

Concurrent radiation therapy has not been adequately studied and is not recommended.1

Sensitivity Reactions

Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported.1 65

Other Warnings and Precautions

Patients homozygous for UGT1A1*28 allele have reduced UGT1A1 activity; these patients have increased exposure to the active metabolite SN-38 and are at an increased risk for neutropenia during irinotecan treatment; consider decreasing initial dose.1 65 (See Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 [UGT1A1] Activity under Dosage and Administration.)

Heterozygous patients may be at increased risk, but clinical results are variable.1

Renal impairment and acute renal failure have occurred, usually in patients who became volume depleted from severe vomiting and/or diarrhea.1 65

ILD, sometimes fatal, reported.1 65

Monitor patients with risk factors for ILD (e.g., preexisting lung disease, use of pneumotoxic drugs, radiation therapy, colony-stimulating factors) closely for respiratory symptoms.1

Interrupt therapy pending diagnostic evaluation in patients with new or progressive dyspnea, cough, and fever; discontinue drug if treatment-related ILD is diagnosed.1 65

Use in combination with the “Mayo Clinic” regimen of rapid IV injection (“bolus”) fluorouracil/leucovorin (i.e., administration for 4–5 consecutive days every 4 weeks) associated with increased toxicity, including deaths.1 Do not use in combination with this regimen outside of a well-designed clinical trial. 1

Higher rates of hospitalization, neutropenic fever, thromboembolism, treatment discontinuance during the first cycle, and early deaths reported in patients with a baseline performance status of 2 (versus 0 or 1) regardless of treatment regimen (conventional irinotecan in combination with fluorouracil/leucovorin versus fluorouracil/leucovorin alone).1

May cause fetal harm; embryotoxic and teratogenic in animals.1 65

Conventional irinotecan: Advise women of childbearing potential to avoid pregnancy during therapy with conventional irinotecan.1

Liposomal irinotecan: Advise women of childbearing potential to use effective contraception during and for 1 month after discontinuance of liposomal irinotecan.65 Sexually mature males must use a condom each time they have sexual contact with a woman of childbearing potential during and for at least 4 months after discontinuance of liposomal irinotecan.65

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1 65

Conventional irinotecan contains sorbitol;1 63 do not use in patients with hereditary fructose intolerance.63

Specific Populations

Conventional irinotecan: Category D.1

Liposomal irinotecan: May cause fetal harm.65 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Distributed into milk in animals; not known whether distributed into human milk.1 65

Conventional irinotecan: Discontinue nursing or the drug because of potential risk to nursing infants.1

Liposomal irinotecan: Discontinue nursing during therapy and for 1 month after drug discontinuance.65

Conventional irinotecan: Efficacy not established.1 Variable safety results observed for children relative to adults.1 Although adverse effects in children with refractory solid tumors receiving 50 mg/m2 IV daily for 5 consecutive days every 3 weeks were consistent with adverse effect profile in adults, increased rates of severe infection and dehydration resulting in severe hypokalemia and hyponatremia were observed in children with previously untreated rhabdomyosarcoma receiving 20 mg/m2 IV daily for 5 consecutive days of weeks 0, 1, 3, and 4.1 (See Special Populations under Pharmacokinetics.)

Liposomal irinotecan: Safety and efficacy not established.65

Conventional irinotecan: Possible increased risk of treatment-related toxicity (e.g., early and late diarrhea); close monitoring recommended in patients >65 years of age.1 56 Reduce initial dose in patients ≥70 years of age receiving the once-every-3-weeks dosage schedule as monotherapy for recurrent or progressive colorectal cancer.1 (See Geriatric Patients under Dosage and Administration.)

Liposomal irinotecan: No overall differences in safety and efficacy relative to younger adults.65

Conventional irinotecan: Irinotecan clearance decreased and exposure to SN-38 active metabolite increased in patients with hepatic impairment.1 Increased risk of irinotecan-induced toxicity (e.g., severe neutropenia) in patients with modestly elevated total serum bilirubin concentrations (1–2 mg/dL); consider possible need for dosage reduction.1 Possible increased risk of myelosuppression in patients with deficient glucuronidation of bilirubin (e.g., Gilbert’s syndrome).1 Use not established in patients with serum aminotransferase concentrations >3 times the ULN in the absence of hepatic metastasis or in those with hepatic metastasis and aminotransferase concentrations >5 times the ULN.1 Safety not adequately studied in patients with bilirubin concentrations >2 mg/dL.1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Liposomal irinotecan: Pharmacokinetics not evaluated.65 In a population pharmacokinetic analysis, steady-state concentrations of SN-38 were increased in patients with modestly elevated serum bilirubin concentrations (1–2 mg/dL); however, elevated serum aminotransferase concentrations did not affect SN-38 concentrations.65 Not studied in patients with bilirubin concentrations >2 mg/dL.65 (See Special Populations under Pharmacokinetics.)

Conventional irinotecan: Pharmacokinetics not evaluated.1 Caution advised in patients with renal impairment.1 Not recommended for use in dialysis patients.1

Liposomal irinotecan: In a population pharmacokinetic analysis, systemic exposure to SN-38 not altered by mild or moderate renal impairment.65 Limited data in patients with severe renal impairment.65 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Conventional irinotecan: Diarrhea, nausea, abdominal pain, vomiting, anorexia, constipation, mucositis, cholinergic syndrome, neutropenia, leukopenia, anemia, thrombocytopenia, bilirubin abnormalities, decreased body weight, asthenia, pain, fever, infection, alopecia, dyspnea, cough, dizziness.1

Liposomal irinotecan: Anemia, lymphopenia, diarrhea, fatigue/asthenia, neutropenia, vomiting, elevated ALT concentrations, nausea, decreased appetite, hypoalbuminemia, thrombocytopenia, hypomagnesemia, hypokalemia, hypocalcemia, stomatitis, hypophosphatemia, hyponatremia, pyrexia.65

Storage

Parenteral

Conventional irinotecan: 15–30°C; protect from light.1 Store vial in carton until time of use.1 Following dilution, store at 15–30°C and use within 4 hours; if diluted under strict aseptic (e.g., laminar airflow) conditions, use within 12 hours.1 Alternatively, store at 2–8°C and use within 24 hours; protect refrigerated solutions from light.1 Do not refrigerate solutions prepared in 0.9% sodium chloride.1 Do not freeze.1

Liposomal irinotecan: 2–8°C.65 Following dilution, store at 15–30°C and use within 4 hours; alternatively, store at 2–8°C and use within 24 hours.65 Protect concentrate and diluted solutions from light; do not freeze.65

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• A type I DNA topoisomerase inhibitor.1 2 3 6 7 9 13

• Binds and stabilizes the DNA–DNA topoisomerase cleavable complex,1 9 11 12 13 14 prevents the topoisomerase from religating the single-strand breaks,9 10 11 12 13 14 and interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA.1 2 4 9 10 11 12 13 This DNA damage is not efficiently repaired and leads to apoptosis (programmed cell death).1 2 9 17 18 19 29 30

• Risk of severe hypersensitivity reactions.1 65 Importance of promptly seeking medical attention if signs of severe hypersensitivity (e.g., chest tightness, shortness of breath, wheezing, dizziness, faintness, angioedema) occur.65

• Risk of myelosuppression resulting in severe or potentially fatal infections.1 65 Importance of patients monitoring their temperature frequently and immediately notifying clinician if fever or other manifestations of infection (e.g., chills, dizziness, shortness of breath) occur.1 65

• Importance of routine monitoring of blood cell counts.1 65

• Risk of serious GI effects, including diarrhea, nausea, vomiting, abdominal cramping, and infection.1 65

• Importance of immediately informing clinician of diarrhea occurring for the first time during treatment, black or bloody stools, symptoms of dehydration (e.g., lightheadedness, dizziness, faintness), nausea or vomiting resulting in inability to take fluids by mouth, or inability to control diarrhea within 24 hours.1 65

• Importance of beginning treatment for late diarrhea at the first episode of poorly formed or loose stools or any increase in frequency of bowel movements.1 Importance of not using loperamide for >48 consecutive hours at high doses.1

• If diarrhea occurs, importance of avoiding drugs with laxative or diuretic properties.1

• Risk of interstitial lung disease.1 65 Importance of immediately informing clinician if new-onset cough or dyspnea occurs.65

• Risk of dizziness or visual disturbances; importance of not driving or operating machinery if these symptoms occur.1 63

• Risk of alopecia.1 65

• Importance of advising patients with hereditary fructose intolerance that conventional irinotecan contains sorbitol.1 63

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1 65

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.1 65 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of informing patients of other important precautionary information.1 65 (See Cautions.)