Brand name: Camptosar
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-β]quinolin-9-yl ester[1,4′-bipiperidine]-1′-carboxylic acid trihydrate monohydrochloride
Molecular formula: C₃₃H₃₈N₄O₆•HCl•3H₂O
CAS number: 136572-09-3

Medically reviewed by Drugs.com on Jun 24, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a semisynthetic derivative of camptothecin.^{1 2 3 6 7 9 13}

Uses for Irinotecan

Colorectal Cancer

Conventional irinotecan: Used as a component of first-line therapy in combination with fluorouracil and leucovorin for the treatment of metastatic carcinoma of the colon or rectum.^{1 27 36 37}

Conventional irinotecan: Used as a single agent for treatment of metastatic carcinoma of the colon or rectum in patients whose disease has recurred or progressed following initial therapy with fluorouracil-based antineoplastic regimens.^{1 2 3 8 11 17 18 19 28 32 33 36 37}

Pancreatic Cancer

Liposomal irinotecan: Used in combination with fluorouracil and leucovorin for the treatment of metastatic adenocarcinoma of the pancreas in patients whose disease has progressed following gemcitabine-based chemotherapy^{65 68} (designated an orphan drug by FDA for treatment of this cancer⁶⁷ ).

Small Cell Lung Cancer

Conventional irinotecan: Used in combination with cisplatin for the initial treatment of extensive small cell lung cancer^{† [off-label]}.^{27 46}

Cervical Cancer

Conventional irinotecan: Under investigation for the treatment of metastatic or recurrent cervical cancer^{† [off-label]}.^{27 47 48 49 50 51}

Irinotecan Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{1 65}

• Administer effective antiemetic therapy for management of nausea and vomiting (e.g., dexamethasone 8 mg and a serotonin 5-HT₃ receptor antagonist such as palonosetron) orally or IV at least 30 minutes prior to irinotecan therapy.^{1 7 8 22 28 64 65} Consider additional oral antiemetic therapy for home use as needed.^{1 22 64}

• Unless clinically contraindicated, consider prophylactic or therapeutic administration of antimuscarinic therapy (e.g., 0.25–1 mg of atropine sulfate IV or sub-Q) for patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, abdominal cramping, or early diarrhea (i.e., onset within 24 hours of administration).^{1 8 22 28 65}

Restricted Distribution Program for Liposomal Irinotecan

• Liposomal irinotecan is available only through select specialty distributors.⁶⁶ Consult the Onivyde website for specific availability information ([Web]).⁶⁶

Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer conventional or liposomal irinotecan by IV infusion.^{1 65}

Handle cautiously; use protective equipment (e.g., protective clothing and gloves); avoid exposure during handling and preparation of IV solution.^{1 65} If skin or mucosal contact occurs, immediately and thoroughly wash skin with soap and water and flush mucosa with water.¹

IV Administration of Conventional Irinotecan

Avoid extravasation; monitor infusion site for signs of inflammation.^{1 22} If extravasation occurs, immediately stop the infusion, flush infusion site promptly with sterile water, apply an ice pack, and restart infusion in another vein.^{1 22}

Do not admix with other drugs.¹

Discard any unused portions.¹

Inadvertent overdosage has occurred because the manufacturer’s label on the vial was misread.³¹ Take particular care to ensure that the correct dose is administered, including careful attention to the concentration of irinotecan hydrochloride for injection concentrate present in the vial and the appropriate volume needed to provide the prescribed dose.³¹

Dilution

Conventional irinotecan hydrochloride for injection concentrate must be diluted prior to IV administration.^{1 22}

Dilute in 5% dextrose injection (preferred diluent) or 0.9% sodium chloride injection to a final irinotecan hydrochloride concentration of 0.12–2.8 mg/mL; usual diluent volume is 250–500 mL.^{1 3 16 17 18 19}

Rate of Administration

Infuse diluted solution over a period of 90 minutes;¹ more rapid infusion rates may increase the likelihood of cholinergic symptoms.²² (See Diarrhea under Cautions.)

IV Administration of Liposomal Irinotecan

Do not use in-line filters.⁶⁵

Discard any unused solution.⁶⁵

Dilution

Liposomal irinotecan hydrochloride for injection concentrate must be diluted prior to IV infusion.⁶⁵

Dilute in 500 mL of 5% dextrose injection or 0.9% sodium chloride injection.⁶⁵

Rate of Administration

Infuse diluted solution over a period of 90 minutes.⁶⁵

Dosage

Conventional irinotecan: Available as irinotecan hydrochloride as the trihydrate; dosage expressed in terms of the hydrated salt.¹

Liposomal irinotecan: Available as liposomal irinotecan hydrochloride as the trihydrate; dosage expressed in terms of anhydrous irinotecan.^{65 69}

Do not substitute liposomal irinotecan for other irinotecan formulations.⁶⁵

Adults

Colorectal Cancer (First-line Combination Therapy)

Optimal dosage regimen for irinotecan-based combination therapy has not been established; an unexpectedly high rate of death has been reported in 2 clinical trials using irinotecan with fluorouracil given by rapid IV injection (“bolus”), and some clinicians prefer administration of fluorouracil by IV infusion in this regimen.^{55 56 58}

Monitor patients receiving irinotecan in combination with fluorouracil/leucovorin closely (e.g., weekly assessment), particularly during the first cycle of treatment; most of the treatment-related toxicities leading to early death have occurred within the first 3–4 weeks.⁵⁶

Regimen 1

IV (Conventional Irinotecan)

Initially, irinotecan hydrochloride 125 mg/m² infused over 90 minutes, followed immediately by leucovorin 20 mg/m² given by rapid IV injection (“bolus”), followed immediately by fluorouracil 500 mg/m² given by rapid IV injection (“bolus”).^{1 54} Administer weekly for 4 weeks on days 1, 8, 15, and 22 during a 6-week cycle; the next cycle begins on day 43.¹

Modify dosage within a cycle of therapy or when initiating a subsequent cycle of therapy based on individual patient tolerance; monitor patient carefully to obtain optimum therapeutic response with minimum adverse effects.^{1 7 8 17 18 19 22} (See Dosage Modification for Toxicity [Regimen 1 or 2] under Dosage and Administration.)

Unless intolerable toxicity develops, additional cycles may be administered every 6 weeks in patients who continue to experience clinical benefit.¹

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele.¹ (See Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 [UGT1A1] Activity under Dosage and Administration.)

Regimen 2

IV (Conventional Irinotecan)

Initially, irinotecan hydrochloride 180 mg/m² infused over 90 minutes, followed immediately by leucovorin 200 mg/m² infused IV over 2 hours, followed immediately by fluorouracil 400 mg/m² by rapid IV injection (“bolus”) and then fluorouracil 600 mg/m² infused IV over 22 hours.^{1 53} Administer irinotecan on days 1, 15, and 29 of a 6-week cycle with administration of the leucovorin and fluorouracil (rapid IV injection [“bolus”] and infusional) component of the regimen on days 1, 2, 15, 16, 29, and 30; the next cycle begins on day 43.¹

Modify dosage within a cycle of therapy or when initiating a subsequent cycle of therapy based on individual patient tolerance; monitor patient carefully to obtain optimum therapeutic response with minimum adverse effects.^{1 7 8 17 18 19 22} (See Dosage Modification for Toxicity [Regimen 1 or 2] under Dosage and Administration.)

Unless intolerable toxicity develops, additional cycles may be administered every 6 weeks in patients who continue to experience clinical benefit.¹

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele.¹ (See Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 [UGT1A1] Activity under Dosage and Administration.)

Dosage Modification for Toxicity (Regimen 1 or 2)

IV (Conventional Irinotecan)

Reduce dosage within a cycle of therapy or when initiating a subsequent cycle of therapy as necessary based on toxicity (see Table 1 and Table 2).¹ Further reductions in dosage (i.e., beyond dose level 2) in decrements of 20% may be warranted in patients who continue to experience toxicity.¹ If multiple toxicities occur, adjust dose based on the toxicity requiring the largest dose reduction.^{1 17 18 19}

Delay subsequent doses of combination therapy until pretreatment bowel function has been restored for ≥24 hours without the need for antidiarrheal agents.¹

Do not initiate a new cycle of therapy until treatment-related diarrhea has fully resolved, granulocyte count has recovered to ≥1500/mm³, and platelet count has recovered to ≥100,000/mm³.¹

May delay treatment for 1–2 weeks to allow for recovery from treatment-related toxicities.¹ Consider discontinuing therapy if the treatment-induced toxicity does not resolve after delaying administration for 2 weeks.¹

Treatment on days 1, 8, 15, and 22.

Administration of irinotecan on days 1, 15, and 29, and administration of leucovorin, “bolus” fluorouracil, and infusional fluorouracil on days 1, 2, 15, 16, 29, and 30.

National Cancer Institute Common Toxicity Criteria (version 1.0).

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease: Weekly Dosage Schedule)

IV (Conventional Irinotecan)

Initially, 125 mg/m² infused over 90 minutes.^{1 3 7 8 28} Administer once weekly for 4 weeks followed by a 2-week rest period.^{1 3 7 8 17 18 19 22}

Modify dosage within a cycle of therapy or for a new cycle of therapy based on individual patient tolerance; monitor patient carefully to obtain optimum therapeutic response with minimum adverse effects.^{1 7 8 17 18 19 22} (See Dosage Modification for Toxicity [Weekly Schedule] under Dosage and Administration.)

If no toxicity occurs during an entire 6-week cycle of therapy, increase dose by 25 mg/m² at the start of the next cycle, but dose should not exceed 150 mg/m².^{1 17 18 19}

Unless intolerable toxicity develops, additional cycles may be administered every 6 weeks in patients who continue to experience clinical benefit.^{1 7 8}

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele, patients who have received prior pelvic or abdominal radiation therapy, those with elevated serum bilirubin concentrations, and those with a performance status of 2.¹ (See Special Populations under Dosage and Administration.)

Dosage Modification for Toxicity (Weekly Schedule)

IV (Conventional Irinotecan)

Modify dosage within a cycle of therapy or for a new cycle of therapy in increments of 25–50 mg/m² to a dose within the range of 50–150 mg/m² as necessary based on toxicity (see Table 3).^{1 7 17 18 19 22} If multiple toxicities occur, adjust dose based on the toxicity requiring the largest dose reduction.^{1 17 18 19}

Delay subsequent doses until pretreatment bowel function has been restored for ≥24 hours without the need for antidiarrheal agents.¹

Do not initiate a new cycle of therapy until treatment-related diarrhea has fully resolved, granulocyte count has recovered to ≥1500/mm³, and platelet count has recovered to ≥100,000/mm³.¹

May delay treatment for 1–2 weeks to allow for recovery from treatment-related toxicities.¹ Consider discontinuing therapy if the treatment-induced toxicity does not resolve after delaying administration for 2 weeks.¹

National Cancer Institute Common Toxicity Criteria (version 1.0).

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease: Once-Every-3-Weeks Dosage Schedule)

IV (Conventional Irinotecan)

Initially, 350 mg/m² infused over 90 minutes.¹

Adjust subsequent doses based on individual patient tolerance; monitor patient carefully to obtain optimum therapeutic response with minimum adverse effects.^{1 7 8 17 18 19 22} (See Dosage Modification for Toxicity [Once-Every-3-Weeks Schedule] under Dosage and Administration.)

Administer once every 3 weeks for as long as intolerable toxicity does not occur and the patient continues to experience clinical benefit.¹

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele, geriatric patients, patients who have received prior pelvic or abdominal radiation therapy, those with elevated serum bilirubin concentrations, and those with a performance status of 2.¹ (See Special Populations under Dosage and Administration.)

Dosage Modification for Toxicity (Once-Every-3-Weeks Schedule)

IV (Conventional Irinotecan)

Decrease dose in decrements of 50 mg/m² to a dose as low as 200 mg/m² as necessary based on toxicity encountered with the previous dose of irinotecan (see Table 4).¹ If multiple toxicities occur, adjust dose based on the toxicity requiring the largest dose reduction.^{1 17 18 19}

Delay subsequent doses until pretreatment bowel function has been restored for ≥24 hours without the need for antidiarrheal agents.¹

Do not initiate a new cycle of therapy until treatment-related diarrhea has fully resolved, granulocyte count has recovered to ≥1500/mm³, and platelet count has recovered to ≥100,000/mm³.¹

May delay treatment for 1–2 weeks to allow for recovery from treatment-related toxicities.¹ Consider discontinuing therapy if the treatment-induced toxicity does not resolve after delaying administration for 2 weeks.¹

National Cancer Institute Common Toxicity Criteria (version 1.0).

Pancreatic Cancer

IV (Liposomal Irinotecan)

70 mg/m² infused over 90 minutes, followed by leucovorin 400 mg/m² infused IV over 30 minutes, followed by fluorouracil 2.4 g/m² infused IV over 46 hours.⁶⁵

Administer once every 2 weeks.⁶⁵

Reduced initial dose recommended in patients known to be homozygous for the UGT1A1*28 allele.⁶⁵ (See Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 [UGT1A1] Activity under Dosage and Administration.)

Manufacturer makes no specific dosage recommendations for patients with bilirubin concentrations exceeding ULN.⁶⁵

Dosage Modification for Toxicity

IV (Liposomal Irinotecan)

If grade 2–4 diarrhea occurs, withhold therapy until diarrhea resolves to grade 1 or less, then resume at reduced dosage (i.e., 70 mg/m² reduced to 50 mg/m² or 50 mg/m² reduced to 43 mg/m²).⁶⁵ If grade 2–4 diarrhea recurs following dosage reduction, withhold therapy again until diarrhea resolves to grade 1 or less, then resume at further reduced dosage (i.e., 50 mg/m² reduced to 43 mg/m² or 43 mg/m² reduced to 35 mg/m²).⁶⁵ If grade 2–4 diarrhea recurs at this dosage, discontinue treatment.⁶⁵

If neutropenic fever or ANC <1500/mm³ occurs, withhold therapy until ANC ≥1500/mm³.⁶⁵ Reduce subsequent doses if grade 3 or 4 neutropenia or neutropenic fever was observed.⁶⁵

If other grade 3 or 4 adverse event occurs, withhold therapy until toxicity resolves to grade 1 or less, then resume at reduced dosage (i.e., 70 mg/m² reduced to 50 mg/m² or 50 mg/m² reduced to 43 mg/m²).⁶⁵ If grade 3 or 4 adverse events recur following dosage reduction, withhold therapy again until toxicity resolves to grade 1 or less, then resume at further reduced dosage (i.e., 50 mg/m² reduced to 43 mg/m² or 43 mg/m² reduced to 35 mg/m²).⁶⁵ If grade 3 or 4 adverse events recur at this dosage, discontinue treatment.⁶⁵

Prescribing Limits

Adults

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease: Weekly Dosage Schedule)

IV (Conventional Irinotecan)

Maximum dose: 150 mg/m².^{1 17 18 19}

Special Populations

Hepatic Impairment

In clinical trials evaluating conventional irinotecan in patients with colorectal cancer, conventional irinotecan was not administered to patients with serum bilirubin concentrations >2 mg/dL, patients without hepatic metastases who had serum aminotransferase concentrations >3 times the ULN, or those with hepatic metastases who had serum aminotransferase concentrations >5 times the ULN.^{1 22} (See Hepatic Impairment under Cautions.)

In clinical trial evaluating liposomal irinotecan in patients with pancreatic cancer, liposomal irinotecan was not administered to patients with serum bilirubin concentrations exceeding the ULN.⁶⁵

Conventional Irinotecan (First-line Combination Therapy for Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for regimen 1 or to 150 mg/m² for regimen 2) in patients with modestly elevated total serum bilirubin concentrations (1–2 mg/dL); specific dosage recommendations not available for patients with bilirubin concentrations >2 mg/dL.¹

Conventional Irinotecan (Monotherapy for Recurrent or Progressive Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for the weekly dosage schedule or to 300 mg/m² for the once-every-3-weeks dosage schedule) in patients with modestly elevated total serum bilirubin concentrations (1–2 mg/dL); specific dosage recommendations not available for patients with bilirubin concentrations >2 mg/dL.¹

Liposomal Irinotecan

Specific dosage recommendations not available for patients with bilirubin concentrations exceeding the ULN.⁶⁵

Renal Impairment

Conventional Irinotecan

Manufacturer makes no specific dosage recommendations for patients with impaired renal function; use with caution.¹ Not recommended in dialysis patients.¹ (See Renal Impairment under Cautions.)

Liposomal Irinotecan

Manufacturer makes no specific dosage recommendations for patients with impaired renal function.⁶⁵ (See Renal Impairment under Cautions.)

Geriatric Patients

Conventional Irinotecan (Monotherapy for Recurrent or Progressive Colorectal Cancer)

Initial dosage adjustment not necessary in patients ≥65 years of age receiving the weekly dosage schedule.¹

In patients ≥70 years of age receiving the once-every-3-weeks dosage schedule, reduce initial dose to 300 mg/m² (the dose used in this age group in clinical trials of this regimen).¹ (See Geriatric Use under Cautions.)

Liposomal Irinotecan

Manufacturer makes no specific dosage recommendations for patients ≥65 years of age.⁶⁵ (See Geriatric Use under Cautions.)

Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 (UGT1A1) Activity

Conventional Irinotecan (First-line Combination Therapy for Colorectal Cancer)

Consider reducing initial dose by at least one dose level (e.g., to 100 mg/m² for regimen 1 or to 150 mg/m² for regimen 2) in patients homozygous for the UGT1A1*28 allele.¹ Optimal dosage reduction is not known; modify subsequent doses based on patient tolerance.¹ (See Reduced UGT1A1 Activity under Cautions and also see Colorectal Cancer [First-line Combination Therapy] under Dosage and Administration.)

Conventional Irinotecan (Monotherapy for Recurrent or Progressive Colorectal Cancer)

Consider reducing initial dose by at least one dose level (e.g., to 100 mg/m² for the weekly dosage schedule or to 300 mg/m² for the once-every-3-weeks dosage schedule) in patients homozygous for the UGT1A1*28 allele.¹ Optimal dosage reduction is not known; modify subsequent doses based on patient tolerance.¹ (See Reduced UGT1A1 Activity under Cautions and also see Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Liposomal Irinotecan (Pancreatic Cancer)

Reduce initial dose to 50 mg/m² in patients homozygous for the UGT1A1*28 allele; may increase dose to 70 mg/m² as tolerated during subsequent cycles.⁶⁵ (See Reduced UGT1A1 Activity under Cautions and also see Pancreatic Cancer under Dosage and Administration.)

Performance Status of 2

Conventional Irinotecan (First-line Combination Therapy for Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for regimen 1 or to 150 mg/m² for regimen 2).¹ (See Performance Status of Patient under Cautions and also see Colorectal Cancer [First-line Combination Therapy] under Dosage and Administration.)

Conventional Irinotecan (Monotherapy for Recurrent or Progressive Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for the weekly dosage schedule or to 300 mg/m² for the once-every-3-weeks dosage schedule).¹ (See Hematologic Effects under Cautions and also see Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Prior Pelvic or Abdominal Radiation Therapy

Conventional Irinotecan (First-line Combination Therapy for Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for regimen 1 or to 150 mg/m² for regimen 2).¹ (See Hematologic Effects under Cautions and also see Colorectal Cancer [First-line Combination Therapy] under Dosage and Administration.)

Conventional Irinotecan (Monotherapy for Recurrent or Progressive Colorectal Cancer)

Consider reducing initial dose by one dose level (e.g., to 100 mg/m² for the weekly dosage schedule or to 300 mg/m² for the once-every-3-weeks dosage schedule).¹ (See Hematologic Effects under Cautions and also see Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Cautions for Irinotecan

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

Diarrhea

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 night^{1 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}

Hematologic Effects

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

Reduced UGT1A1 Activity

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 Effects

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

Interstitial Lung Disease (ILD)

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}

Risks Associated with Combined Regimen of Irinotecan and Rapid-injection (“Bolus”) Fluorouracil

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

Performance Status of Patient

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

Fetal/Neonatal Morbidity and Mortality

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}

Fructose Intolerance

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

Specific Populations

Pregnancy

Conventional irinotecan: Category D.¹

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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.)

Renal Impairment

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

Drug Interactions

Partially metabolized by CYP3A4;^{c d} active metabolite SN-38 is conjugated by UGT1A1.^{1 65 c}

Irinotecan and its metabolites SN-38 and aminopentane carboxylic acid (APC) do not inhibit CYP isoenzymes in vitro.⁶⁵

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased systemic exposure to irinotecan or SN-38.^{1 65} Avoid concomitant use if possible; discontinue potent CYP3A4 inhibitor ≥1 week before initiating irinotecan.^{1 65}

Potent CYP3A4 inducers: Possible decreased systemic exposure to irinotecan or SN-38.^{1 65} Avoid concomitant use if possible.^{1 65} Appropriate initial dosage of irinotecan not defined; consider substituting alternative non-enzyme-inducing agent ≥2 weeks before initiating irinotecan.^{1 65}

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

Potent UGT1A1 inhibitors: Possible increased systemic exposure to irinotecan and/or SN-38.^{1 65} Avoid concomitant use if possible.^{1 65}

Specific Drugs

Irinotecan Pharmacokinetics

Distribution

Extent

Irinotecan crosses the placenta and is distributed into milk in rats.^{1 65}

Plasma Protein Binding

Conventional irinotecan: 30–68% (irinotecan) and 95% (SN-38), mainly to albumin.¹

Liposomal irinotecan: <0.44% of total irinotecan; 95% of irinotecan remains encapsulated in liposomes.⁶⁵

Elimination

Metabolism

Partially metabolized via CYP3A4 to oxidative metabolites.^{1 65 c d}

Metabolized via carboxylesterases^{1 65} to the active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), which is 1000 times as potent as irinotecan in vitro as a topoisomerase I inhibitor.^{1 2 4 7 8 9 10 11 13 14 16 18 19 28 c d}

SN-38 undergoes conjugation via UGT1A1 to form a glucuronide metabolite.^{1 65 c d}

Elimination Route

Disposition not fully elucidated.^{1 65} Excreted in urine as irinotecan (11–20%), SN-38 (<1%), and SN-38 glucuronide (3%).^{1 65}

Half-life

Conventional irinotecan: 6–12 hours (irinotecan) and 10–20 hours (SN-38).¹

Liposomal irinotecan: 26 hours (irinotecan) and 68 hours (SN-38).⁶⁵

Special Populations

Patients with hepatic impairment receiving conventional irinotecan: Decreased clearance of irinotecan and increased exposure to SN-38; magnitude of effect is proportional to elevation in bilirubin and aminotransferase concentrations.¹

Patients with hepatic impairment receiving liposomal irinotecan: Average steady-state concentrations of SN-38 increased by 37% in patients with bilirubin concentrations of 1–2 mg/dL compared with those with bilirubin concentrations <1 mg/dL.⁶⁵ Elevated ALT/AST concentrations did not substantially alter SN-38 concentrations.⁶⁵

Patients with renal impairment: Conventional irinotecan not evaluated.¹

Patients with renal impairment receiving liposomal irinotecan: Mild to moderate renal impairment (Cl_cr 30–89 mL/minute) did not substantially alter exposure to SN-38.⁶⁵ Limited data in severe renal impairment (Cl_cr<30 mL/minute).⁶⁵

Geriatric patients receiving conventional irinotecan (weekly dosage schedule): Age ≥65 years did not substantially alter exposure to irinotecan, SN-38, or SN-38 glucuronide.¹

Geriatric patients receiving liposomal irinotecan: Age (range: 28–87 years) did not substantially affect exposure to irinotecan and SN-38.⁶⁵

Pediatric patients receiving conventional irinotecan: Clearance of irinotecan and exposure to SN-38 similar to values in adults.¹ Minimal accumulation of irinotecan and SN-38.¹

Gender: No influence on pharmacokinetics.^{1 65}

UGT1A1*28 genetic polymorphism: In individuals homozygous for UGT1A1*28 allele, reduced UGT1A1 activity results in increased exposure to SN-38.^{1 65}

Stability

Storage

Parenteral

Injection Concentrate

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

Parenteral

Solution Compatibility (Conventional Irinotecan Hydrochloride)1 HID

Drug Compatibility (Conventional Irinotecan Hydrochloride)HID

Solution Compatibility (Liposomal Irinotecan Hydrochloride)65

Actions

• 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}

Advice to Patients

• 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of liposomal irinotecan is restricted.⁶⁶ (See Restricted Distribution Program for Liposomal Irinotecan under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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