Irinotecan (Conventional)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride:

Generic: 40 mg/2 mL (2 mL); 100 mg/5 mL (5 mL)

Solution, Intravenous, as hydrochloride [preservative free]:

Camptosar: 40 mg/2 mL (2 mL); 100 mg/5 mL (5 mL); 300 mg/15 mL (15 mL)

Generic: 40 mg/2 mL (2 mL); 100 mg/5 mL (5 mL); 500 mg/25 mL (25 mL)

Pharmacology

Mechanism of Action

Irinotecan and its active metabolite (SN-38) bind reversibly to topoisomerase I-DNA complex preventing religation of the cleaved DNA strand. This results in the accumulation of cleavable complexes and double-strand DNA breaks. As mammalian cells cannot efficiently repair these breaks, cell death consistent with S-phase cell cycle specificity occurs, leading to termination of cellular replication.

Pharmacokinetics/Pharmacodynamics

Distribution

Children and Adolescents: ~37 L/m² (range: 15.2 to 77 L/m²) (Ma 2000); distributes to pleural fluid, sweat, and saliva

Adults: 33 to 150 L/m²

Metabolism

Primarily hepatic to SN-38 (active metabolite) by carboxylesterase enzymes; may also undergo CYP3A4-mediated metabolism to inactive metabolites (one of which may be hydrolyzed to release SN-38). SN-38 undergoes conjugation by UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. SN-38 is increased by UGT1A1*28 polymorphism (10% of North Americans are homozygous for UGT1A1*28 allele).

Excretion

Urine: Irinotecan (11% to 20%), metabolites (SN-38 <1%, SN-38 glucuronide, 3%)

Time to Peak

Irinotecan: Oral: Children and Adolescents: 3 hours (Wagner 2010a)

SN-38: Following 90-minute infusion: ~1 hour

Half-Life Elimination

Children and Adolescents (Ma 2000): Irinotecan: 2.66 hours (range: 1.82 to 4.47 hours); SN-38 (active metabolite): 1.58 hours (range: 0.29 to 8.28 hours)

Adults: Irinotecan: 6 to 12 hours; SN-38: ~10 to 20 hours

Protein Binding

Plasma: Predominantly albumin; Irinotecan: 30% to 68%, SN-38 (active metabolite): ~95%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Cl of irinotecan is decreased and exposure to the active metabolite (SN-38) is increased proportional to the degree of hepatic impairment.

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of metastatic carcinoma of the colon or rectum, either as first-line therapy (in combination with fluorouracil and leucovorin), or for recurrent disease following initial fluorouracil-based treatment.

Use: Off Label

Cervical cancer (recurrent or metastatic)b

Data from a small phase II study support the use of irinotecan in the treatment of recurrent and/or metastatic cervical cancer Verschraegen 1997.

CNS tumor, (recurrent glioblastoma)b

Data from two phase II trials support the use of irinotecan (in combination with bevacizumab) in the treatment of recurrent glioblastoma Friedman 2009, Vredenburgh 2007.

Esophageal cancer (metastatic or locally advanced)a

Data from a phase III randomized trial support the use of irinotecan, in combination with leucovorin and fluorouracil, for the treatment of locally advanced or metastatic adenocarcinoma of the esophagogastric junction Guimbaud 2014. Additional data from phase II trials also support the utility of irinotecan, in combination with cisplatin, for the management of advanced or metastatic esophageal cancer Ajani 2002, Ilson 1999; other phase II trials suggest that irinotecan, in combination with capecitabine, may be beneficial in the treatment of advanced or metastatic adenocarcinoma of the esophagus or esophagogastric junction Leary 2009, Moehler 2010.

Ewing sarcoma (recurrent or progressive)c

Data from a limited number of patients in a retrospective study suggest that irinotecan (in combination with temozolomide) may be beneficial in the treatment of recurrent or progressive Ewing sarcoma Casey 2009.

Gastric cancer (metastatic or locally advanced)a

Data from a phase III trial support the use of irinotecan as single-agent therapy in the management of metastatic or locally advanced gastric cancer after failure of combination therapy with a fluoropyrimidine and platinum Hironaka 2013. Another phase III prospective trial supports using irinotecan, in combination with leucovorin and fluorouracil, for the management of locally advanced or metastatic gastric cancer Guimbaud 2014. Additional data from phase II trials also support the utility of irinotecan, in combination with cisplatin Ajani 2002, Park 2005 or leucovorin and fluorouracil Bouche 2004, for the management of advanced or metastatic gastric cancer. Another phase II trial suggests that irinotecan, in combination with capecitabine, may be beneficial in the treatment of metastatic gastric cancer Moehler 2010.

Non-small cell lung cancer (advanced)a

Data from a phase III randomized trial support the use of irinotecan, in combination with cisplatin, in the management of patients with advanced non-small cell lung cancer Ohe 2007.

Ovarian cancer (recurrent)c

Data from a small retrospective study support the use of irinotecan as salvage treatment for recurrent epithelial ovarian cancer which is both platinum- and taxane-resistant Matsumoto 2006.

Pancreatic cancer (advanced or metastatic)ayes

Data from a phase II/III randomized trial support the use of irinotecan (in combination with fluorouracil, oxaliplatin, and leucovorin; FOLFIRINOX regimen) in the management of patients with advanced pancreatic cancer Conroy 2005, Conroy 2011.

According to the American Society of Clinical Oncology Guidelines for Metastatic Pancreatic Cancer, irinotecan, as part of the FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan) is recommended as first-line therapy in patients with Eastern Cooperative Oncology Group performance status of 0 or 1, a favorable comorbidity profile, a preference for aggressive therapy, a suitable support system, and access to a chemotherapy port/infusion pump management service. For patients who received an alternative (gemcitabine-based) first-line therapy and meet the above criteria, while fluorouracil in combination with irinotecan (liposomal) is the preferred second-line therapy, fluorouracil in combination with conventional irinotecan may be used if liposomal irinotecan is unavailable.

Pancreatic cancer, potentially curable, adjuvant therapyayes

Data from a multicenter, randomized phase 3 study support the use of irinotecan (in combination with fluorouracil, leucovorin, and oxaliplatin [modified FOLFIRINOX regimen]) as adjuvant therapy following complete resection of pancreatic ductal adenocarcinoma Conroy 2018.

According to the American Society of Clinical Oncology Guidelines for Potentially Curable Pancreatic Cancer, irinotecan, as part of the modified FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan) is the preferred adjuvant therapy in patients without concerns for toxicity or tolerance and in the absence of medical or surgical contraindications.

Small cell lung cancer (extensive stage)ayes

Data from phase III randomized trials support the use of irinotecan, in combination with cisplatin Hanna 2006, Noda 2002 or carboplatin Hermes 2008, Schmittel 2006, in the management of patients with extensive stage small cell lung cancer.

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, irinotecan (or etoposide), in combination with platinum-based therapy, is recommended over other chemotherapy regimens for extensive stage disease.

Small cell lung cancer (limited stage)byes

Data from a randomized phase III study in patients with limited stage small cell lung cancer comparing cisplatin plus etoposide to cisplatin plus irinotecan as consolidation therapy after induction with cisplatin, etoposide, and radiation therapy showed no statistically significant difference between the groups Kubota 2014.

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, irinotecan (or etoposide), in combination with platinum-based therapy, is recommended over other chemotherapy regimens for limited stage, although no clinical trials in the United States or Europe have demonstrated a benefit of irinotecan- over etoposide-based regimens.

Unknown primary adenocarcinomab

Data from a randomized phase III study support the use of irinotecan (in combination with gemcitabine) in the treatment of unknown primary adenocarcinoma Hainsworth 2010.

Contraindications

Known hypersensitivity to irinotecan or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Coadministration with azole antifungals (ketoconazole, fluconazole, itraconazole); patients with hereditary fructose intolerance

Dosage and Administration

Dosing: Adult

Note: A reduction in the starting dose by at least one dose level should be considered for prior pelvic/abdominal radiotherapy, performance status of 2, or known homozygosity for UGT1A1*28 allele (subsequent dosing/adjustments should be based on individual tolerance). Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.

Premedications: Consider premedication of atropine 0.25 to 1 mg IV or SubQ in patients with cholinergic symptoms (eg, increased salivation, rhinitis, miosis, diaphoresis, abdominal cramping) or early-onset diarrhea. Irinotecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

Colorectal cancer, metastatic (single-agent therapy): IV:

Weekly regimen: 125 mg/m² over 90 minutes on days 1, 8, 15, and 22 of a 6-week treatment cycle (may adjust upward to 150 mg/m² if tolerated).

Adjusted dose level -1: 100 mg/m²

Adjusted dose level -2: 75 mg/m²

Further adjust to 50 mg/m² (in decrements of 25 to 50 mg/m²) if needed

Once-every-3-week regimen: 350 mg/m² over 90 minutes, once every 3 weeks

Adjusted dose level -1: 300 mg/m²

Adjusted dose level -2: 250 mg/m²

Further adjust to 200 mg/m² (in decrements of 25 to 50 mg/m²) if needed

Colorectal cancer, metastatic (in combination with fluorouracil and leucovorin): IV: Six-week (42-day) cycle:

Regimen 1: 125 mg/m² over 90 minutes on days 1, 8, 15, and 22; to be given in combination with bolus leucovorin and fluorouracil (leucovorin administered immediately following irinotecan; fluorouracil immediately following leucovorin).

Adjusted dose level -1: 100 mg/m²

Adjusted dose level -2: 75 mg/m²

Further adjust if needed in decrements of ~20%

Regimen 2: 180 mg/m² over 90 minutes on days 1, 15, and 29; to be given in combination with infusional leucovorin and bolus/infusion fluorouracil (leucovorin administered immediately following irinotecan; fluorouracil immediately following leucovorin).

Adjusted dose level -1: 150 mg/m²

Adjusted dose level -2: 120 mg/m²

Further adjust if needed in decrements of ~20%

Colorectal cancer, metastatic (off-label dosing): IV: FOLFOXIRI regimen: 165 mg/m² over 1 hour once every 2 weeks (in combination with oxaliplatin, leucovorin, and fluorouracil) (Falcone 2007).

Cervical cancer, recurrent or metastatic (off-label use): IV: 125 mg/m² over 90 minutes once weekly for 4 consecutive weeks followed by a 2-week rest during each 6-week treatment cycle (Verschraegen 1997).

CNS tumor, recurrent glioblastoma (off-label use): IV: 125 mg/m² over 90 minutes once every 2 weeks (in combination with bevacizumab). NOTE: In patients taking concurrent antiepileptic enzyme-inducing medications irinotecan dose was increased to 340 mg/m² (Friedman 2009; Vredenburgh 2007).

Esophageal cancer, metastatic or locally advanced (off-label use): IV: 65 mg/m² over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) (Ajani 2002; Ilson 1999) or 180 mg/m² over 90 minutes every 2 weeks (in combination with leucovorin and fluorouracil) (Guimbaud 2014) or 250 mg/m² every 3 weeks (in combination with capecitabine) (Leary 2009; Moehler 2010).

Ewing sarcoma, recurrent or progressive (off-label use): IV: 20 mg/m² days 1 to 5 and days 8 to 12 every 3 weeks (in combination with temozolomide) (Casey 2009).

Gastric cancer, metastatic or locally advanced (off-label use): IV: 150 mg/m² (as a single agent) on days 1 and 15 of a 4-week treatment cycle (Hironaka 2013) or 65 mg/m² over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) (Ajani 2002) or 70 mg/m² over 90 minutes on days 1 and 15 of a 4-week treatment cycle (in combination with cisplatin) for up to 6 cycles (Park 2005) or 180 mg/m² over 90 minutes every 2 weeks (in combination with leucovorin and fluorouracil) (Bouche 2004; Guimbaud 2014) or 250 mg/m² every 3 weeks (in combination with capecitabine) (Moehler 2010).

Non-small cell lung cancer, advanced (off-label use): IV: 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin) (Ohe 2007).

Ovarian cancer, recurrent, platinum- and taxane-resistant (off-label use): IV: 100 mg/m² days 1, 8, and 15 every 4 weeks (as a single-agent) for up to 6 cycles (Matsumoto 2006).

Pancreatic cancer, advanced or metastatic (off-label use): IV: FOLFIRINOX regimen: 180 mg/m² over 90 minutes every 2 weeks (in combination with oxaliplatin, leucovorin, and fluorouracil) (Conroy 2005; Conroy 2011).

Pancreatic cancer, potentially curable, adjuvant therapy (off-label use): Note: American Society of Clinical Oncology (ASCO) guidelines recommend 6 months of adjuvant therapy if recovery is complete; if preoperative chemotherapy therapy was received, a total of 6 months of adjuvant therapy (including the preoperative regimen) is recommended (ASCO [Khorana 2019]).

mFOLFIRINOX regimen: IV: 150 mg/m² every 2 weeks (in combination with fluorouracil, leucovorin, and oxaliplatin; modified FOLFIRINOX regimen) for 24 weeks (Conroy 2018). According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for potentially curable disease (ASCO [Khorana 2019]).

Small cell lung cancer, extensive stage (off-label use): IV: 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin) (Noda 2002) or 65 mg/m² days 1 and 8 every 3 weeks (in combination with cisplatin) (Hanna 2006) or 175 mg/m² day 1 every 3 weeks (in combination with carboplatin) (Hermes 2008) or 50 mg/m² days 1, 8 and 15 every 4 weeks (in combination with carboplatin) (Schmittel 2006). According to ASCO guidelines, platinum-based therapy (cisplatin or carboplatin) in combination with either etoposide or irinotecan for 4 to 6 cycles is recommended over other regimens for extensive stage disease (Rudin 2015).

Small cell lung cancer, limited stage (off-label use): IV: Consolidation therapy (administer after induction cisplatin, etoposide, and radiation therapy): 60 mg/m² days 1, 8, and 15 every 3 to 4 weeks (in combination with cisplatin) for 3 cycles (Kubota 2014). Additional studies are necessary to further define the role of irinotecan in the treatment of limited stage disease.

Unknown primary adenocarcinoma (off-label use): IV: 100 mg/m² days 1 and 8 every 3 weeks (in combination with gemcitabine) for 4 to 6 cycles (Hainsworth 2010).

Dosing: Geriatric

Weekly dosing schedule: No dosing adjustment is recommended

Every 3-week dosing colorectal cancer schedule: Recommended initial dose is 300 mg/m²/dose for patients ≥70 years

Dosing: Pediatric

Note: A reduction in the starting dose by at least one dose level should be considered for prior pelvic/abdominal radiotherapy, performance status of ≥2, or known homozygosity for UGT1A1*28 allele. Consider prophylaxis with oral third generation cephalosporins (McGregor 2012; McNall-Knapp 2010), and/or atropine IV or SubQ for treatment in patients with cholinergic symptoms (eg, increased salivation, diaphoresis, abdominal cramping) or diarrhea. Details concerning dosage in combination regimens should also be consulted. Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.

Neuroblastoma, refractory or palliative: Limited data available: Children ≥2 years and Adolescents: IV: 50 mg/m² over 1 hour once daily on days 1 to 5 (5 doses), in combination with temozolomide; repeat cycle every 21 days (Kushner 2005)

Solid tumor or CNS tumor; refractory or relapsed (low-dose, protracted schedule): Limited data available: Children ≥2 years and Adolescents: IV: 15 mg/m² over 1 hour once daily on days 1 to 5 (5 doses) and days 8 to 12 (5 doses) of a 28-day treatment cycle; in the trial, a maximum dose of 30 mg/dose was reported; may repeat cycle if tolerated in combination with temozolomide and vincristine (McNall-Knapp 2010)

Solid tumor or CNS tumor; refractory or relapsed: Limited data available: Children and Adolescents:

Daily regimen:

IV: Children ≥2 years and Adolescents: 50 mg/m² over 1 hour once daily on days 1 to 5 (5 doses) as a single agent; repeat cycle every 21 days (Kushner 2005); some protocols include combination with temozolomide (Morganstern 2013)

Oral: Children and Adolescents: 90 mg/m² once daily on days 1 to 5 (5 doses) repeat every 3 weeks; in combination with vincristine and temozolomide (Wagner 2010a)

Weekly regimen (Bomgaars 2006):

Heavily pretreated patients (eg, ≥2 prior chemotherapy regimens): IV: 125 mg/m²/dose once weekly for 4 weeks over 90 minutes, repeat cycle every 6 weeks

Less-heavily pretreated patients (≤2 prior chemotherapy regimens): IV: 160 mg/m²/dose once weekly for 4 weeks over 90 minutes, repeat cycle every 6 weeks

Rhabdomyosarcoma, refractory or metastatic: Limited data available: Children and Adolescents: IV: 50 mg/m² once daily for 5 days (maximum dose: 100 mg/dose) on protocol specific weeks (Mascarenhas 2010; Weigel 2016)

Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available. See tables for adult dosage recommendations.

It is recommended that new courses begin only after the granulocyte count recovers to ≥1,500/mm³, the platelet counts recover to ≥100,000/mm³, and treatment-related diarrhea has fully resolved. Depending on the patient's ability to tolerate therapy, adult doses should be adjusted in increments of 25 to 50 mg/m². 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, consider discontinuing irinotecan. See tables for adult dosage recommendations.

Table has been converted to the following text.

Colorectal Cancer: Single-Agent Schedules: Adult Dosing Adjustment for Toxicities

Dosage modifications are based on NCI Common Toxicity Criteria grade (value). Note: All dose modifications should be based on the worst preceding toxicity.

Neutropenia: NCI Grade 1 (1,500-1,999/mm³):

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next course of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next course of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Neutropenia: NCI Grade 2 (1,000 to 1,499/mm³):

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Neutropenia: NCI Grade 3 (500 to 999/mm³):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ Grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Neutropenia: NCI Grade 4 (<500/mm³):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ Grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Neutropenic fever (Grade 4 neutropenia and ≥ Grade 2 fever):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Other hematologic toxicities:

• Dose modifications for leukopenia, thrombocytopenia, and anemia during a course of therapy and at the start of subsequent courses of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

Diarrhea: NCI Grade 1 (2-3 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Diarrhea: NCI Grade 2 (4-6 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Diarrhea: NCI Grade 3 (7-9 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Diarrhea: NCI Grade 4 (≥10 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Other Nonhematologic Toxicities (excludes alopecia, anorexia, asthenia)

NCI Grade 2:

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

NCI Grade 3:

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

NCI Grade 4:

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Dosing: Adjustment for Toxicity

It is recommended that new courses begin only after the granulocyte count recovers to ≥1,500/mm³, the platelet counts recover to ≥100,000/mm³, and treatment-related diarrhea has fully resolved. Depending on the patient's ability to tolerate therapy, doses should be adjusted in increments of 25 to 50 mg/m². 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, consider discontinuing irinotecan. See tables.

Table has been converted to the following text.

Colorectal Cancer: Single-Agent Schedules: Dosing Adjustment for Toxicities

Dosage modifications are based on NCI Common Toxicity Criteria grade (value). Note: All dose modifications should be based on the worst preceding toxicity.

NCI Grade (Value): No toxicity

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Increase by 25 mg/m² up to a maximum of 150 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Neutropenia: NCI Grade 1 (1,500 to 1,999/mm³):

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Neutropenia: NCI Grade 2 (1,000 to 1,499/mm³):

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Neutropenia: NCI Grade 3 (500 to 999/mm³):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ Grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Neutropenia: NCI Grade 4 (<500/mm³):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ Grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Neutropenic fever (Grade 4 neutropenia and ≥ Grade 2 fever):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Other hematologic toxicities:

• Dose modifications for leukopenia, thrombocytopenia, and anemia during a course of therapy and at the start of subsequent courses of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

Diarrhea: NCI Grade 1 (2 to 3 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Diarrhea: NCI Grade 2 (4 to 6 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

Diarrhea: NCI Grade 3 (7 to 9 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Diarrhea: NCI Grade 4 (≥10 stools/day > pretreatment):

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Other Nonhematologic Toxicities (excludes alopecia, anorexia, asthenia)

NCI Grade 1:

• Weekly schedule:

– During a course of therapy: Maintain dose level.

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Maintain dose level.

NCI Grade 2:

• Weekly schedule:

– During a course of therapy: Decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

NCI Grade 3:

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 25 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 25 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

NCI Grade 4:

• Weekly schedule:

– During a course of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 50 mg/m².

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

• Once-every-3-weeks schedule:

– At the start of the next courses of therapy (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 50 mg/m².

Table has been converted to the following text.

Colorectal Cancer: Combination Schedules: Dosing Adjustment for Toxicities

Dosage modifications are based on NCI Common Toxicity Criteria grade (value). Note: All dose modifications should be based on the worst preceding toxicities.

NCI Grade (Value): No toxicity

• During a cycle of therapy: Maintain dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycle: Maintain dose level.

Neutropenia: NCI Grade 1 (1,500 to 1,999/mm³):

• During a cycle of therapy: Maintain dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

Neutropenia: NCI Grade 2 (1,000 to 1,499/mm³):

• During a cycle of therapy: Decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

Neutropenia: NCI Grade 3 (500 to 999/mm³):

• During a cycle of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 1 dose level.

Neutropenia: NCI Grade 4 (<500/mm³):

• During a cycle of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 2 dose levels.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 2 dose levels.

Neutropenic fever (grade4 neutropenia and ≥ grade 2 fever):

• During a cycle of therapy: Omit dose until resolved, then decrease by 2 dose levels.

Other hematologic toxicities:

• Dose modifications 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.

Diarrhea: NCI Grade 1 (2 to 3 stools/day > pretreatment):

• During a cycle of therapy: Delay dose until resolved to baseline, then give same dose.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

Diarrhea: NCI Grade 2 (4 to 6 stools/day > pretreatment):

• During a cycle of therapy: Omit dose until resolved to baseline, then decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

Diarrhea: NCI Grade 3 (7 to 9 stools/day > pretreatment):

• During a cycle of therapy: Omit dose until resolved to baseline, then decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 1 dose level.

Diarrhea: NCI Grade 4 (≥10 stools/day > pretreatment):

• During a cycle of therapy: Omit dose until resolved to baseline, then decrease by 2 dose levels.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 2 dose levels.

Other Nonhematologic Toxicities (excludes alopecia, anorexia, asthenia)

NCI Grade 1:

• During a cycle of therapy: Maintain dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

NCI Grade 2:

• During a cycle of therapy: Omit dose until resolved to ≤ grade 1, then decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Maintain dose level.

NCI Grade 3:

• During a cycle of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 1 dose level.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 1 dose level.

NCI Grade 4:

• During a cycle of therapy: Omit dose until resolved to ≤ grade 2, then decrease by 2 dose levels.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease by 2 dose levels.

Mucositis/stomatitis:

• During a cycle of therapy: Decrease only 5-FU, not irinotecan.
• At the start of subsequent cycles of therapy (after adequate recovery), compared to the starting dose in the previous cycles: Decrease only 5-FU, not irinotecan.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Dilute in D₅W (preferred) or NS to a final concentration of 0.12 to 2.8 mg/mL.

Administration

IV: Administer by IV infusion, usually over 90 minutes.

Premedications: Irinotecan is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); premedication with dexamethasone and a 5-HT₃ blocker is recommended 30 minutes prior to administration; prochlorperazine may be considered for subsequent use (if needed). Consider atropine 0.25 to 1 mg IV or SubQ as premedication for or treatment of cholinergic symptoms (eg, increased salivation, rhinitis, miosis, diaphoresis, abdominal cramping) or early onset diarrhea.

Diarrhea management: The recommended regimen to manage late diarrhea is loperamide 4 mg orally at onset of late diarrhea, followed by 2 mg every 2 hours (or 4 mg every 4 hours at night) until 12 hours have passed without a bowel movement. If diarrhea recurs, then repeat administration. Loperamide should not be used for more than 48 consecutive hours.

Dietary Considerations

Contains sorbitol; do not use in patients with hereditary fructose intolerance.

Storage

Store intact vials at 15°C to 30°C (59°F to 86°F). Protect from light; retain vials in original carton until use. Solutions diluted in NS may precipitate if refrigerated. Solutions diluted in D5W are stable for 24 hours at room temperature or 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F), although the manufacturer recommends use within 24 hours if refrigerated, or within 4 to 12 hours (manufacturer dependent; refer to specific prescribing information) at room temperature (including infusion time) only if prepared under strict aseptic conditions (eg, laminar flow hood). Do not freeze.

Extemporaneously prepared oral solutions (pediatric): Undiluted commercially available injectable solution prepared in oral syringes is stable for 21 days under refrigeration (Wagner 2010).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gemfibrozil: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. Rifabutin may decrease the serum concentration of Irinotecan Products. Monitor therapy

Rifapentine: May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. Rifapentine may decrease the serum concentration of Irinotecan Products. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

St John's Wort: May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. St John's Wort may decrease the serum concentration of Irinotecan Products. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tobacco (Smoked): May decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

UGT1A1 Inhibitors: May increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Exceptions: Atazanavir; Ombitasvir, Paritaprevir, and Ritonavir; Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Avoid combination

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency of adverse reactions reported for single-agent use of irinotecan only. In limited pediatric experience, dehydration (often associated with severe hypokalemia and hyponatremia) was among the most significant grade 3/4 adverse events, with a frequency up to 29%. In addition, grade 3/4 infection was reported in 24%.

>10%:

Cardiovascular: Vasodilation (9% to 11%)

Central nervous system: Cholinergic syndrome (47%; includes diaphoresis, flushing, increased peristalsis, lacrimation, miosis, rhinitis, sialorrhea), pain (23% to 24%), dizziness (15% to 21%), insomnia (19%), headache (17%), chills (14%)

Dermatologic: Alopecia (46% to 72%), diaphoresis (16%), skin rash (13% to 14%)

Endocrine & metabolic: Weight loss (30%), dehydration (15%)

Gastrointestinal: Diarrhea (late: 83% to 88%, grades 3/4: 14% to 31%; early: 43% to 51%, grades 3/4: 7% to 22%), nausea (70% to 86%), abdominal pain (57% to 68%), vomiting (62% to 67%), abdominal cramps (57%), anorexia (44% to 55%), constipation (30% to 32%), mucositis (30%), flatulence (12%), stomatitis (12%)

Hematologic & oncologic: Anemia (60% to 97%; grades 3/4: 5% to 7%), leukopenia (63% to 96%, grades 3/4: 14% to 28%), thrombocytopenia (96%, grades 3/4: 1% to 4%), neutropenia (30% to 96%; grades 3/4: 14% to 31%)

Hepatic: Increased serum bilirubin (84%), increased serum alkaline phosphatase (13%)

Infection: Infection (14%)

Neuromuscular & skeletal: Weakness (69% to 76%), back pain (14%)

Respiratory: Dyspnea (22%), cough (17% to 20%), rhinitis (16%)

Miscellaneous: Fever (44% to 45%)

1% to 10%:

Cardiovascular: Edema (10%), hypotension (6%), thromboembolism (5%)

Central nervous system: Drowsiness (9%), confusion (3%)

Gastrointestinal: Abdominal distention (10%), dyspepsia (10%)

Hematologic & oncologic: Febrile neutropenia (grades 3/4: 2% to 6%), hemorrhage (grades 3/4: 1% to 5%), neutropenic infection (grades 3/4: 1% to 2%)

Hepatic: Increased serum AST (10%), ascites (grades 3/4: ≤9%), jaundice (grades 3/4: ≤9%)

Respiratory: Pneumonia (4%)

<1%, postmarketing, and/or case reports: Acute renal failure, anaphylactoid reaction, anaphylaxis, angina pectoris, arterial thrombosis, bradycardia, cardiac arrhythmia, cerebral infarction, cerebrovascular accident, circulatory shock, colitis, deep vein thrombophlebitis, dysarthria, embolism, gastrointestinal hemorrhage, gastrointestinal obstruction, hepatomegaly, hiccups, hyperglycemia, hypersensitivity reaction, hyponatremia, immune thrombocytopenia, increased amylase, increased serum ALT, increased serum lipase, interstitial pulmonary disease, intestinal obstruction, intestinal perforation, ischemic colitis, ischemic heart disease, lymphocytopenia, megacolon, muscle cramps, myocardial infarction, pancreatitis, paresthesia, peripheral vascular disease, pulmonary embolism; pulmonary toxicity (includes dyspnea, fever, reticulonodular infiltrates on chest x-ray), renal insufficiency, syncope, thrombophlebitis, thrombosis, typhlitis (including neutropenic typhlitis), ulcer, ulcerative colitis, vertigo

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: May cause severe myelosuppression. Deaths due to sepsis following severe neutropenia have been reported. Complications due to neutropenia should be promptly managed with antibiotics. Therapy should be temporarily withheld if neutropenic fever occurs or if the absolute neutrophil count is <1,000/mm³; reduce the dose upon recovery to an absolute neutrophil count ≥1,000/mm³. Patients who have previously received pelvic/abdominal radiation therapy have an increased risk of severe bone marrow suppression; the incidence of grade 3 or 4 neutropenia was higher in patients receiving weekly irinotecan who have previously received pelvic/abdominal radiation therapy. Concurrent radiation therapy is not recommended with irinotecan (based on limited data).
• Diarrhea: [US Boxed Warning]: Severe diarrhea may be dose-limiting and potentially fatal; early-onset and late-onset diarrhea may occur. Early diarrhea occurs during or within 24 hours of receiving irinotecan and is characterized by cholinergic symptoms; may be prevented or treated with atropine. Late diarrhea may be life-threatening and should be promptly treated with loperamide. Antibiotics may be necessary if patient develops ileus, fever, or severe neutropenia. Interrupt treatment and reduce subsequent doses for severe diarrhea. Early diarrhea is generally transient and rarely severe; cholinergic symptoms may include increased salivation, rhinitis, miosis, diaphoresis, flushing, abdominal cramping, and lacrimation; bradycardia may also occur. Cholinergic symptoms may occur more frequently with higher irinotecan doses. Late diarrhea occurs more than 24 hours after treatment, which may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea may be complicated by colitis, ulceration, bleeding, ileus, obstruction, or infection; cases of megacolon and intestinal perforation have been reported. The median time to onset for late diarrhea is 5 days with every 3 week irinotecan dosing and 11 days with weekly dosing. Advise patients to have loperamide readily available for the treatment of late diarrhea. Patients with diarrhea should be carefully monitored and treated promptly; may require fluid and electrolyte therapy. Bowel function should be returned to baseline for at least 24 hours prior to resumption of weekly irinotecan dosing. Avoid diuretics and laxatives in patients experiencing diarrhea.
• Extravasation: Irinotecan is an irritant. Avoid extravasation; if extravasation occurs, the manufacturer recommends flushing the external site with sterile water and applying ice.
• Gastrointestinal toxicity: Irinotecan is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).
• Hypersensitivity: Severe hypersensitivity reactions (including anaphylaxis) have occurred. Monitor closely; discontinue therapy if hypersensitivity occurs.
• Pulmonary toxicity: Fatal cases of interstitial pulmonary disease (IPD)-like events have been reported with single-agent and combination therapy. Risk factors for pulmonary toxicity include preexisting lung disease, use of pulmonary toxic medications, radiation therapy, and colony-stimulating factors. Patients with risk factors should be monitored for respiratory symptoms before and during irinotecan treatment. Promptly evaluate progressive changes in baseline pulmonary symptoms or any new-onset pulmonary symptoms (eg, dyspnea, cough, fever). Discontinue all chemotherapy if IPD is diagnosed.
• Renal toxicity: Renal impairment and acute renal failure have been reported, possibly due to dehydration secondary to diarrhea. Use with caution in patients with renal impairment; not recommended in patients on dialysis.
• Thromboembolism: Thromboembolic events have been reported.

Disease-related concerns:

• Bowel obstruction: Patients with bowel obstruction should not be treated with irinotecan until resolution of obstruction.
• Hepatic impairment: Use with caution in patients with hepatic impairment; exposure to the active metabolite (SN-38) is increased; toxicities may be increased. Patients with even modest elevations in total serum bilirubin levels (1 to 2 mg/dL) have a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were <1 mg/dL. Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert syndrome, may also be at greater risk of myelosuppression when receiving therapy with irinotecan. Use caution when treating patients with known hepatic dysfunction or hyperbilirubinemia; dosage adjustments should be considered.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. CYP3A4 enzyme inducers may decrease exposure to irinotecan and SN-38 (active metabolite); enzyme inhibitors may increase exposure. For use in patients with CNS tumors (off-label use), selection of antiseizure medications that are not enzyme inducers is preferred.

Special populations:

• Elderly: Patients >65 years of age are at greater risk for early and late diarrhea. A dose reduction is recommended for patients ≥70 years of age receiving the every-3-week regimen.
• Patients homozygous/heterozygous for the UGT1A1*28 allele: Patients homozygous for the UGT1A1*28 allele are at increased risk of neutropenia; consider reducing the initial dose by at least one dose level for both single-agent and combination regimens. Heterozygous carriers of the UGT1A1*28 allele may also be at increased neutropenic risk; however, most patients have tolerated normal starting doses. A test is available for clinical determination of UGT phenotype, although a dose reduction is already recommended in patients who have experienced toxicity.
• Pelvic/abdominal radiation recipients: Use with caution in patients who have previously received pelvic/abdominal radiation; may increase risk of severe myelosuppression.
• Performance status: Higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle discontinuation, and early mortality were observed in patients with a performance status of 2 than in patients with a performance status of 0 or 1.

Dosage form specific issues:

• Conventional vs liposomal formulation dosing: Irinotecan (conventional) and irinotecan (liposomal) are NOT interchangeable. Dosing differs between formulations; verify intended product and dose prior to preparation and administration.
• Sorbitol: Product contains sorbitol; do not use in patients with hereditary fructose intolerance.

Other warnings/precautions:

• Appropriate use: Except as part of a clinical trial, use in combination with the fluorouracil and leucovorin administered for 4 or 5 consecutive days every 4 weeks (“Mayo Clinic” regimen) is not recommended due to increased toxicity.

Monitoring Parameters

CBC with differential, platelet count, and hemoglobin with each dose; bilirubin, electrolytes (with severe diarrhea); monitor for cholinergic reactions; monitor bowel movements and hydration status; signs/symptoms of pulmonary toxicity or hypersensitivity reactions; monitor infusion site for signs of inflammation and avoid extravasation

A test is available for genotyping of UGT1A1; however, use of the test is not widely accepted and a dose reduction is already recommended in patients who have experienced toxicity.

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to the use of irinotecan (conventional) during pregnancy is limited (Cirillo 2012; Taylor 2009). May cause fetal harm if administered during pregnancy. Females of reproductive potential should avoid becoming pregnant while receiving treatment.

Patient Education

What is this drug used for?

• It is used to treat colorectal cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Trouble sleeping
• Headache
• Mouth sores
• Nausea
• Vomiting
• Abdominal pain
• Lack of appetite
• Constipation
• Hair loss
• Back pain
• Sweating a lot
• Weight loss
• Fatigue
• Passing gas

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Diarrhea
• Infection
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, more thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, weight gain.
• Severe loss of strength and energy
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe bleeding or persistent bleeding.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Severe dizziness
• Passing out
• Redness or irritation of palms or soles of feet
• Severe injection site burning, pain, edema, or redness
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.