Irinotecan Hydrochloride

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
Brands: Camptosar

• Experience of Supervising Clinician


• 
  

  Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.¹ Adequate diagnostic and treatment facilities should be readily available to manage complications.^{1 b}

  
  

• GI Toxicity


• 
  

  Early and late forms of diarrhea may occur; both may be severe.^{1 2 16 17 18 19 27 28} (See Diarrhea under Cautions.)

  
  


• 
  

  Early diarrhea (onset within 24 hours of administration) is cholinergic in nature (possibly preceded by diaphoresis, flushing, rhinitis, increased salivation, miosis, lacrimation, and abdominal cramping) and may be prevented or ameliorated by administration of atropine.^{1 28}

  
  


• 
  

  Late diarrhea (occurring >24 hours after administration) may be prolonged, life-threatening, and lead to dehydration, electrolyte imbalance, or sepsis.¹ Treat late diarrhea promptly with intensive oral loperamide therapy.^{1 2 16 17 18 19 21 22 28 56}

  
  


• 
  

  Carefully monitor patients with diarrhea; administer fluid and electrolyte replacement for dehydration and anti-infective therapy for ileus, fever, or severe neutropenia.^{22 b} Interrupt therapy and reduce subsequent doses if severe diarrhea occurs.¹ (See Dosage Modification for Toxicity sections under Dosage and Administration.)

  
  

• Myelosuppression


• 
  

  Severe myelosuppression may occur.^{1 16 17 18 19 27 b} (See Hematologic Effects under Cautions.)

  
  

Introduction

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

Uses for Irinotecan Hydrochloride

Colorectal Cancer

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}

Also 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}

Small Cell Lung Cancer

Used in combination with cisplatin for the initial treatment of extensive small cell lung cancer†.^{27 46}

Cervical Cancer

Under investigation for the treatment of metastatic or recurrent cervical cancer†.^{27 47 48 49 50 51}

Irinotecan Hydrochloride Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^b

  
  


• 
  

  Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.¹ Adequate diagnostic and treatment facilities should be readily available to manage complications.^{1 b}

  
  


• 
  

  Before each irinotecan dose, determine WBC count with differential, hemoglobin, and platelet count.^b Obtain tests no sooner than 48 hours before scheduled treatment.⁵⁶ Consider trends as well as absolute values.⁵⁶

  
  


• 
  

  Administer effective antiemetic therapy for management of nausea and vomiting (e.g., dexamethasone 10 mg and a serotonin 5-HT₃ receptor antagonist such as ondansetron or granisetron) IV at least 30 minutes prior to irinotecan therapy.^{1 7 8 22 28 64} 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, abdominal cramping, or early diarrhea (i.e., onset within 24 hours of administration).^{1 8 22 28 b}

  
  

Administration

IV Administration

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

Administer by IV infusion.¹

Avoid extravasation; monitor infusion site for signs of inflammation.^{1 22} (See Local Effects under Cautions.)

Do not admix with other drugs.¹

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

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 b}

Rate of Administration

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

Dosage

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

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}

Regimen 1

IV

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].)

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

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele.^b (See Special Populations under Dosage and Administration.)

Regimen 2

IV

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].)

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

Consider reducing the initial dose in patients known to be homozygous for the UGT1A1*28 allele.^b (See Special Populations under Dosage and Administration.)

Dosage Modification for Toxicity (Regimen 1 or 2)

IV

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 any serious treatment-induced toxicity (as defined by NCI Common Toxicity Criteria) has improved to grade 1 or less.^{1 15} 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.

Table 1. Dosage Modifications of Irinotecan-based Combination Therapy for Metastatic Colorectal Cancerb

	Dosage Modifications for Irinotecan-based Combination Therapy (mg/m2)
Regimen/Agent	Reduced Dosage Level 1	Reduced Dosage Level 2
Regimen 1
Irinotecan	100	75
Leucovorin	20	20
Fluorouracil	400	300
Regimen 2
Irinotecan	150	120
Leucovorin	200	200
Fluorouracil “bolus”	320	240
Fluorouracil infusion	480	360

National Cancer Institute Common Toxicity Criteria (version 1.0).

Table 2. Recommended Dosage Modifications for Toxicity for Irinotecan-based Combination Therapy for Metastatic Colorectal Cancerb

Toxicity – NCI Grade (Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of Therapy (compared with the starting dose in the previous cycle)
No toxicity	Maintain dose level	Maintain dose level
Neutropenia
1 (1500–1999/mm3)	Maintain dose level	Maintain dose level
2 (1000–1499/mm3)	Decrease by 1 dose level	Maintain dose level
3 (500–999/mm3)	Omit dose until resolved to grade 2 or less, then decrease by 1 dose level	Decrease by 1 dose level
4 (<500/mm3)	Omit dose until resolved to grade 2 or less, then decrease by 2 dose levels	Decrease by 2 dose levels
Neutropenic fever	Omit dose until resolved, then decrease by 2 dose levels
Other hematologic toxicities	Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are based on NCI toxicity criteria and are the same as those recommended for neutropenia above
Diarrhea
1 (increase of 2–3 stools/day)	Delay dose until resolved to baseline, then resume the same dose	Maintain dose level
2 (increase of 4–6 stools/day)	Omit dose until resolved to baseline, then decrease by 1 dose level	Maintain dose level
3 (increase of 7–9 stools/day)	Omit dose until resolved to baseline, then decrease by 1 dose level	Decrease by 1 dose level
4 (increase of ≥10 stools/day)	Omit dose until resolved to baseline, then decrease by 2 dose levels	Decrease by 2 dose levels
Other nonhematologic toxicities (excluding alopecia, anorexia, asthenia)
1	Maintain dose level	Maintain dose level
2	Omit dose until resolved to grade 1 or less, then decrease by 1 dose level	Maintain dose level
3	Omit dose until resolved to grade 2 or less, then decrease by 1 dose level	Decrease by 1 dose level
4	Omit dose until resolved to grade 2 or less, then decrease by 2 dose levels	Decrease by 2 dose levels
	Note: For mucositis/stomatitis, decrease only fluorouracil, not irinotecan	Note: For mucositis/stomatitis, decrease only fluorouracil, not irinotecan

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

IV

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].)

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 b}

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.^b (See Special Populations under Dosage and Administration.)

Dosage Modification for Toxicity (Weekly Schedule)

IV

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 any serious treatment-induced toxicity (as defined by NCI Common Toxicity Criteria) has improved to grade 1 or less.^{1 15} 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).

Table 3. Recommended Dosage Modifications for Toxicity for Irinotecan Monotherapy Given on a Weekly Dosage Schedule for Colorectal Cancerb

Toxicity – NCI Grade	During a Cycle of Therapy	At the Start of the Next Cycle of Therapy (after adequate recovery, compared with the starting dose in the previous cycle)
No toxicity	Maintain dose level	Increase dose by 25 mg/m2 up to a maximum dose of 150 mg/m2
Neutropenia
1 (1500–1999/mm3)	Maintain dose level	Maintain dose level
2 (1000–499/mm3)	Decrease dose by 25 mg/m2	Maintain dose level
3 (500–999/mm3)	Omit dose until resolved to grade 2 or less, then decrease dose by 25 mg/m2	Decrease dose by 25 mg/m2
4 (<500/mm3)	Omit dose until resolved to grade 2 or less, then decrease dose by 50 mg/m2	Decrease dose by 50 mg/m2
Neutropenic fever	Omit dose until resolved, then decrease dose by 50 mg/m2	Decrease dose by 50 mg/m2
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy also are based on NCI toxicity criteria and are the same as those recommended for neutropenia above	Dose modifications for leukopenia, thrombocytopenia, and anemia at the start of subsequent cycles of therapy also are based on NCI toxicity criteria and are the same as those recommended for neutropenia above
Diarrhea
1 (increase of 2–3 stools/day)	Maintain dose level	Maintain dose level
2 (increase of 4–6 stools/day)	Decrease dose by 25 mg/m2	Maintain dose level
3 (increase of 7–9 stools/day)	Omit dose until resolved to grade 2 or less, then decrease dose by 25 mg/m2	Decrease dose by 25 mg/m2
4 (increase of ≥10 stools/day)	Omit dose until resolved to grade 2 or less, then decrease dose by 50 mg/m2	Decrease dose by 50 mg/m2
Other nonhematologic toxicities (excluding alopecia, anorexia, asthenia)
1	Maintain dose level	Maintain dose level
2	Decrease dose by 25 mg/m2	Decrease dose by 25 mg/m2
3	Omit dose until resolved to grade 2 or less, then decrease dose by 25 mg/m2	Decrease dose by 25 mg/m2
4	Omit dose until resolved to grade 2 or less, then decrease dose by 50 mg/m2	Decrease dose by 50 mg/m2

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

IV

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].)

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.^b (See Special Populations under Dosage and Administration.)

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

IV

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 any serious treatment-induced toxicity (as defined by NCI Common Toxicity Criteria) has improved to grade 1 or less.^{1 15} 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).

Table 4. Recommended Dosage Modifications for Toxicity for Irinotecan Monotherapy Given on a Once-Every-3-Weeks Schedule for Colorectal Cancerb

Toxicity – NCI Grade	At the Start of the Next Cycle of Therapy (after adequate recovery, compared with the starting dose in the previous cycle)
No toxicity	Maintain dose level
Neutropenia
1 (1500–1999/mm3)	Maintain dose level
2 (1000–1499/mm3)	Maintain dose level
3 (500–999/mm3)	Decrease dose by 50 mg/m2
4 (<500/mm3)	Decrease dose by 50 mg/m2
Neutropenic fever	Decrease dose by 50 mg/m2
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia at the start of subsequent cycles of therapy also are based on NCI toxicity criteria and are the same as those recommended for neutropenia above
Diarrhea
1 (increase of 2–3 stools/day)	Maintain dose level
2 (increase of 4–6 stools/day)	Maintain dose level
3 (increase of 7–9 stools/day)	Decrease dose by 50 mg/m2
4 (≥ 10 increase of stools/day)	Decrease dose by 50 mg/m2
Other nonhematologic toxicities (excluding alopecia, anorexia, asthenia)
1	Maintain dose level
2	Decrease dose by 50 mg/m2
3	Decrease dose by 50 mg/m2
4	Decrease dose by 50 mg/m2

Prescribing Limits

Adults

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

IV

Maximum dose: 150 mg/m².^{1 17 18 19}

Special Populations

Hepatic Impairment

In clinical trials for colorectal cancer, irinotecan was not administered to patients with serum bilirubin concentrations >2 mg/dL,^{1 22} patients without hepatic metastases who had serum aminotransferase (transaminase) concentrations >3 times the ULN, or those with hepatic metastases who had serum aminotransferase values >5 times the ULN.^{1 22}

Colorectal Cancer (First-line Combination Therapy)

Specific dosage recommendations not available for patients with bilirubin >2 mg/dL.¹

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease)

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 baseline total serum bilirubin concentrations (i.e., 1–2 mg/dL).¹ (See Colorectal Cancer [Monotherapy] sections under Dosage and Administration and also see Hepatic Impairment under Cautions.)

Specific dosage recommendations not available for patients with bilirubin >2 mg/dL;¹ reduction in the initial dose may be considered.³⁸

Renal Impairment

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

Geriatric Patients

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease)

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 ≥65 years of age.¹ (See Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

In patients ≥70 years of age receiving the once-every-3-weeks regimen, reduction of initial dose to 300 mg/m² (the dose used in this age group in clinical trials of this regimen) is recommended.^b

Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 (UGT1A1) Activity

Colorectal Cancer (First-line Combination Therapy)

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; some heterozygous patients may tolerate usual initial doses.^b Precise dosage reduction is not known; modify subsequent doses based on patient tolerance to treatment.^b (See Reduced UGT1A1 Activity under Cautions and also see Colorectal Cancer [First-line Combination Therapy] under Dosage and Administration.)

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease)

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; heterozygous patients may tolerate usual initial doses.^b Precise dosage reduction is not known; modify subsequent doses based on patient tolerance to treatment.^b (See Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Performance Status of 2

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease)

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 Performance Status of Patient under Cautions and also see Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Prior Pelvic or Abdominal Radiation Therapy

Colorectal Cancer (Monotherapy for Recurrent or Progressive Disease)

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 Radiation Therapy under Cautions and also see Colorectal Cancer [Monotherapy] sections under Dosage and Administration.)

Cautions for Irinotecan Hydrochloride

Contraindications

• 
  

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

  
  


• 
  

  Concurrent use with ketoconazole; discontinue use ≥1 week before beginning irinotecan therapy.^b (See Specific Drugs under Interactions.)

  
  


• 
  

  Concurrent use with St. John's wort (Hypericum perforatum); discontinue use ≥2 weeks before beginning irinotecan therapy.^b (See Specific Drugs under Interactions.)

  
  

Warnings/Precautions

Warnings

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 (GI and vascular syndromes), including deaths.¹ Do not use in combination with this regimen outside of a well-designed clinical trial. ¹

Potentially fatal GI syndrome is manifested by diarrhea, nausea, vomiting, anorexia, and abdominal cramping, and often is associated with severe dehydration, neutropenia, fever, and electrolyte abnormalities.⁵⁶

Vascular syndrome is characterized by acute, fatal MI, pulmonary embolus, or cerebrovascular accident.⁵⁶

GI and vascular syndromes typically occur during or immediately following the first treatment cycle.⁵⁶

Closely monitor patients; institute prompt, aggressive treatment of toxicity; discontinue treatment in patients experiencing unresolved drug-related toxicity.⁵⁶

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 (irinotecan in combination with fluorouracil/leucovorin versus fluorouracil/leucovorin alone).¹

Diarrhea

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

Early diarrhea (onset within 24 hours of administration) generally is transient and cholinergic in nature (possibly preceded by diaphoresis, flushing, rhinitis, increased salivation, miosis, lacrimation, and abdominal cramping).^{1 27 28} Higher doses and more rapid infusion rates 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

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

Treat late diarrhea 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} Do not use loperamide at these dosages for >48 consecutive hours; risk of paralytic ileus.^{63 b} Premedication with loperamide is not recommended.^b

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.^b (See Dosage Modification for Toxicity sections under Dosage and Administration.)

Hematologic Effects

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

Increased risk of grade 3 or 4 neutropenia observed in patients with even 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 Initiate prophylactic treatment with an oral fluoroquinolone in patients with ANC <500/ mm³, even in the absence of fever or diarrhea.^{1 56}

Interrupt therapy if neutropenic fever occurs or if ANC <1000/mm³.^{1 18 19} Reduced dosage recommended following recovery to an ANC ≥1000/mm³ (see Tables 2, 3, and 4 under Dosage and Administration.)¹ Interrupt therapy in patients with a rapidly falling ANC, even if the current ANC is considered adequate to permit treatment.⁵⁶

Manufacturer states that routine administration of a hematopoietic agent (e.g., filgrastim, sargramostim) is not necessary; however, such use may be considered in individual patients experiencing severe neutropenia.¹

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

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

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.^b (See Reduced Uridine Diphosphate-glucuronosyltransferase 1A1 [UGT1A1] Activity under Dosage and Administration.)

Heterozygous patients may be at increased risk, but clinical results are variable; most tolerate usual initial doses.^b

Colitis and Ileus

Possible colitis complicated by ulceration, bleeding, ileus, and infection; initiate anti-infective therapy promptly if ileus develops.¹

Renal Effects

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

Cardiovascular Effects

A vascular syndrome characterized by acute, fatal MI, pulmonary embolus, or cerebrovascular accident has been reported in patients receiving irinotecan in combination with rapid IV (“bolus”) fluorouracil/leucovorin.⁵⁶ (See Risks Associated with Combined Regimen of Irinotecan and Rapid-injection [“Bolus”] Fluorouracil under Cautions.)

Cardiovascular and thromboembolic events also reported in patients receiving irinotecan with fluorouracil as IV infusion.⁶⁰

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;¹ embryotoxic and teratogenic in animals.¹ Avoid pregnancy during therapy.¹ If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.¹

Sensitivity Reactions

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

General Precautions

Adequate Patient Evaluation and Monitoring

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

Local Effects

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

Nausea and Vomiting

Nausea and/or vomiting occur frequently and may be severe.¹

Administer effective antiemetic therapy (e.g., dexamethasone 10 mg and a serotonin 5-HT₃ receptor antagoni