No

Antineoplastic Agent, Natural Source (Plant) Derivative

A component of first-line therapy in combination with 5-fluorouracil and leucovorin for the treatment of metastatic carcinoma of the colon or rectum; treatment of metastatic carcinoma of the colon or rectum which has recurred or progressed following fluorouracil-based therapy

D

Hypersensitivity to irinotecan or any component

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered

Early diarrhea treatment: 0.25-1 mg of intravenous atropine should be considered (unless clinically contraindicated) in patients experiencing diaphoresis, abdominal cramping, or early diarrhea

Late diarrhea treatment: High-dose loperamide: Oral: 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Premedication with loperamide is not recommended.

Deaths due to sepsis following severe myelosuppression have been reported. Therapy should be discontinued if neutropenic fever occurs or if the absolute neutrophil count is <500/mm³. The dose of irinotecan should be reduced if there is a clinically significant decrease in the total WBC (<200/mm³), neutrophil count (<1000/mm³), hemoglobin (<8 g/dL), or platelet count (<100,000/mm³). Routine administration of a colony-stimulating factor is generally not necessary. Avoid extravasation.

Patients with even modest elevations in total serum bilirubin levels (1.0-2.0 mg/dL) have a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were <1.0 mg/dL. Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's 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

>10%:

Cardiovascular: Vasodilation

Central nervous system: Insomnia, dizziness, fever (45.4%)

Dermatologic: Alopecia (60.5%), rash

Gastrointestinal: Irinotecan therapy may induce two different forms of diarrhea. Onset, symptoms, proposed mechanisms and treatment are different. Overall, 56.9% of patients treated experience abdominal pain and/or cramping during therapy. Anorexia, constipation, flatulence, stomatitis, and dyspepsia have also been reported.

Diarrhea: Dose-limiting toxicity with weekly dosing regimen

Early diarrhea (50.7% incidence) usually occurs during or within 24 hours of administration. May be accompanied by symptoms of cramping, vomiting, flushing, and diaphoresis. It is thought to be mediated by cholinergic effects which can be successfully managed with atropine (refer to Warnings/Precautions).

Late diarrhea (87.8% incidence) usually occurs >24 hours after treatment. National Cancer Institute (NCI) grade 3 or 4 diarrhea occurs in 30.6% of patients. Late diarrhea generally occurs with a median of 11 days after therapy and lasts approximately 3 days. Patients experiencing grade 3 or 4 diarrhea were noted to have symptoms a total of 7 days. Correlated with irinotecan or SN-38 levels in plasma and bile. Due to the duration, dehydration and electrolyte imbalances are significant clinical concerns. Loperamide therapy is recommended. The incidence of grade 3 or 4 late diarrhea is significantly higher in patients greater than or equal to 65 years of age; close monitoring and prompt initiation of high-dose loperamide therapy is prudent (refer to Warnings/Precautions).

Emetic potential: Moderately high (86.2% incidence, however, only 12.5% grade 3 or 4 vomiting)

Hematologic: Myelosuppressive: Dose-limiting toxicity with 3 week dosing regimen

Grade 1-4 neutropenia occurred in 53.9% of patients. Patients who had previously received pelvic or abdominal radiation therapy were noted to have a significantly increased incidence of grade 3 or 4 neutropenia. White blood cell count nadir is 15 days after administration and is more frequent than thrombocytopenia. Recovery is usually within 24-28 days and cumulative toxicity has not been observed.

WBC: Mild to severe

Platelets: Mild

Onset (days): 10

Nadir (days): 14-16

Recovery (days): 21-28

Neuromuscular & skeletal: Weakness (75.7%)

Respiratory: Dyspnea (22%), coughing, rhinitis

Miscellaneous: Diaphoresis

1% to 10%: Irritant chemotherapy; thrombophlebitis has been reported

<1% or post-marketing reports: Pulmonary toxicity (dyspnea, fever, reticulonodular infiltrates on chest x-ray), colitis, bleeding, ileus, renal impairment, acute renal failure

Symptoms of overdose include bone marrow suppression, leukopenia, thrombocytopenia, nausea, vomiting

Treatment is supportive

Increased toxicity: Prochlorperazine: Increased incidence of akathisia

Store intact vials of injection at room temperature and protected from light

Doses should be diluted in D₅W or NS to a final concentration of 0.12-1.1 mg/mL. Due to the relatively acidic pH, irinotecan appears to be more stable in D₅W than NS. D₅W (500 mL) is the preferred diluent for most doses

Standardized dose: Dose/500 mL D₅W

Stability at room temperature (15°C to 30°C/59°F to 86°F): 24 hours

Stability at refrigeration (2°C to 8°C/36°F to 46°F): 48 hours

Standardized dose: Dose/500 mL NS

Stability at room temperature (15°C to 30°C/59°F to 86°F): 24 hours

Stability at refrigeration (2°C to 8°C/36°F to 46°F): NOT RECOMMENDED DUE TO THE OCCURRENCE OF VISIBLE PARTICULATES

Irinotecan and its active metabolite (SN-38) bind reversibly to topoisomerase I and stabilize the cleavable complex so that religation of the cleaved DNA strand cannot occur. This results in the accumulation of cleavable complexes and single-strand DNA breaks. This interaction results in double-stranded DNA breaks and cell death consistent with S-phase cell cycle specificity.

Distribution: Average V_d: 263 L/m²

Protein binding: 30% to 68%; SN-38 is highly protein bound (95%) predominately to albumin

Metabolism: Irinotecan is a water-soluble prodrug of SN-38, which is approximately 1000 times the potency of the potency of irinotecan. In the liver, irinotecan undergoes metabolic conversion to the active metabolite SN-38; high interpatient variability.

Half-life: Terminal: Irinotecan = 10 hours; SN-38 = 10 hours

Elimination: Irinotecan is eliminated via biliary excretion, urinary excretion, and conversion to SN-38. SN-38 is eliminated via glucuronidation and biliary excretion.

Refer to individual protocols; courses may be repeated indefinitely as long as the patient continues to experience clinical benefit: Adults: I.V.:

Weekly regimen: 125 mg/m² over 90 minutes on days 1, 8, 15, and 22, followed by a 2-week rest

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

A reduction in the starting dose by one dose level may be considered for patients greater than or equal to 65 years of age, prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin (dosing for patients with a bilirubin >2 mg/dL cannot be recommended based on lack of data per manufacturer)

Depending on the patient's ability to tolerate therapy, doses should be adjusted in increments of 25-50 mg/m². Irinotecan doses may range 50-150 mg/m².

Combination therapy with 5-FU and leucovorin: Six-week (42-day) cycle (next cycle beginning on day 45):

125 mg/m² over 90 minutes on days 1, 8, 15, and 22; to be given in combination with bolus leucovorin and 5-FU (leucovorin administered immediately following irinotecan; 5-FU immediately following leucovorin)

180 mg/m² over 90 minutes on days 1, 15, and 22; to be given in combination with infusional leucovorin and bolus/infusion 5-FU (leucovorin administered immediately following irinotecan; 5-FU immediately following leucovorin)

Note: For all regimens: It is recommended that new courses begin only after the granulocyte count recovers to greater than or equal to 1500/mm³, the platelet count recovers to greater than or equal to 100,000/mm³, and treatment-related diarrhea has fully resolved. Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan.

Dosing adjustment for toxicities: A decrease in dose level corresponds to a decrease in irinotecan dosage by 25-50 mg/m²; specific dose levels corresponding to individual protocols should be consulted. Single-agent schedules and combination schedules: See Additional Information

The following are examples of dosing adjustments cited by the manufacturer:

Standard dose: 125 mg/m²

Dose level -1: 100 mg/m²

Dose level -2: 75 mg/m²

Standard dose: 180 mg/m²

Dose level -1: 150 mg/m²

Dose level -2: 120 mg/m²

Standard dose: 350 mg/m²

Dose level -1: 300 mg/m²

Dose level -2: 250 mg/m²

Dosing adjustment in renal impairment: Effects have not been evaluated

Dosing adjustment in hepatic impairment:

AUC of irinotecan and SN-38 have been reported to be higher in patients with known hepatic tumor involvement. The manufacturer recommends that no change in dosage or administration be made for patients with liver metastases and normal hepatic function.

In patients with a combined history of prior pelvic/abdominal irradiation and modestly elevated total serum bilirubin levels (1.0-2.0 mg/dL) prior to treatment with irinotecan, there may be substantially increased likelihood of grade 3 or 4 neutropenia. Consideration may be given to starting irinotecan at a lower dose (eg, 100 mg/m²) in such patients. Definite recommendations regarding the most appropriate starting dose in patients who have pretreatment total serum bilirubin elevations >2.0 mg/dL are not available, but it is likely that lower starting doses will need to be considered in such patients.

CBC with differential, platelet count, and hemoglobin with each dose

Dizziness and insomnia are common

May cause myelosuppression; use caution with clozapine and carbamazepine; concurrent use with prochlorperazine has produced akathisia

No information available to require special precautions

No effects or complications reported

This drug may cause nausea, vomiting, and acute diarrhea. Immediately report these or any signs of dehydration (eg, fainting, dizziness, lightheadedness) to prescriber. Avoid the use of laxatives or food with laxative properties. This drug may cause hair loss; hair will regrow when drug is discontinued. Report difficulty breathing, weight loss, or signs or symptoms of opportunistic infection (eg, fever, fatigue, furry tongue, thrush, perineal itching or vaginal discharge, loose foul-smelling stools). Avoid crowds or exposure to infected persons; you will be susceptible to infection. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures (may cause severe fetal abnormalities). Do not breast-feed.

Monitor infusion site for signs of inflammation and avoid extravasation

Injection: 20 mg/mL (5 mL)

It is recommended that new courses begin only after the granulocyte count recovers to greater than or equal to 1500/mm³, the platelet counts recovers to greater than or equal 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 25-50 mg/m². Irinotecan doses may range 50-150 mg/m². Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan.

Dosage modifications based on NCI toxicity grade (value)

*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 (1500-1999/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 (1000-1499/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 (500-999/mm³):

Weekly schedule:

During a course of therapy*: Omit dose, then decrease by 25 mg/m² when resolved to less than or equal to grade 2

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, then decrease by 50 mg/m² when resolved to less than or equal to grade 2

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 greater than or equal to grade 2 fever):

Weekly schedule:

During a course of therapy*: Omit dose, then decrease by 50 mg/m² when resolved

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

Leukopenia, thrombocytopenia, or anemia:

Dose modifications 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

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 (4-6 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, then decrease by 25 mg/m² when resolved to less than or equal to grade 2

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 25 mg/m²

Diarrhea: NCI Grade 4 ( greater than or equal to 10 stools/day > pretreatment):

Weekly schedule:

During a course of therapy*: Omit dose, then decrease by 50 mg/m² when resolved to less than or equal to grade 2

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:

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, then decrease by 25 mg/m² when resolved to less than or equal to grade 2

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, then decrease by 50 mg/m² when resolved to less than or equal to grade 2

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

COMBINATION SCHEDULES: DOSING ADJUSTMENT FOR TOXICITIES

Dosage modifications based on NCI toxicity Grade (Value)

*All dose modifications should be based on the worst preceding toxicities

NCI Grade (Value): No toxicity

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

Neutropenia: NCI Grade 1 (1500-1999/mm³):

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

Neutropenia: NCI Grade 2 (1000-1499/mm³):

During a course of therapy*: Decrease by 1 dose level

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 1 dose level

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

During a course of therapy*: Omit dose; then decrease by 1 dose level when resolved to less than or equal to grade 2

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 1 dose level

Neutropenia: NCI Grade 4 (<500/mm³):

During a course of therapy*: Omit dose; then decrease by 2 dose levels when resolved to less than or equal to grade 2

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 2 dose levels

Neutropenic fever (grade 4 neutropenia and greater than or equal to grade 2 fever):

During a course of therapy*: Omit dose, then decrease by 50 mg/m² when resolved

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 2 dose levels

Leukopenia or thrombocytopenia toxicities:

Dose modifications 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):

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):

During a course of therapy*: Decrease by 1 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 3 (7-9 stools/day > pretreatment):

During a course of therapy*: Omit dose, then decrease by 1 dose level when resolved to less than or equal to grade 2

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 4 ( greater than or equal to 10 stools/day > pretreatment):

During a course of therapy*: Omit dose, the decrease by 2 dose levels when resolved to less than or equal to grade 2

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 2 dose levels

Other nonhematologic toxicities: For mucositis/stomatitis, decrease only 5-FU, not irinotecan (during course of therapy and at the start of subsequent courses of therapy)

NCI Grade 1:

During a course of therapy*: Maintain dose level

At the start of the next courses 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:

NCI Grade 2:

During a course of therapy*: Decrease by 1 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

NCI Grade 3:

During a course of therapy*: Omit dose, then decrease by 1 dose level when resolved to less than or equal to grade 2

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 1 dose level

NCI Grade 4:

During a course of therapy*: Omit dose, then decrease by 2 dose levels when resolved to less than or equal to grade 2

At the start of the next courses of therapy* (after adequate recovery), compared to the starting dose in the previous courses: Decrease by 2 dose levels