Irinotecan Hydrochloride

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Irinotecan Hydrochloride Prescribing Information

•

Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if severe diarrhea occurs

[see

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

Table 3. Single-Agent Regimens of Irinotecan Hydrochloride injection and Dose Modifications
^aSubsequent doses may be adjusted as high as 150 mg/m²or to as low as 50 mg/m²in 25 to 50 mg/m²decrements depending upon individual patient tolerance. ^bSubsequent doses may be adjusted as low as 200 mg/m²in 50 mg/m²decrements depending upon individual patient tolerance. ^cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)^a	125 mg/m²intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
	Starting Dose and Modified Dose Levels^c(mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Regimen 2 (every 3 weeks)^b	350 mg/m²intravenous infusion over 90 minutes, once every 3 weeks^c
	Starting Dose and Modified Dose Levels (mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	350	300	250

Dose Modifications

Based on recommended dose-levels described in Table 3, Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

Table 4. Recommended Dose Modifications For Single-Agent Schedules^a
^aAll dose modifications should be based on the worst preceding toxicity ^bNational Cancer Institute Common Toxicity Criteria (version 1.0) ^cPretreatment ^dExcludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing irinotecan hydrochloride injection.
Worst Toxicity NCI Grade^b(Value)	During a Cycle of Therapy	At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle^a
Worst Toxicity NCI Grade^b(Value)	Weekly	Weekly	Once Every 3 Weeks
No toxicity	Maintain dose level	↑ 25 mg/m²up to a maximum dose of 150 mg/m²	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Neutropenic fever	Omit dose until resolved, then ↓ 50 mg/m²when resolved	↓ 50 mg/m²	↓ 50 mg/m²
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia 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
1 (2-3 stools/day > pretx^c)	Maintain dose level	Maintain dose level	Maintain dose level
2 (4-6 stools/day > pretx)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (7-9 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (≥10 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Other nonhematologic^dtoxicities
1	Maintain dose level	Maintain dose level	Maintain dose level
2	↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
3	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²

and

5.1 Diarrhea and Cholinergic Reactions

Early diarrhea (occurring during or shortly after infusion of Irinotecan hydrochloride injection) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses.

Late diarrhea (generally occurring more than 24 hours after administration of irinotecan hydrochloride injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3-4 late diarrhea occurred in 23-31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 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. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan hydrochloride injection should be decreased

[

see Dosage and Administration (2)

]

Avoid diuretics or laxatives in patients with diarrhea.

]

•

Severe myelosuppression may occur

[see

5.2 Myelosuppression

Irinotecan hydrochloride injection can cause severe myelosuppression. Bacterial, viral, and fungal infections have occurred in patients treated with irinotecan hydrochloride injection.

Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride injection. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support

[

see Warnings and Precautions (5.2)

]

. Hold irinotecan hydrochloride injection if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm³. After recovery to an absolute neutrophil count ≥1000/mm³, subsequent doses of irinotecan hydrochloride injection should be reduced

[

see Dosage and Administration (2)

]

When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan hydrochloride injection. Based on sparse available data, the concurrent administration of irinotecan hydrochloride injection with irradiation is not recommended.

Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with irinotecan hydrochloride injection

[see Warnings and Precautions (5.3)

]

Dosage and Administration, Dosage in Patients With Reduced UGT1A1 Activity ( 2.3 Dosage in Patients With Reduced UGT1A1 Activity When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of irinotecan hydrochloride injection for patients known to be homozygous for the UGT1A128 or 6 alleles (28/28, 6/6) or compound heterozygous for the UGT1A128 and 6 alleles (6/28) [see Dosage and Administration (2.1, 2.2 ), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3, 12.5 )] . Subsequent dosage modifications may be required based on individual patient tolerance to treatment [see Dosage and Administration (2.1, 2.2)] . )	1/2022
Dosage and Administration, Preparation of Infusion Solution ( 2.5 Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe. Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded. Irinotecan hydrochloride injection must be diluted prior to infusion using aseptic technique. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution. Prepare the infusion solution immediately prior to use and commence infusion as soon as possible after preparation. If visible particulates are present in the infusion solution discard. If it is not possible to use the infusion solution immediately, the infusion solution may be stored for up to 24 hours at 2°C to 8°C or discarded. )	1/2022
Dosage and Administration, Safe Handling ( 2.6 Safe Handling Irinotecan hydrochloride injection is a hazardous drug. Follow applicable special handling and disposal procedures.¹ Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water. )	1/2022
Warnings and Precautions, Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity ( 5.3 Increased Risk of Neutropenia in Patients With Reduced UGT1A1 Activity Published studies have shown that individuals who are homozygous for either the UGT1A128 or 6 alleles (28/28, 6/6) or who are compound or double heterozygous for the UGT1A128 and 6 alleles (6/28) are at increased risk for severe or life-threatening neutropenia during treatment with Irinotecan hydrochloride injection. These individuals are UGT1A1 poor metabolizers and experience increased systemic exposure to SN-38, an active metabolite of irinotecan. Individuals who are heterozygous for either the UGT1A128 or 6 alleles (1/28, 1/6) are intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration (2) and Clinical Pharmacology (12.3, 12.5 )] . Consider UGT1A1 genotype testing for the 28 and 6 alleles to determine UGT1A1 metabolizer status [see Clinical Pharmacology (12.5)] . When administering irinotecan hydrochloride injection, consider a reduction in the irinotecan hydrochloride injection starting dose by at least one level for patients known to be homozygous or compound heterozygous for the UGT1A128 and/or 6 alleles (28/28, 6/6, 6/28). Closely monitor patients with UGT1A128 or 6 alleles for neutropenia during and after treatment with irinotecan hydrochloride injection. The precise dosage reduction in this patient population is not known. Subsequent dosage modifications may be required based on individual patient tolerance to treatment [see Dosage and Administration (2.1, 2.2)] . )	1/2022

•Irinotecan hydrochloride injection is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum.

•Irinotecan hydrochloride injection is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Colorectal cancer combination regimen 1: Irinotecan hydrochloride injection 125 mg/m² intravenous infusion over 90 minutes on days 1, 8,15, 22 with LV 20 mg/m² intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-FU intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks. (

2.1 Colorectal Cancer Combination Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1.

Table 1. Combination-Agent Dosage Regimens and Dose ModificationsDose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection LV 5-FU	125 mg/m²intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m²intravenous injection bolus, days 1,8,15,22 500 mg/m²intravenous injection bolus, days 1,8,15,22
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	125	100	75
	LV	20	20	20
	5-FU	500	400	300
Regimen 2 6-wk cycle with infusional 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection	180 mg/m²intravenous infusion over 90 minutes, days 1,15,29
	LV	200 mg/m²intravenous infusion over 2 hours, days 1,2,15,16,29,30
	5-FU Bolus	400 mg/m²intravenous injection bolus, days 1,2,15,16,29,30
	5-FU InfusionInfusion follows bolus administration.	600 mg/m²intravenous infusion over 22 hours, days 1,2,15,16,29,30
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	180	150	120
	LV	200	200	200
	5-FU Bolus	400	320	240
	5-FU Infusion	600	480	360

Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients

[see Warnings and Precautions (5.10), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

Dose Modifications

Based on recommended dose levels described in Table 1, Combination Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Combination Regimens. All dose modifications should be based on the worst preceding toxicity.

Table 2. Recommended Dose Modifications for Irinotecan Hydrochloride injection/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing therapy.
Toxicity NCI CTC GradeNational Cancer Institute Common Toxicity Criteria (version 1.0)(Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of TherapyRelative to the starting dose used in the previous cycle
No toxicity	Maintain dose level	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 1 dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
Neutropenic fever	Omit dose until resolved, then ↓ 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 also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2–3 stools/day > pretxPretreatment)	Delay dose until resolved to baseline, then give same dose	Maintain dose level
2 (4–6 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	Maintain dose level
3 (7–9 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	↓ 1 dose level
4 (≥10 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 2 dose levels	↓ 2 dose levels
Other nonhematologic toxicitiesExcludes alopecia, anorexia, asthenia
1	Maintain dose level	Maintain dose level
2	Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level	Maintain dose level
3	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection.

)

Colorectal cancer combination regimen 2: Irinotecan hydrochloride injection 180 mg/m² intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m² intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m² intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m² intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30. (

2.1 Colorectal Cancer Combination Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1.

Table 1. Combination-Agent Dosage Regimens and Dose ModificationsDose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection LV 5-FU	125 mg/m²intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m²intravenous injection bolus, days 1,8,15,22 500 mg/m²intravenous injection bolus, days 1,8,15,22
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	125	100	75
	LV	20	20	20
	5-FU	500	400	300
Regimen 2 6-wk cycle with infusional 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection	180 mg/m²intravenous infusion over 90 minutes, days 1,15,29
	LV	200 mg/m²intravenous infusion over 2 hours, days 1,2,15,16,29,30
	5-FU Bolus	400 mg/m²intravenous injection bolus, days 1,2,15,16,29,30
	5-FU InfusionInfusion follows bolus administration.	600 mg/m²intravenous infusion over 22 hours, days 1,2,15,16,29,30
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	180	150	120
	LV	200	200	200
	5-FU Bolus	400	320	240
	5-FU Infusion	600	480	360

Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients

[see Warnings and Precautions (5.10), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

Dose Modifications

Table 2. Recommended Dose Modifications for Irinotecan Hydrochloride injection/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing therapy.
Toxicity NCI CTC GradeNational Cancer Institute Common Toxicity Criteria (version 1.0)(Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of TherapyRelative to the starting dose used in the previous cycle
No toxicity	Maintain dose level	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 1 dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
Neutropenic fever	Omit dose until resolved, then ↓ 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 also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2–3 stools/day > pretxPretreatment)	Delay dose until resolved to baseline, then give same dose	Maintain dose level
2 (4–6 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	Maintain dose level
3 (7–9 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	↓ 1 dose level
4 (≥10 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 2 dose levels	↓ 2 dose levels
Other nonhematologic toxicitiesExcludes alopecia, anorexia, asthenia
1	Maintain dose level	Maintain dose level
2	Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level	Maintain dose level
3	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection.

)

Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m² intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest. (

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

Table 3. Single-Agent Regimens of Irinotecan Hydrochloride injection and Dose Modifications
^aSubsequent doses may be adjusted as high as 150 mg/m²or to as low as 50 mg/m²in 25 to 50 mg/m²decrements depending upon individual patient tolerance. ^bSubsequent doses may be adjusted as low as 200 mg/m²in 50 mg/m²decrements depending upon individual patient tolerance. ^cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)^a	125 mg/m²intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
	Starting Dose and Modified Dose Levels^c(mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Regimen 2 (every 3 weeks)^b	350 mg/m²intravenous infusion over 90 minutes, once every 3 weeks^c
	Starting Dose and Modified Dose Levels (mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	350	300	250

Dose Modifications

Table 4. Recommended Dose Modifications For Single-Agent Schedules^a
^aAll dose modifications should be based on the worst preceding toxicity ^bNational Cancer Institute Common Toxicity Criteria (version 1.0) ^cPretreatment ^dExcludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing irinotecan hydrochloride injection.
Worst Toxicity NCI Grade^b(Value)	During a Cycle of Therapy	At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle^a
Worst Toxicity NCI Grade^b(Value)	Weekly	Weekly	Once Every 3 Weeks
No toxicity	Maintain dose level	↑ 25 mg/m²up to a maximum dose of 150 mg/m²	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Neutropenic fever	Omit dose until resolved, then ↓ 50 mg/m²when resolved	↓ 50 mg/m²	↓ 50 mg/m²
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia 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
1 (2-3 stools/day > pretx^c)	Maintain dose level	Maintain dose level	Maintain dose level
2 (4-6 stools/day > pretx)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (7-9 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (≥10 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Other nonhematologic^dtoxicities
1	Maintain dose level	Maintain dose level	Maintain dose level
2	↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
3	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²

)

Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m² intravenous infusion over 90 minutes on day 1 every 3 weeks. (

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

Table 3. Single-Agent Regimens of Irinotecan Hydrochloride injection and Dose Modifications
^aSubsequent doses may be adjusted as high as 150 mg/m²or to as low as 50 mg/m²in 25 to 50 mg/m²decrements depending upon individual patient tolerance. ^bSubsequent doses may be adjusted as low as 200 mg/m²in 50 mg/m²decrements depending upon individual patient tolerance. ^cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)^a	125 mg/m²intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
	Starting Dose and Modified Dose Levels^c(mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Regimen 2 (every 3 weeks)^b	350 mg/m²intravenous infusion over 90 minutes, once every 3 weeks^c
	Starting Dose and Modified Dose Levels (mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	350	300	250

Dose Modifications

Table 4. Recommended Dose Modifications For Single-Agent Schedules^a
^aAll dose modifications should be based on the worst preceding toxicity ^bNational Cancer Institute Common Toxicity Criteria (version 1.0) ^cPretreatment ^dExcludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing irinotecan hydrochloride injection.
Worst Toxicity NCI Grade^b(Value)	During a Cycle of Therapy	At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle^a
Worst Toxicity NCI Grade^b(Value)	Weekly	Weekly	Once Every 3 Weeks
No toxicity	Maintain dose level	↑ 25 mg/m²up to a maximum dose of 150 mg/m²	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Neutropenic fever	Omit dose until resolved, then ↓ 50 mg/m²when resolved	↓ 50 mg/m²	↓ 50 mg/m²
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia 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
1 (2-3 stools/day > pretx^c)	Maintain dose level	Maintain dose level	Maintain dose level
2 (4-6 stools/day > pretx)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (7-9 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (≥10 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Other nonhematologic^dtoxicities
1	Maintain dose level	Maintain dose level	Maintain dose level
2	↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
3	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²

)

•

Lactation:

Advise not to breastfeed. (

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status in female patients of reproductive potential prior to initiating irinotecan hydrochloride injection.

Contraception

Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman.

Females

Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the final dose of irinotecan hydrochloride injection

[see Use in Specific Populations (8.1)and Nonclinical Toxicology (13.1)].

Males

Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of irinotecan hydrochloride injection

[see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on postmarketing reports, female fertility may be impaired by treatment with irinotecan hydrochloride injection. Menstrual dysfunction has been reported following irinotecan hydrochloride injection administration.

Males

Based on findings from animal studies, male fertility may be impaired by treatment with irinotecan hydrochloride injection

[see Nonclinical Toxicology (13.1)].

)

•

Geriatric Use:

Closely monitor patients greater than 65 years of age because of a greater risk of early and late diarrhea in this population. (

8.5 Geriatric Use

Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population

[

see Clinical Pharmacology (12.3)

and

Adverse Reactions (6.1)

]

. The starting dose of irinotecan hydrochloride injection in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m²

[

see Clinical Pharmacology (12.3)and Dosage and Administration (2)

]

The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92].

)

•

Patients With Renal Impairment:

Use caution and do not use in patients on dialysis. (

8.6 Renal Impairment

The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.

)

•

Patients With Hepatic Impairment:

Use caution. (

2 DOSAGE AND ADMINISTRATION

Colorectal cancer combination regimen 1: Irinotecan hydrochloride injection 125 mg/m²intravenous infusion over 90 minutes on days 1, 8,15, 22 with LV 20 mg/m²intravenous bolus infusion on days 1, 8, 15, 22 followed by 5-FU intravenous bolus infusion on days 1, 8, 15, 22 every 6 weeks.
Colorectal cancer combination regimen 2: Irinotecan hydrochloride injection 180 mg/m²intravenous infusion over 90 minutes on days 1, 15, 29 with LV 200 mg/m²intravenous infusion over 2 hours on days 1, 2, 15, 16, 29, 30 followed by 5-FU 400 mg/m²intravenous bolus infusion on days 1, 2, 15, 16, 29, 30 and 5-FU 600 mg/m²intravenous infusion over 22 hours on days 1, 2, 15, 16, 29, 30.
Colorectal cancer single agent regimen 1: Irinotecan hydrochloride injection 125 mg/m²intravenous infusion over 90 minutes on days 1, 8, 15, 22 then 2-week rest.
Colorectal cancer single agent regimen 2: Irinotecan hydrochloride injection 350 mg/m²intravenous infusion over 90 minutes on day 1 every 3 weeks.

2.1 Colorectal Cancer Combination Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1.

Table 1. Combination-Agent Dosage Regimens and Dose ModificationsDose reductions beyond Dose Level –2 by decrements of ≈ 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection LV 5-FU	125 mg/m²intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m²intravenous injection bolus, days 1,8,15,22 500 mg/m²intravenous injection bolus, days 1,8,15,22
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	125	100	75
	LV	20	20	20
	5-FU	500	400	300
Regimen 2 6-wk cycle with infusional 5-FU/LV (next cycle begins on day 43)	Irinotecan hydrochloride injection	180 mg/m²intravenous infusion over 90 minutes, days 1,15,29
	LV	200 mg/m²intravenous infusion over 2 hours, days 1,2,15,16,29,30
	5-FU Bolus	400 mg/m²intravenous injection bolus, days 1,2,15,16,29,30
	5-FU InfusionInfusion follows bolus administration.	600 mg/m²intravenous infusion over 22 hours, days 1,2,15,16,29,30
		Starting Dose & Modified Dose Levels (mg/m²)
		Starting Dose	Dose Level -1	Dose Level -2
	Irinotecan hydrochloride injection	180	150	120
	LV	200	200	200
	5-FU Bolus	400	320	240
	5-FU Infusion	600	480	360

Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients

[see Warnings and Precautions (5.10), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

Dose Modifications

Table 2. Recommended Dose Modifications for Irinotecan Hydrochloride injection/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing therapy.
Toxicity NCI CTC GradeNational Cancer Institute Common Toxicity Criteria (version 1.0)(Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of TherapyRelative to the starting dose used in the previous cycle
No toxicity	Maintain dose level	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 1 dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
Neutropenic fever	Omit dose until resolved, then ↓ 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 also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
Diarrhea
1 (2–3 stools/day > pretxPretreatment)	Delay dose until resolved to baseline, then give same dose	Maintain dose level
2 (4–6 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	Maintain dose level
3 (7–9 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 1 dose level	↓ 1 dose level
4 (≥10 stools/day > pretx)	Omit dose until resolved to baseline, then ↓ 2 dose levels	↓ 2 dose levels
Other nonhematologic toxicitiesExcludes alopecia, anorexia, asthenia
1	Maintain dose level	Maintain dose level
2	Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level	Maintain dose level
3	Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level	↓ 1 dose level
4	Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels	↓ 2 dose levels
	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection	For mucositis/stomatitis decrease only 5-FU, not irinotecan hydrochloride injection.

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

Table 3. Single-Agent Regimens of Irinotecan Hydrochloride injection and Dose Modifications
^aSubsequent doses may be adjusted as high as 150 mg/m²or to as low as 50 mg/m²in 25 to 50 mg/m²decrements depending upon individual patient tolerance. ^bSubsequent doses may be adjusted as low as 200 mg/m²in 50 mg/m²decrements depending upon individual patient tolerance. ^cProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)^a	125 mg/m²intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
	Starting Dose and Modified Dose Levels^c(mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Regimen 2 (every 3 weeks)^b	350 mg/m²intravenous infusion over 90 minutes, once every 3 weeks^c
	Starting Dose and Modified Dose Levels (mg/m²)
	Starting Dose	Dose Level -1	Dose Level -2
	350	300	250

Dose Modifications

Table 4. Recommended Dose Modifications For Single-Agent Schedules^a
^aAll dose modifications should be based on the worst preceding toxicity ^bNational Cancer Institute Common Toxicity Criteria (version 1.0) ^cPretreatment ^dExcludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. 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, consideration should be given to discontinuing irinotecan hydrochloride injection.
Worst Toxicity NCI Grade^b(Value)	During a Cycle of Therapy	At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle^a
Worst Toxicity NCI Grade^b(Value)	Weekly	Weekly	Once Every 3 Weeks
No toxicity	Maintain dose level	↑ 25 mg/m²up to a maximum dose of 150 mg/m²	Maintain dose level
Neutropenia
1 (1500 to 1999/mm³)	Maintain dose level	Maintain dose level	Maintain dose level
2 (1000 to 1499/mm³)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (500 to 999/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (<500/mm³)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Neutropenic fever	Omit dose until resolved, then ↓ 50 mg/m²when resolved	↓ 50 mg/m²	↓ 50 mg/m²
Other hematologic toxicities	Dose modifications for leukopenia, thrombocytopenia, and anemia 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
1 (2-3 stools/day > pretx^c)	Maintain dose level	Maintain dose level	Maintain dose level
2 (4-6 stools/day > pretx)	↓ 25 mg/m²	Maintain dose level	Maintain dose level
3 (7-9 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4 (≥10 stools/day > pretx)	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²
Other nonhematologic^dtoxicities
1	Maintain dose level	Maintain dose level	Maintain dose level
2	↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
3	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m²	↓ 25 mg/m²	↓ 50 mg/m²
4	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m²	↓ 50 mg/m²	↓ 50 mg/m²

2.3 Dosage in Patients With Reduced UGT1A1 Activity

When administered in combination with other agents, or as a single-agent, consider a reduction in the starting dose by at least one level of irinotecan hydrochloride injection for patients known to be homozygous for the UGT1A1*28 or *6 alleles (*28/*28, *6/*6) or compound heterozygous for the UGT1A1*28 and *6 alleles (*6/*28)

[see Dosage and Administration (2.1, 2.2 ), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3, 12.5

)]

. Subsequent dosage modifications may be required based on individual patient tolerance to treatment

[see Dosage and Administration (2.1, 2.2)]

2.4 Premedication

It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT³blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. A similar antiemetic regimen should be used with irinotecan hydrochloride injection in combination therapy.

Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

2.5 Preparation of Infusion Solution

Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan hydrochloride injection must be diluted prior to infusion using aseptic technique. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

Prepare the infusion solution immediately prior to use and commence infusion as soon as possible after preparation. If visible particulates are present in the infusion solution discard. If it is not possible to use the infusion solution immediately, the infusion solution may be stored for up to 24 hours at 2°C to 8°C or discarded.

2.6 Safe Handling

Irinotecan hydrochloride injection is a hazardous drug. Follow applicable special handling and disposal procedures.¹

Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water.

2.7 Extravasation

Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

5.10 Patients With Hepatic Impairment

The use of irinotecan hydrochloride injection in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001)

[

see Dosage and Administration (2.1), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)

]

8.7 Hepatic Impairment

Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. Therefore, use caution when administering irinotecan hydrochloride injection to patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made

[

see Dosage and Administration (2.1), Warnings and Precautions (5.10)and Clinical Pharmacology (12.3)

]

12.3 Pharmacokinetics

After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.

Over the recommended dose range of 50 to 350 mg/m², the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m²determined in two clinical studies in patients with solid tumors are summarized in Table 9:

Table 9. Summary of Mean (±Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients with Solid Tumors
C_max- Maximum plasma concentration AUC_0-24- Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion t_1/2- Terminal elimination half-life V_z- Volume of distribution of terminal elimination phase CL - Total systemic clearance ^aPlasma specimens collected for 24 hours following the end of the 90-minute infusion. ^bPlasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan and SN-38.
Dose (mg/m²)	Irinotecan					SN-38
Dose (mg/m²)	C_max (ng/mL)	AUC_0-24 (ng·h/mL)	t_1/2 (h)	V_z (L/m²)	CL (L/h/m²)	C_max (ng/mL)	AUC_0-24(ng·h/mL)	t_1/2 (h)
125 (N = 64)	1,660 ±797	10,200 ±3,270	5.8^a ±0.7	110 ±48.5	13.3 ±6.01	26.3 ±11.9	229 ±108	10.4^a ±3.1
340 (N = 6)	3,392 ±874	20,604 ±6,027	11.7^b ±1.0	234 ±69.6	13.9 ±4.0	56.0 ±28.2	474 ±245	21.0^b ±4.3

Distribution

Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin.

Elimination

Metabolism

Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases that form an active metabolite SN-38, and UGT1A1 which mediates the glucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38. Patients who are homozygous for either the UGT1A1*28 or *6 alleles, or who are compound heterozygous for these alleles, have higher SN-38 AUC than patients with the wild-type UGT1A1 alleles

[see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.5)]

Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release the active metabolite SN-38.

Excretion

The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).

Specific Populations

Geriatric Patients

The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients ≥65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients ≥65 years of age were observed. Although dose-normalized AUC_0-24for SN-38 in patients ≥65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan

[

see Dosage and Administration (2)

]

Male and Female Patients

The pharmacokinetics of irinotecan do not appear to be influenced by gender.

Racial and Ethnic Groups

The influence of race on the pharmacokinetics of irinotecan has not been evaluated.

Patients with Renal Impairment

The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated.

Patients with Hepatic Impairment

Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.

In Vitro Studies

Irinotecan and the metabolites SN-38 and aminopentane carboxylic acid (APC) do not inhibit cytochrome P-450 isozymes.

)

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