Irinotecan Hydrochloride: Package Insert and Label Information

IRINOTECAN HYDROCHLORIDE- irinotecan hydrochloride injection, solution
Qilu Pharmaceutical Co., Ltd.

WARNING: DIARRHEA and MYELOSUPPRESSION

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 Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Severe myelosuppression may occur [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

•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.

2 DOSAGE AND ADMINISTRATION

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.

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 1. Combination-Agent Dosage Regimens and Dose Modifications *
*
Dose 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.
Infusion follows bolus administration.
Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) Irinotecan hydrochlorideinjection LV5-FU 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,2220 mg/m2 intravenous injection bolus, days 1,8,15,22500 mg/m2 intravenous injection bolus, days 1,8,15,22
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose Dose Level -1 Dose Level -2
Irinotecan hydrochlorideinjection 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 hydrochlorideinjection 180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29
LV 200 mg/m2 intravenous infusion over 2 hours, days 1,2,15,16,29,30
5-FU Bolus 400 mg/m2 intravenous injection bolus, days 1,2,15,16,29,30
5-FU Infusion 600 mg/m2 intravenous 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 hydrochlorideinjection 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.
ToxicityNCI CTC Grade * (Value) During a Cycle of Therapy At the Start of Subsequent Cycles of Therapy
*
National Cancer Institute Common Toxicity Criteria (version 1.0)
Relative to the starting dose used in the previous cycle
Pretreatment
§
Excludes alopecia, anorexia, asthenia
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 > pretx ) 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 toxicities §
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.

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
a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. c 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 (weekly) a

125 mg/m2 intravenous 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/m2 intravenous infusion over 90 minutes, once every 3 weeksc

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 Schedulesa
a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes 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

Weekly

Weekly

Once Every 3 Weeks

No toxicity

Maintain dose level

↑ 25 mg/m2 up 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/m2 when 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 > pretxc)

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 d toxicities

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

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