irinotecan hydrochloride injection, USP 2 DOSAGE AND ADMINISTRATION

Prescribing Information

2 DOSAGE AND ADMINISTRATION

2.1 Colorectal Cancer Combination Regimens 1 and 2

Administer Irinotecan Hydrochloride Injection, USP 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, USP 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 Hydrochloride Injection, USP LV 5-FU	125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m2 intravenous injection bolus, days 1,8,15,22 500 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 Hydrochloride Injection, USP	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, USP LV 5-FU Bolus 5-FU Infusion†	180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29 200 mg/m2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 400 mg/m2 intravenous injection bolus, days 1,2,15,16,29,30 600 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 Hydrochloride Injection, USP	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, USP 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, USP /5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules
* National Cancer Institute Common Toxicity Criteria (version 1.0) † Relative to the starting dose used in the previous cycle ‡ Pretreatment § Excludes alopecia, anorexia, asthenia
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 Grade* (Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of Therapy†
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, USP	For mucositis/stomatitis decrease only 5-FU, not Irinotecan Hydrochloride Injection, USP.

2.2 Colorectal Single Agent Regimens 1 and 2

Administer Irinotecan Hydrochloride Injection, USP as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

Table 3. Single-Agent Regimens of Irinotecan Hydrochloride Injection, USP and Dose Modifications
* 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. † Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. ‡ Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance.
Regimen 1 (weekly)*	125 mg/m2 intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
	Starting Dose and Modified Dose Levels† (mg/m2)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Regimen 2 (every 3 weeks)‡	350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeks†
	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, USP 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*
* All dose modifications should be based on the worst preceding toxicity † National Cancer Institute Common Toxicity Criteria (version 1.0) ‡ Pretreatment § 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, USP.
Worst Toxicity NCI Grade† (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*
Worst Toxicity NCI Grade† (Value)	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 > pretx‡)	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§ 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

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, USP 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-HT3 blocker (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, USP. 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, USP 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, USP 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan Hydrochloride Injection, USP must be diluted prior to infusion using aseptic technique. Irinotecan Hydrochloride Injection, USP 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, USP 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, USP. The use of gloves is recommended. If a solution of Irinotecan Hydrochloride Injection, USP contacts the skin, wash the skin immediately and thoroughly with soap and water. If Irinotecan Hydrochloride Injection, USP 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.

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