CAMPTOSAR Injection is indicated as a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. CAMPTOSAR is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Combination-Agent Dosage

Dosage Regimens

CAMPTOSAR Injection in Combination with 5-Fluorouracil (5-FU) and Leucovorin (LV)

CAMPTOSAR should be administered as an intravenous infusion over 90 minutes (see Preparation of Infusion Solution). For all regimens, the dose of LV should be administered immediately after CAMPTOSAR, with the administration of 5-FU to occur immediately after receipt of LV. CAMPTOSAR should be used as recommended; the currently recommended regimens are shown in Table 10.

Table 10. Combination-Agent Dosage Regimens & Dose Modifications^a

Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43)	CAMPTOSAR	125 mg/m2 IV over 90 min, d 1,8,15,22
	LV	20 mg/m2 IV bolus, d 1,8,15,22
	5-FU	500 mg/m2 IV bolus, d 1,8,15,22
		Starting Dose & Modified Dose Levels (mg/m2)
		Starting Dose	Dose Level -1	Dose Level -2
		125	100	75
	LV	20	20	20
	5-FU	500	400	300
Regimen 26-wk cycle with infusional 5-FU/LV (next cycle begins on day 43)	CAMPTOSAR	180 mg/m2 IV over 90 min, d 1,15,29
	LV	200 mg/m2 IV over 2 h, d 1,2,15,16,29,30
	5-FU Bolus	400 mg/m2 IV bolus, d 1,2,15,16,29,30
	5-FU Infusionb	600 mg/m2 IV over 22 h, d 1,2,15,16,29,30
		Starting Dose & Modified Dose Levels (mg/m2)
		Starting Dose	Dose Level -1	Dose Level -2
		180	150	120
	LV	200	200	200
	5-FU Bolus	400	320	240
	5-FU Infusionb	600	480	360

^aDose 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. bInfusion follows bolus administration. bilirubin >2 mg/dL cannot be recommended since such patients were not included in clinical studies. It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. See PRECAUTIONS, General.

Dose Modifications

Patients should be carefully monitored for toxicity and assessed prior to each treatment. Doses of CAMPTOSAR and 5-FU should be modified as necessary to accommodate individual patient tolerance to treatment. Based on the recommended dose-levels described in Table 10, Combination-Agent Dosage Regimens & Dose Modifications, subsequent doses should be adjusted as suggested in Table 11, Recommended Dose Modifications for Combination Schedules. All dose modifications should be based on the worst preceding toxicity. After the first treatment, patients with active diarrhea should return to pretreatment 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 toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of CAMPTOSAR/5-FU/LV may be continued indefinitely as long as patients continue to experience clinical benefit.

Table 11. Recommended Dose Modifications for CAMPTOSAR/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 gradea (Value)	During a Cycle of Therapy	At the Start of Subsequent Cycles of Therapyb
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 > pretxc)	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 onhematologic toxicitiesd
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	For mucositis/stomatitis decrease
	CAMPTOSAR	only 5-FU, not CAMPTOSAR.

^a National Cancer Institute Common Toxicity Criteria (version 1.0)

^b Relative to the starting dose used in the previous cycle

^c Pretreatment d Excludes alopecia, anorexia, asthenia

Single-Agent Dosage Schedules

Dosage Regimens

CAMPTOSAR should be administered as an intravenous infusion over 90 minutes for both the weekly and once-every-3-week dosage schedules (see Preparation of Infusion Solution). Single-agent dosage regimens are shown in Table 12.

Table 12. Single-Agent Regimens of CAMPTOSAR and Dose Modifications

Weekly Regimena	125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest
	Starting Dose & Modified Dose Levelsc (mg/m2)
	Starting Dose	Dose Level -1	Dose Level -2
	125	100	75
Once-Every-3-Week Regimenb	350 mg/m2 IV over 90 min, once every 3 wksc
	Starting Dose & Modified Dose Levels (mg/m2)
	Starting Dose	Dose Level -1	Dose Level -2
	350	300	250
	2	2	2

^aSubsequent 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.

^bSubsequent 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.

A reduction in the starting dose by one dose level of CAMPTOSAR may be considered for patients with any of the following conditions: age ≥ 65 years, prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended since such patients were not included in clinical studies. It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. See PRECAUTIONS, General.

Dose Modifications

Patients should be carefully monitored for toxicity and doses of CAMPTOSAR should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose-levels described in Table 12, Single-Agent Regimens of CAMPTOSAR and Dose Modifications, subsequent doses should be adjusted as suggested in Table 13, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity. A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing this combination therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of CAMPTOSAR may be continued indefinitely as long as patients continue to experience clinical benefit.

Table 13. Recommended Dose Modifications For Single-Agent Schedules^a

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 CAMPTOSAR.
Worst Toxicity NCI Gradeb (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 Cyclea
	Weekly	Weekly	Once Every 3 Week
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 nonhematologicd toxicities
1	Maintain dose level	Maintain dose level	Maintain dose level
2	↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
34	Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2	↓ 25 mg/m2	↓ 50 mg/m2
	Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2	↓ 50 mg/m2	↓ 50 mg/m2

^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

Preparation & Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from CAMPTOSAR Injection. The use of gloves is recommended. If a solution of CAMPTOSAR contacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.^1-7

Preparation of Infusion Solution

Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe. CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials, CAMPTOSAR was administered in 250 mL to 500 mL of 5% Dextrose Injection, USP. The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may result in precipitation of the drug and should be avoided. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 6 hours if kept at room temperature (15° to 30°C, 59° to 86°F). Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Each mL of CAMPTOSAR Injection contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. CAMPTOSAR Injection is available in single-dose amber glass vials in the following package sizes:

2 mL NDC 0009-7529-02

5 mL NDC 0009-7529-01

This is packaged in a backing/plastic blister to protect against inadvertent breakage and leakage. The vial should be inspected for damage and visible signs of leaks before removing the backing/plastic blister. If damaged, incinerate the unopened package.

Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is recommended that the vial (and backing/plastic blister) should remain in the carton until the time of use.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

2. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 1985; 253(11): 1590-2. Cytotoxic Exposure. Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990;47:1033-49. 7. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm 1996;53:1669-85. Manufactured by :Pharmacia & Upjohn Company A subsidiary of Pharmacia Corporation Kalamazoo, Michigan 49001, USA, Licensed from Yakult Honsha Co, LTD, Japan, and Daiichi Pharmaceutical Co, LTD, Japan