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Usual Diluents
D5W (preferred), NS
Dilution Data
DILUTION SUMMARY
[Amount of drug] [Infusion volume] [Infusion rate]
[Prescribed dose] [ 250-500 ml]* [90 minutes] *final concentration range of 0.12 to 2.8 mg/mL
----------------------------------------------------------------------- Preparation of Infusion Solution ----------------------------------------------------------------------- Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.
CAMPTOSAR should be administered as an intravenous infusion over 90 minutes.
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.
Storage/Stability: 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).
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is recommended that the vial should remain in the carton until the time of use.
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WARNINGS CAMPTOSAR Injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. CAMPTOSAR can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or shortly after infusion of CAMPTOSAR) may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine (see PACKAGE INSERT FOR PRECAUTIONS, General). Late diarrhea (generally occurring more than 24 hours after administration of CAMPTOSAR) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia (see PACKAGE INSERT FOR WARNINGS). Administration of CAMPTOSAR should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION).
Severe myelosuppression may occur (see PACKAGE INSERT FOR WARNINGS).
INDICATIONS AND USAGE 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.
CONTRAINDICATIONS CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients
CLINICAL PHARMACOLOGY Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form.
Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
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.
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.
*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)
CAMPTOSAR LV 5-FU
125 mg/m2 IV over 90 min, d 1,8,15,22 20 mg/m2 IV bolus, d 1,8,15,22 500 mg/m2 IV bolus, d 1,8,15,22
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose
Dose Level -1
Dose Level -2
CAMPTOSAR
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)
CAMPTOSAR LV 5-FU Bolus 5-FU Infusion†
180 mg/m2 IV over 90 min, d 1,15,29 200 mg/m2 IV over 2 h, d 1,2,15,16,29,30 400 mg/m2 IV bolus, d 1,2,15,16,29,30 600 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
CAMPTOSAR
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. 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 PACKAGE INSERT FOR 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 pre-treatment bowel function without requiring anti-diarrhea 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 maybe 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.
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 †
*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 CAMPTOSAR
For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR.
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
*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.
†Subsequent doses may be adjusted as low as 200 mg/m2 in 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.
Weekly Regimen*
125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest
Starting Dose & Modified Dose Levels‡ (mg/m2)
Starting Dose
Dose Level -1
Dose Level -2
125
100
75
Once-Every-3-Week Regimen†
350 mg/m2 IV over 90 min, once every 3 wks‡
Starting Dose & Modified Dose Levels (mg/m2)
Starting Dose
Dose Level -1
Dose Level -2
350
300
250
A reduction in the starting dose by one dose level of CAMPTOSAR 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.
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 PACKAGE INSERT FOR 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 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 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*
Weekly
Weekly
Once Every 3 Weeks
*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
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
Dosage in Patients with Reduced UGT1A1 Activity When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele (see CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 10–13).
----------------------------------------------------------------------- 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.
----------------------------------------------------------------------- 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
HOW SUPPLIED 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
The vial should be inspected for damage and visible signs of leaks before removing from the carton. 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 should remain in the carton until the time of use.
Procedures for proper handling and disposal: NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. https://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172–1193. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society
1 dose level
25 mg/m2 up to a maximum dose of 150 mg/m2 
