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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) .

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

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 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.

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 one to two weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a two-week delay, consideration should be given to discontinuing therapy.

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

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 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 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 one to two 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

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 25ºC) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2º to 8ºC), 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 (2º to 8ºC, 36º to 46ºF). 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 (15º to 30ºC, 59º to 86ºF).

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.

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