Usual Adult Dose for Colorectal Cancer

COMBINATION REGIMEN 1:
125 mg/m2 IV over 90 minutes on Days 1, 8,15, and 22 with LV 20 mg/m2 IV bolus on Days 1, 8, 15, and 22 followed by 5-FU 500 mg/m2 IV bolus on Days 1, 8, 15, and 22 every 6 weeks

COMBINATION REGIMEN 2:
180 mg/m2 IV over 90 minutes on Days 1, 15, and 29 with LV 200 mg/m2 IV over 2 hours on Days 1, 2, 15, 16, 29, and 30 followed by 5-FU 400 mg/m2 IV bolus on Days 1, 2, 15, 16, 29, and 30 and 5-FU 600 mg/m2 IV over 22 hours on Days 1, 2, 15, 16, 29, 30 (NOTE: 5-FU IV follows 5-FU bolus)

SINGLE AGENT REGIMEN 1:
125 mg/m2 IV over 90 minutes on Days 1, 8, 15, and 22 then 2-week rest

SINGLE AGENT REGIMEN 2:
350 mg/m2 IV over 90 minutes on Day 1 every 3 weeks

Comments:

• It is recommended that patients receive premedication with antiemetics (e.g., 10 mg dexamethasone given in conjunction with another antiemetic agent, such as a 5-HT 3 blocker [e.g., ondansetron or granisetron]).
• Antiemetic agents should be given at least 30 minutes before this drug.
• Physicians should consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.
• A similar antiemetic regimen should be used with combination therapy.
• Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

Uses:

• First-line therapy in combination with 5-fluorouracil (5-fu) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum
• Patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy

Renal Dose Adjustments

Caution recommended.

Liver Dose Adjustments

Caution recommended.

Dose Adjustments

DOSE REGIMEN MODIFICATIONS FOR COMBINATION REGIMEN 1:
IRINOTECAN:

• Starting dose: 125 mg/m2
• Adjusted dose level -1: 100 mg/m2
• Adjusted dose level -2: 75 mg/m2

LV:

• Starting dose: 20 mg/m2
• Adjusted dose level -1: 20 mg/m2
• Adjusted dose level -2: 20 mg/m2

5FU:

• Starting dose: 500 mg/m2
• Adjusted dose level -1: 400 mg/m2
• Adjusted dose level -2: 300 mg/m2

NOTE: Dose beyond dose level -2 by decrements of about 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

DOSE REGIMEN MODIFICATIONS FOR COMBINATION REGIMEN 2:
IRINOTECAN:

• Starting dose: 180 mg/m2
• Adjusted dose level -1: 150 mg/m2
• Adjusted dose level -2: 120 mg/m2

LV:

• Starting dose: 200 mg/m2
• Adjusted dose level -1: 200 mg/m2
• Adjusted dose level -2: 200 mg/m2

5FU bolus:

• Starting dose: 400 mg/m2
• Adjusted dose level -1: 320 mg/m2
• Adjusted dose level -2: 240 mg/m2

5FU IV (NOTE: 5-FU IV follows 5-FU bolus):

• Starting dose: 600 mg/m2
• Adjusted dose level -1: 480 mg/m2
• Adjusted dose level -2: 360 mg/m2

NOTE: Dose beyond dose level -2 by decrements of about 20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

RECOMMENDED DOSE MODIFICATIONS FOR IRINOTECAN HYDROCHLORIDE INJECTION /5-FLUOROURACIL (5-FU)/LEUCOVORIN (LV) COMBINATION SCHEDULES:

• Patients 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 granulocyte count has recovered to 1500/mm 3 or greater and the platelet count has recovered to 100,000/mm 3 or greater and treatment-related diarrhea is fully resolved.
• Therapy should be delayed 1 to 2 weeks to allow for recovery from therapy-related toxicities.
• If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy.

NEUTROPENIA:

• No toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 1 dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less then decrease by 1 dose level during a cycle of therapy; decrease 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less then decrease by 2 dose levels during a cycle of therapy; decrease 2 dose levels at the start of subsequent cycles relative to the starting dose used in the previous cycle.

NEUTROPENIC FEVER:

• Omit dose until resolved then decrease 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 the same as recommended for neutropenia.

DIARRHEA:

• Two to 3 stools/day greater than pretreatment: Delay dose until resolved to baseline, then give same dose; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 1 dose level; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 1 dose level; decrease by 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to baseline, then decrease by 2 dose levels; decrease by 2 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.

OTHER NONHEMATOLOGIC TOXICITIES (excluding alopecia, anorexia, asthenia):

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Omit dose until resolved to Grade 1 or less then decrease by 1 dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less then decrease by 1 dose level during a cycle of therapy; decrease by 1 dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less then decrease by 2 dose levels during a cycle of therapy; decrease by 2 dose levels at the start of subsequent cycles relative to the starting dose used in the previous cycle.

* For mucositis/stomatitis decrease only 5-FU, not irinotecan during a cycle of therapy.
* For mucositis/stomatitis decrease only 5-FU, not irinotecan at the start of subsequent cycles relative to the starting dose used in the previous cycle.

DOSE REGIMEN MODIFICATIONS FOR SINGLE AGENT REGIMEN 1:
IRINOTECAN:

• Starting dose: 125 mg/m2
• Adjusted dose level -1: 100 mg/m2
• Adjusted dose level -2: 75 mg/m2

NOTE: Subsequent doses may be adjusted to as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg increments depending on individual patient tolerance. Provided intolerable toxicity does not develop, therapy with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

DOSE REGIMEN MODIFICATIONS FOR SINGLE AGENT REGIMEN 2:
IRINOTECAN:

• Starting dose: 350 mg/m2
• Adjusted dose level -1: 300 mg/m2
• Adjusted dose level -2: 250 mg/m2

NOTE: Subsequent doses may be adjusted to as low as 200 mg/m2 in 50 mg/m2 decrements depending on individual patient tolerance. Provided intolerable toxicity does not develop, therapy with additional cycles may be continued indefinitely if patients continue to experience clinical benefit.

RECOMMENDED DOSE MODIFICATIONS FOR SINGLE-AGENT SCHEDULES:

• A new cycle of therapy should not begin until the granulocyte count has recovered to 1500/mm3 or greater and the platelet count has recovered to 100,000/mm3 or greater and therapy-related diarrhea is fully resolved.
• Therapy should be delayed 1 to 2 weeks to allow for recovery from therapy-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing this drug.

NEUTROPENIA:
Weekly Schedule:

• No toxicity: Maintain dose level during a cycle of therapy; increase by 25 mg/m2 up to a maximum dose of 150 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less then decrease by 50 mg/m2; decrease 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• No toxicity: Maintain dose level during a cycle of therapy; increase by 25 mg/m2 up to a maximum dose of 150 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1500 to 1999/mm3: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 1000 to 1499/mm3: Decrease by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils 500 to 999/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Neutrophils less than 500/mm3: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2; decrease by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

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 the same as recommended for neutropenia.

DIARRHEA:
Weekly Schedule:

• Two to 3 stools/day greater than pretreatment: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Decrease dose by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• Two to 3 stools/day greater than pretreatment: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Four to 6 stools/day greater than pretreatment: Decrease dose by 25 mg/m2 during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Seven to 9 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Greater than 10 stools/day greater than pretreatment: Omit dose until resolved to Grade 2 or less, then decrease dose by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

OTHER NONHEMATOLOGIC TOXICITIES (excluding alopecia, anorexia, asthenia):
Weekly Schedule:

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2 during a cycle of therapy; decrease dose by 25 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less then decrease by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

Once Every Three Weeks Schedule:

• First toxicity: Maintain dose level during a cycle of therapy; maintain dose level at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Second toxicity: Decrease dose by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Third toxicity: Omit dose until resolved to Grade 2 or less then decrease by 25 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.
• Fourth toxicity: Omit dose until resolved to Grade 2 or less then decrease by 50 mg/m2 during a cycle of therapy; decrease dose by 50 mg/m2 at the start of subsequent cycles relative to the starting dose used in the previous cycle.

DOSE 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 should be considered for patients known to be homozygous for the UGT1A1 *28 allele; 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 therapy.

Precautions

US BOXED WARNINGS:
DIARRHEA:

• 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 with loperamide.

Recommendations:

• Monitor patients with diarrhea and give fluid and electrolytes as needed.
• Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia.
• Withhold therapy and reduce subsequent doses if severe diarrhea occurs.

MYELOSUPPRESSION:

• Severe myelosuppression may occur.

CONTRAINDICATIONS:

• Hypersensitivity to the active component or any of the ingredients

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Not recommended.

Other Comments

Administration advice:

• All patients should be premedicated prior to infusing this drug.
• Care should be taken to avoid extravasation, and the infusion site should be monitored for inflammation.
• If extravasation occurs, flush the site with sterile water and apply ice.

Storage requirements:

• Store unused product at 20C to 25C (68F to 77F).
• Protect from light.
• Keep the vial in the carton until the time of use.

Reconstitution/preparation techniques:

• Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.
• This drug is intended for single use only and any unused portion should be discarded.
• This drug should be diluted prior to infusion with 5% dextrose (preferred) or 0.9% sodium chloride Injection.
• Other drugs should not be added to the infusion solution.
• The manufacturer product information should be consulted for reconstitution directions.

IV compatibility:

• Dextrose 5%
• Sodium chloride 0.9%

Patient advice:

• This drug causes GI complications, such as nausea, vomiting, abdominal cramping, and diarrhea. You should have loperamide available to begin treatment for late diarrhea (generally occurring more than 24 hours after therapy). Begin loperamide at the first episode of loose stools or the earliest onset of bowel movements more frequent than normal.
• Contact your physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.
• This drug can cause dizziness or visual disturbances which may occur within 24 hours following administration.
• Monitor your temperature frequently and immediately report any occurrence of fever or infection.
• This drug may cause fetal harm. Avoid becoming pregnant while receiving this drug.
• This drug can cause alopecia.