Irinotecan Dosage

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Usual Adult Dose for:

Additional dosage information:

Usual Adult Dose for Colorectal Cancer

Either as a single agent or in combination with fluorouracil and leucovorin:
125 mg/m2 intravenously over 90 minutes once a week for four doses

or

as a single agent:
350 mg/m2 intravenously over 90 minutes every three weeks

or

in combination with fluorouracil and leucovorin:
180 mg/m2 intravenously over 90 minutes every other week for three doses.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Use of irinotecan for the treatment of patients with significant liver dysfunction has not been established.

Dose Adjustments

Subsequent doses of irinotecan 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 to treatment. Provided intolerable toxicity does not develop, treatment with additional courses of therapy may be continued indefinitely in patients who attain a response or in patients whose disease remains stable. Patients should be carefully monitored for toxicity.

* Recommended dose modifications for single agent regimens:

If there is no toxicity during a cycle of therapy, the dosage level should be maintained during the cycle of therapy. The weekly dosage level may be increased by 25 mg/m2 (up to a maximum dose of 150 mg/m2). The once every 3 week dosage level should be maintained.

Neutropenia:
NCI Grade 1 - If the neutrophil count is between 1500 and 1999/mm3, the dosage level should be maintained during the cycle of therapy. Both the weekly dosage level and the once every 3 week dosage level should be maintained.
NCI Grade 2 - If the neutrophil count is between 1000 and 1499/mm3, the dosage level should be decreased by 25 mg/m2 during the cycle of therapy. Both the weekly dosage level and the once every 3 week dosage level should be maintained.
NCI Grade 3 - If the neutrophil count is between 500 and 999/mm3, the dosage level should be omitted until the neutropenia resolves to less than or equal to grade 2, then the dosage level should be decreased by 25 mg/m2. At the start of the next weekly dosing regimen, the dosage level should be decreased by 25 mg/m2. At the start of the next every 3 week dose regimen, the dosage level should be decreased by 50 mg/m2.
NCI Grade 4 - If the neutrophil count is less than 500/mm3, the dose should be omitted until the neutropenia resolves to less than or equal to grade 2, then the dosage level should be decreased by 50 mg/m2. At the start of the next weekly or every 3 week dose regimen, the dosage level should be decreased by 50 mg/m2.

Neutropenic Fever: The dose should be omitted until the neutropenic fever resolves, then the dosage level should be decreased by 50 mg/m2. At the start of the next weekly or every 3 week dose regimen, the dosage level should be decreased by 50 mg/m2.

Other hematologic toxicities: Dose modifications for leukopenia, thrombocytopenia, and anemia during a course 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:
NCI Grade 1 - If the patient has 2 to 3 stools a day more than before the start of therapy, the dose level should be maintained during the cycle of therapy. Both the weekly dosing regimen and the once every 3 week dosage levels should be maintained.
NCI Grade 2 - If the patient has 4 to 6 stools a day more than before the start of therapy, the dose level should be decreased by 25 mg/m2 during the cycle of therapy. Both the weekly dosing regimen and the once every 3 week dosage levels should be maintained.
NCI Grade 3 - If the patient has 7 to 9 stools a day more than before the start of therapy, the dose should be omitted until the diarrhea resolves to less than or equal to grade 2, then the dose should be decreased by 25 mg/m2. At the start of the next weekly dosing regimen, the dose should be decreased by 25 mg/m2. At the start of the next every 3 week dose regimen, the dose should be decreased by 50 mg/m2.
NCI Grade 4 - If the patient has 10 or more stools a day more than before the start of therapy, the dose should be omitted until the diarrhea resolves to less than or equal to grade 2, then the dose should be decreased by 50 mg/m2. At the start of the next weekly or every 3 week dose regimen, the dose should be decreased by 50 mg/m2.

Other Nonhematologic Toxicities:
NCI Grade 1 - The dose level should be maintained during the cycle of therapy. Both the weekly dosing regimen and the once every 3 week dosage levels should be maintained.
NCI Grade 2 - The dose level should be decreased by 25 mg/m2 during the cycle of therapy. Both the weekly dosing regimen and the once every 3 week dosage levels should be maintained.
NCI Grade 3 - The dose should be omitted until the nonhematologic toxicities resolves to less than or equal to grade 2, then the dose should be decreased by 25 mg/m2. At the start of the next weekly dosing regimen, the dose should be decreased by 25 mg/m2. At the start of the next every 3 week dose regimen, the dose should be decreased by 50 mg/m2.
NCI Grade 4 - The dose should be omitted until the nonhematologic toxicities resolves to less than or equal to grade 2, then the dose should be decreased by 50 mg/m2. At the start of the next weekly or every 3 week dose regimen, the dose should be decreased by 50 mg/m2.

(End of recommended dose modifications for single agent regimens)

* Recommended dose modifications for use in combination regimens with fluorouracil and leucovorin:
At a starting dose of 125 mg/m2, dose level 1 is defined as 100 mg/m2 and dose level 2 is defined as 75 mg/m2.
At a starting dose of 180 mg/m2, dose level 1 is defined as 150 mg/m2 and dose level 2 is defined as 120 mg/m2.

If there is no toxicity during a cycle of therapy, the dose level should be maintained during the cycle of therapy. At the start of subsequent cycles of therapy, the dosage level should be maintained.

Neutropenia:
NCI Grade 1 - If the neutrophil count is between 1500 and 1999/mm3, the dose level should be maintained during the cycle of therapy. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 2 - If the neutrophil count is between 1000 and 1499/mm3, the dose should be decreased by one dose level during the cycle of therapy. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 3 - If the neutrophil count is between 500 and 999/mm3, the dose should be omitted until the neutropenia resolves to less than or equal to grade 2, then the dose should be decreased by one dose level during the cycle of therapy. At the start of subsequent cycles of therapy, the dose should be decreased by one dose level.
NCI Grade 4 - If the neutrophil count is less than 500/mm3, the dose should be omitted until the neutropenia resolves to less than or equal to grade 2, then the dose should be decreased by two dose levels. At the start of subsequent cycles of therapy, the dose should be decreased by two dose levels.

Neutropenic Fever: The dose should be omitted until the neutropenic fever resolves, then the dose should be decreased by two dose levels.

Other hematologic toxicities: Dose modifications for leukopenia or thrombocytopenia during a course 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:
NCI Grade 1 - If the patient has 2 to 3 stools a day more than before the start of therapy, the dose should be delayed until resolved to baseline, then the same dose should be given. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 2 - If the patient has 4 to 6 stools a day more than before the start of therapy, the dose level should be omitted until resolved to baseline, then decreased by one dose level. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 3 - If the patient has 7 to 9 stools a day more than before the start of therapy, the dose level should be omitted until resolved to baseline, then decreased by one dose level. At the start of subsequent cycles of therapy, the dosage level should be decreased by one dose level.
NCI Grade 4 - If the patient has 10 or more stools a day more than before the start of therapy, the dose should be omitted until resolved to baseline, then decreased by two dose levels. At the start of subsequent cycles of therapy, the dosage level should be decreased by two dose levels.

Other Nonhematologic Toxicities:
NCI Grade 1 - The dose level should be maintained during the cycle of therapy. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 2 - The dose level should be omitted until the toxicity resolves to grade 1 or less, then decrease one dose level. At the start of subsequent cycles of therapy, the dosage level should be maintained.
NCI Grade 3 - The dose level should be omitted until the toxicity resolves to grade 2 or less, then decrease one dose level. At the start of subsequent cycles of therapy, the dosage level should be decreased one dose level.
NCI Grade 4 - The dose level should be omitted until the toxicity resolves to grade 2 or less, then decrease two dose levels. At the start of subsequent cycles of therapy, the dosage level should be decreased two dose levels.

(End of recommended dose modifications for use in combination with fluorouracil and leucovorin.)

A new cycle of therapy should not begin until the granulocyte count has recovered to 1500/mm3 or greater, the platelet count has recovered to 100,000/mm3 or greater and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 to allow for recovery from treatment-related toxicity. If the patient has not recovered after a 2 week delay, discontinuation of irinotecan should be considered.

Precautions

Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following the initiation of irinotecan treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele. Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia. However, clinical results have been variable and such patients have been shown to tolerate normal starting doses.

Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan. Administration of irinotecan with radiation therapy has not been adequately studied and is not recommended.

Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at a greater risk of myelosuppression when receiving therapy with irinotecan.

The effectiveness of irinotecan in pediatric patients (less than 18 years of age) has not been established.

Dialysis

Data not available

Other Comments

Patients should receive premedication with antiemetic agents. In clinical studies, the majority of patients received 10 mg of dexamethasone with another type of antiemetic (such as one of the 5-HT3 blockers, ondansetron or granisetron. Antiemetics should be administered on the day of treatment, starting at least 30 minutes before administration of irinotecan. Physicians should also consider providing patients with an antiemetic regimen (e.g. prochlorperazine) for subsequent use as needed.

At the first indication that a patient is experiencing difficulty with diaphoresis, lacrimation, abdominal cramping or similar cholinergic symptoms, clinicians may consider intravenous administration of atropine at a dose of up to 1 mg. While routine prophylaxis with atropine is not recommended, if a patient experiences a cholinergic reaction during an infusion, prophylaxis may be considered for subsequent doses of irinotecan.

Severe diarrhea may develop during treatment with irinotecan. Patients should be warned to avoid laxative administration unless they have consulted a physician specifically regarding the symptoms prompting them to consider laxative use. For patients requiring laxatives for constipation associated with narcotic administration, the standard regimen may be continued under supervision of the clinician. However, the patient must be educated to contact the clinician with any change in bowel habits so that adjustments or discontinuation of laxative doses may be made promptly.

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