Irinotecan
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Boxed warning
WARNING: DIARRHEA and MYELOSUPPRESSION • 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 promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . • Severe myelosuppression may occur [see Warnings and Precautions (5.2) ] .
WARNING: DIARRHEA and MYELOSUPPRESSION See full prescribing information for complete boxed warning . • 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 promptly with loperamide. Monitor patients with diarrhea and give fluid and electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe neutropenia. Interrupt CAMPTOSAR and reduce subsequent doses if severe diarrhea occurs. ( 2.2 , 5.1 ) • Severe myelosuppression may occur. ( 5.2 )
Handling and access
NIOSH hazardous drug
Table 1NIOSH lists irinotecan as a hazardous drug. AHFS class: 10:00 antineoplastic agents.
- The package insert includes manufacturer's special handling information (MSHI). Follow it when preparing, administering, and disposing of this drug.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Renal Impairment The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. CAMPTOSAR is not recommended for use in patients on dialysis.
Dosing in liver impairment
Hepatic Impairment Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations.
Therefore, use caution when administering CAMPTOSAR to patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made [see Dosage and Administration , Warnings and Precautions and Clinical Pharmacology ] .
Preparation and administration
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Colorectal Cancer Combination Regimens 1 and 2 Administer CAMPTOSAR as a 90-minute intravenous infusion followed by LV and 5-FU. The currently recommended regimens are shown in Table 1. 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. [See table below.] Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients [see Warnings and Precautions , Use in Specific Populations and Clinical Pharmacology ] .
Dose Modifications Based on recommended dose levels described in Table 1, Combination Regimens of CAMPTOSAR and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Combination Regimens. All dose modifications should be based on the worst preceding toxicity. [See table below.]
Colorectal Single Agent Regimens 1 and 2 Administer CAMPTOSAR as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3. 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. [See table below.] Dose Modifications Based on recommended dose-levels described in Table 3, Single-Agent Regimens of CAMPTOSAR and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules.
All dose modifications should be based on the worst preceding toxicity. [See table below.] 4 (<500/mm 3 ) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Neutropenic fever Omit dose until resolved, then ↓ 50 mg/m 2 when resolved ↓ 50 mg/m 2 ↓ 50 mg/m 2 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 Pretreatment ) Maintain dose level Maintain dose level Maintain dose level 2 (4–6 stools/day > pretx) ↓ 25 mg/m 2 Maintain dose level Maintain dose level 3 (7–9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2 Other nonhematologic Excludes alopecia, anorexia, asthenia toxicities 1 Maintain dose level Maintain dose level Maintain dose level 2 ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m 2 ↓ 25 mg/m 2 ↓ 50 mg/m 2 4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m 2 ↓ 50 mg/m 2 ↓ 50 mg/m 2
Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe. CAMPTOSAR Injection 20 mg/mL is intended for single use only and any unused portion should be discarded. CAMPTOSAR Injection must be diluted prior to infusion using aseptic technique.
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 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution. Prepare the infusion solution immediately prior to use and commence infusion as soon as possible after preparation.
If visible particulates are present in the infusion solution discard. If it is not possible to use the infusion solution immediately, the infusion solution may be stored for up to 24 hours at 2 °C to 8 °C or discarded.
Extravasation Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.
| Regimen 1 6-wk cycle with bolus 5-FU/LV (next cycle begins on day 43) | CAMPTOSAR LV 5-FU | 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 20 mg/m2 intravenous injection bolus, days 1,8,15,22 500 mg/m2 intravenous injection bolus, days 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 | 180 mg/m2 intravenous infusion over 90 minutes, days 1,15,29 | ||
| LV | 200 mg/m2 intravenous infusion over 2 hours, days 1,2,15,16,29,30 | |||
| 5-FU Bolus | 400 mg/m2 intravenous injection bolus, days 1,2,15,16,29,30 | |||
| 5-FU InfusionInfusion follows bolus administration. | 600 mg/m2 intravenous infusion over 22 hours, days 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 | |
| Regimen 1 (weekly)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. | 125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest | ||
| Starting Dose and Modified Dose LevelsProvided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. (mg/m2) | |||
| Starting Dose | Dose Level -1 | Dose Level -2 | |
| 125 | 100 | 75 | |
| Regimen 2 (every 3 weeks)Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. | 350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeks | ||
| Starting Dose and Modified Dose Levels (mg/m2) | |||
| Starting Dose | Dose Level -1 | Dose Level -2 | |
| 350 | 300 | 250 | |
Drug interactions
Check irinotecan against a medication listLabel text (5 paragraphs)
7 DRUG INTERACTIONS • Strong CYP3A4 Inducers: Do not administer strong CYP3A4 inducers with CAMPTOSAR. ( 7.2 ) • Strong CYP3A4 Inhibitors: Do not administer strong CYP3A4 inhibitors with CAMPTOSAR. ( 7.3 ) 7.1 5-Fluorouracil (5-FU) and Leucovorin (LV) In a phase 1 clinical study involving irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition of irinotecan was not substantially altered when the drugs were co-administered.
Although the C max and AUC 0–24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed by 5-FU and LV administration compared with when irinotecan was given alone, this sequence of administration was used in the combination trials and is recommended [see Dosage and Administration (2) ] . Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted.
7.2 Strong CYP3A4 Inducers Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital, carbamazepine, or St. John's wort. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of CAMPTOSAR therapy. Do not administer strong CYP3A4 inducers with CAMPTOSAR unless there are no therapeutic alternatives.
7.3 Strong CYP3A4 or UGT1A1 Inhibitors Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), respectively, [see Clinical Pharmacology (12.3) ] . Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38.
Coadministration of CAMPTOSAR with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting CAMPTOSAR therapy. Do not administer strong CYP3A4 or UGT1A1 inhibitors with CAMPTOSAR unless there are no therapeutic alternatives.
Contraindications
4 CONTRAINDICATIONS • CAMPTOSAR Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients. • Hypersensitivity to CAMPTOSAR or its excipients ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
LiverTox has no chapter for irinotecan. Check the label's hepatic warnings.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, CAMPTOSAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Available postmarketing and published data reporting the use of CAMPTOSAR in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In animal studies, intravenous administration of irinotecan to rats and rabbits during the period of organogenesis resulted in embryofetal mortality and teratogenicity in pregnant animals at exposures lower than the human exposure based on AUC at the clinical dose of 125 mg/m 2 ( see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Radioactivity related to 14 C-irinotecan crosses the placenta of rats following intravenous administration.
Intravenous administration of irinotecan to rats at a dose of 6 mg/kg/day (approximately 0.2 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses; at doses ≥ 1.2 mg/kg/day (approximately 0.03 times the clinical exposure (AUC) at the 125 mg/m 2 dose based on exposure data from a separate rat study) there were increases in a variety of external, visceral, and skeletal abnormalities.
Administration of irinotecan to pregnant rabbits at a dose of 6 mg/kg (approximately half of the clinical dose of 125 mg/m 2 based on BSA) resulted in similar findings to those in rats, with increased post-implantation loss, decreased live fetuses, and increased external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.
Breastfeeding (LactMed)
Limited data indicate that irinotecan is found in breastmilk for 2 days and its active metabolite is found in breastmilk for up to a week after a dose of 60 mg/square meter, although the highest amounts occur during the first 4 days after a dose. Higher maternal doses have not been studied and the oral absorption and toxicity in breastfed infants are not known. Based on this limited evidence, it appears that breastfeeding should be avoided for at least a week after a dose of irinotecan 60 mg/square meter. Higher dosages probably require a longer abstinence period. Some authors recommend discontinuing breastfeeding during irinotecan therapy. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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