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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(eye rye no TEE kan)

Generic Available (U.S.)

Yes

Index Terms

• Camptothecin-11
• CPT-11
• Irinotecan HCl
• Irinotecan Hydrochloride

Brand Names: U.S.

• Camptosar®

Brand Names: Canada

• Camptosar®
• Irinotecan Hydrochloride Trihydrate

Pharmacologic Category

• Antineoplastic Agent, Camptothecin
• Antineoplastic Agent, Natural Source (Plant) Derivative
• Antineoplastic Agent, Topoisomerase I Inhibitor

Pharmacologic Category Synonyms

• Chemotherapy Agent, Camptothecin
• Chemotherapy Agent, Natural Source (Plant) Derivative
• Natural Source (Plant) Derivative Antineoplastic Agent

Use: Labeled Indications

Treatment of metastatic carcinoma of the colon or rectum

Use: Unlabeled

Treatment of cervical cancer (recurrent or metastatic), central nervous system tumors (recurrent glioblastoma), esophageal cancer, Ewing's sarcoma (recurrent or progressive), gastric cancer (metastatic or locally advanced), nonsmall cell lung cancer (advanced), ovarian cancer (recurrent), pancreatic cancer (advanced), small cell lung cancer (extensive stage)

Pregnancy Risk Factor

D

Pregnancy Considerations

Teratogenic effects were noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant while receiving treatment.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.

Contraindications

Hypersensitivity to irinotecan or any component of the formulation

Warnings/Precautions

Boxed warnings:

• Bone marrow suppression: See “Concerns related to adverse effects” below.

• Diarrhea: See “Concerns related to adverse effects” below.

• Experienced physician: See “Other warnings/precautions” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warning]: May cause severe myelosuppression. Deaths due to sepsis following severe neutropenia have been reported. Complications due to neutropenia should be promptly managed with antibiotics. Therapy should be temporarily discontinued if neutropenic fever occurs or if the absolute neutrophil count is <1000/mm³. The dose of irinotecan should be reduced if there is a clinically significant decrease in the total WBC (<200/mm³), neutrophil count (<1500/mm³), hemoglobin (<8 g/dL), or platelet count (<100,000/mm³). Routine administration of a colony-stimulating factor is generally not necessary, but may be considered for patients experiencing significant neutropenia.

• Colitis: Colitis, complicated by ulceration, bleeding, ileus, and infection has been reported. Initiate antibiotics promptly in patients with ileus.

• Diarrhea: [U.S. Boxed Warning]: Severe diarrhea may be dose-limiting and potentially fatal; early-onset and late-onset diarrhea may occur. Early diarrhea occurs during or within 24 hours of receiving irinotecan and is characterized by cholinergic symptoms (eg, increased salivation, diaphoresis, flushing, abdominal cramping, lacrimation); may be prevented or treated with atropine. Late diarrhea occurs more than 24 hours after treatment which may lead to dehydration, electrolyte imbalance, or sepsis; may be life-threatening and should be promptly treated with loperamide. Dose reductions may be recommended for future doses within the current cycle. Antibiotics may be necessary if patient develops ileus, fever, or severe neutropenia. Patients with diarrhea should be carefully monitored and treated promptly; may require fluid and electrolyte therapy.

• Hypersensitivity reactions: Severe hypersensitivity reactions (including anaphylaxis) have occurred.

• Pulmonary toxicity: Fatal cases of interstitial pulmonary disease (IPD)-like events have been reported with single-agent and combination therapy. Promptly evaluate changes in baseline pulmonary symptoms or any new-onset pulmonary symptoms. Discontinue therapy if IPD is diagnosed.

• Renal toxicity: Renal impairment and acute renal failure have been reported, possibly due to dehydration secondary to diarrhea. Use with caution in patients with renal impairment; not recommended in patients on dialysis.

Disease-related concerns:

• Bowel obstruction: Patients with bowel obstruction should not be treated with irinotecan until resolution of obstruction.

• Hepatic impairment: Use with caution in patients with hepatic impairment; exposure to the active metabolite (SN-38) is increased; toxicities may be increased. Patients with even modest elevations in total serum bilirubin levels (1-2 mg/dL) have a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were <1 mg/dL. Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk of myelosuppression when receiving therapy with irinotecan. Use caution when treating patients with known hepatic dysfunction or hyperbilirubinemia; dosage adjustments should be considered.

Concurrent drug therapy issues:

• CYP-mediated drug interactions: High potential for CYP-mediated drug interactions. Enzyme inducers may decrease exposure to irinotecan and SN-38 (active metabolite); enzyme inhibitors may increase exposure. For use in patients with CNS tumors (unlabeled use), selection of antiseizure medications which are not enzyme inducers is preferred.

• Immunization: Avoid vaccination with live vaccines during treatment (risk of infection may be increased due to immunosuppression). Although the response to vaccines may be diminished, inactivated vaccines may be administered during treatment.

Special populations:

• Elderly: Use with caution in elderly patients with comorbid conditions, or baseline performance status of 2; close monitoring and dosage adjustments are recommended.

• Patients homozygous/heterozygous for the UGT1A1*28 allele: Patients homozygous for the UGT1A1*28 allele are at increased risk of neutropenia; initial one-level dose reduction should be considered for both single-agent and combination regimens. Heterozygous carriers of the UGT1A1*28 allele may also be at increased risk; however, most patients have tolerated normal starting doses.

• Pelvic/abdominal radiation recipients: Use with caution in patients who have previously received pelvic/abdominal radiation.

Dosage form specific issues:

• Sorbitol: Product contains sorbitol; do not use in patients with hereditary fructose intolerance.

Other warnings/precautions:

• Appropriate use: Except as part of a clinical trial, use in combination with the fluorouracil and leucovorin “Mayo Clinic” regimen is not recommended. Increased toxicity has also been noted in patients with a baseline performance status of 2 in other combination regimens containing irinotecan, leucovorin, and fluorouracil.

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Extravasation: For I.V. use only; monitor infusion site; may cause local tissue necrosis or thrombophlebitis if extravasation occurs.

Adverse Reactions

Frequency of adverse reactions reported for single-agent use of irinotecan only.

>10%:

Cardiovascular: Vasodilation (9% to 11%)

Central nervous system: Cholinergic toxicity (47% - includes rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis); fever (44% to 45%), pain (23% to 24%), dizziness (15% to 21%), insomnia (19%), headache (17%), chills (14%)

Dermatologic: Alopecia (46% to 72%), rash (13% to 14%)

Endocrine & metabolic: Dehydration (15%)

Gastrointestinal: Diarrhea, late (83% to 88%; grade 3/4: 14% to 31%), diarrhea, early (43% to 51%; grade 3/4: 7% to 22%), nausea (70% to 86%), abdominal pain (57% to 68%), vomiting (62% to 67%), cramps (57%), anorexia (44% to 55%), constipation (30% to 32%), mucositis (30%), weight loss (30%), flatulence (12%), stomatitis (12%)

Hematologic: Anemia (60% to 97%; grades 3/4: 5% to 7%), leukopenia (63% to 96%, grades 3/4: 14% to 28%), thrombocytopenia (96%, grades 3/4: 1% to 4%), neutropenia (30% to 96%; grades 3/4: 14% to 31%)

Hepatic: Bilirubin increased (84%), alkaline phosphatase increased (13%)

Neuromuscular & skeletal: Weakness (69% to 76%), back pain (14%)

Respiratory: Dyspnea (22%), cough (17% to 20%), rhinitis (16%)

Miscellaneous: Diaphoresis (16%), infection (14%)

1% to 10%:

Cardiovascular: Edema (10%), hypotension (6%), thromboembolic events (5%)

Central nervous system: Somnolence (9%), confusion (3%)

Gastrointestinal: Abdominal fullness (10%), dyspepsia (10%)

Hematologic: Neutropenic fever (grades 3/4: 2% to 6%), hemorrhage (grades 3/4: 1% to 5%), neutropenic infection (grades 3/4: 1% to 2%)

Hepatic: AST increased (10%), ascites and/or jaundice (grades 3/4: 9%)

Respiratory: Pneumonia (4%)

<1%, postmarketing, and/or case reports: ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, arterial thrombosis, bleeding, bradycardia, cardiac arrest, cerebral infarct, cerebrovascular accident, circulatory failure, colitis, deep thrombophlebitis, dysarthria, dysrhythmia, embolus, gastrointestinal bleeding, gastrointestinal obstruction, hepatomegaly, hiccups, hyperglycemia, hypersensitivity, hyponatremia, ileus, interstitial lung disease, intestinal perforation, ischemic colitis, lipase increased, lymphocytopenia, megacolon, MI, muscle cramps, myocardial ischemia, neutropenic typhlitis, pancreatitis, paresthesia, peripheral vascular disorder, pulmonary embolus; pulmonary toxicity (dyspnea, fever, reticulonodular infiltrates on chest x-ray); renal failure (acute), renal impairment, syncope, thrombocytopenia (immune mediated), thrombophlebitis, thrombosis, typhlitis, ulceration, ulcerative colitis, vertigo

Note: In limited pediatric experience, dehydration (often associated with severe hypokalemia and hyponatremia) was among the most significant grade 3/4 adverse events, with a frequency up to 29%. In addition, grade 3/4 infection was reported in 24%.

Metabolism/Transport Effects

Substrate of CYP2B6 (major), CYP3A4 (major), P-glycoprotein, SLCO1B1, UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Irinotecan. Risk D: Consider therapy modification

Atazanavir: May increase the serum concentration of Irinotecan. The metabolism (via glucuronidation) of the active SN-38 metabolite may be primarily impacted by this interaction. Risk X: Avoid combination

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Bevacizumab: May enhance the adverse/toxic effect of Irinotecan. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Irinotecan. Concentrations of the active metabolite SN-38 may also be reduced. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with carbamazepine, but specific dosing guidelines are not available. Risk D: Consider therapy modification

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination

Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

CYP2B6 Inducers (Strong): May increase the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy

CYP2B6 Inhibitors (Moderate): May decrease the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy

CYP2B6 Inhibitors (Strong): May decrease the metabolism of CYP2B6 Substrates. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Irinotecan. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with phenytoin, but specific dosing guidelines are not available. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

PHENobarbital: May decrease the serum concentration of Irinotecan. Concentrations of the active metabolite SN-38 may also be reduced. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with phenobarbital, but specific dosing guidelines are not available. Risk D: Consider therapy modification

Phenytoin: May decrease the serum concentration of Irinotecan. Concentrations of the active metabolite SN-38 may also be reduced. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with phenytoin, but specific dosing guidelines are not available. Risk D: Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Quazepam: May increase the serum concentration of CYP2B6 Substrates. Risk C: Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy

SORAfenib: May increase the serum concentration of Irinotecan. Sorafenib may also increase the concentration of the active metabolite of irinotecan, SN-38. Risk C: Monitor therapy

St Johns Wort: May diminish the therapeutic effect of Irinotecan. Risk X: Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid St John's wort (decreases the efficacy of irinotecan).

Storage

Store intact vials of injection at room temperature. Protect from light. Solutions diluted in NS may precipitate if refrigerated. Solutions diluted in D₅W are stable for 24 hours at room temperature or 48 hours under refrigeration at 2°C to 8°C, although the manufacturer recommends use within 6 hours at room temperature and 24 hours if refrigerated. Do not freeze.

Reconstitution

Use appropriate precautions for handling and disposal. Dilute in 250-500 mL D₅W or NS to a final concentration of 0.12-2.8 mg/mL. Due to the relatively acidic pH, irinotecan appears to be more stable in D₅W than NS.

Compatibility

Stable in D₅W, NS.

Y-site administration: Compatible: Leucovorin calcium, oxaliplatin, palonosetron. Incompatible: Gemcitabine, pemetrexed.

Mechanism of Action

Irinotecan and its active metabolite (SN-38) bind reversibly to topoisomerase I-DNA complex preventing religation of the cleaved DNA strand. This results in the accumulation of cleavable complexes and double-strand DNA breaks. As mammalian cells cannot efficiently repair these breaks, cell death consistent with S-phase cell cycle specificity occurs, leading to termination of cellular replication.

Pharmacodynamics/Kinetics

Distribution: V_d: 33-150 L/m²

Protein binding, plasma: Predominantly albumin; Irinotecan: 30% to 68%, SN-38 (active metabolite): ~95%

Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase enzymes; SN-38 undergoes conjugation by UDP- glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. Conversion of irinotecan to SN-38 is decreased and glucuronidation of SN-38 is increased patients who smoke cigarettes, resulting in lower levels of the metabolite and overall decreased systemic exposure. SN-38 is increased by UGT1A1*28 polymorphism (10% of North Americans are homozygous for UGT1A1*28 allele). The lactones of both irinotecan and SN-38 undergo hydrolysis to inactive hydroxy acid forms.

Half-life elimination: Irinotecan: 6-12 hours; SN-38: ~10-20 hours

Time to peak: SN-38: Following 90-minute infusion: ∼1 hour

Excretion: Urine: Irinotecan (11% to 20%), metabolites (SN-38 <1%, SN-38 glucuronide, 3%)

Dosage

I.V.: Note: A reduction in the starting dose by one dose level should be considered for prior pelvic/abdominal radiotherapy, performance status of 2, or known homozygosity for UGT1A1*28 allele. Consider premedication of atropine 0.25-1 mg I.V. or SubQ in patients with cholinergic symptoms (eg, increased salivation, diaphoresis, abdominal cramping) or diarrhea. Details concerning dosage in combination regimens should also be consulted.

Children and Adults: Ewing's sarcoma, recurrent or progressive (unlabeled use): 20 mg/m²/dose days 1-5 and days 8-12 every 3 weeks (in combination with temozolomide) (Casey, 2009)

Adults:

Colorectal cancer, metastatic (single-agent therapy):

Weekly regimen: 125 mg/m² over 90 minutes on days 1, 8, 15, and 22 of a 6-week treatment cycle (may adjust upward to 150 mg/m² if tolerated)

Adjusted dose level -1: 100 mg/m²

Adjusted dose level -2: 75 mg/m²

Further adjust to 50 mg/m² (in decrements of 25-50 mg/m²) if needed

Once-every-3-week regimen: 350 mg/m² over 90 minutes, once every 3 weeks

Adjusted dose level -1: 300 mg/m²

Adjusted dose level -2: 250 mg/m²

Further adjust to 200 mg/m² (in decrements of 25-50 mg/m²) if needed

Colorectal cancer, metastatic (in combination with fluorouracil and leucovorin): Six-week (42-day) cycle:

Regimen 1: 125 mg/m² over 90 minutes on days 1, 8, 15, and 22; to be given in combination with bolus leucovorin and fluorouracil (leucovorin administered immediately following irinotecan; fluorouracil immediately following leucovorin)

Adjusted dose level -1: 100 mg/m²

Adjusted dose level -2: 75 mg/m²

Further adjust if needed in decrements of ~20%

Regimen 2: 180 mg/m² over 90 minutes on days 1, 15, and 29; to be given in combination with infusional leucovorin and bolus/infusion fluorouracil (leucovorin administered immediately following irinotecan; fluorouracil immediately following leucovorin)

Adjusted dose level -1: 150 mg/m²

Adjusted dose level -2: 120 mg/m²

Further adjust if needed in decrements of ~20%

Colorectal cancer, metastatic (unlabeled dosing): FOLFOXIRI regimen: 165 mg/m² over 1 hour once every 2 weeks (Falcone, 2007)

Cervical cancer, recurrent or metastatic (unlabeled use): 125 mg/m² over 90 minutes once weekly for 4 consecutive weeks followed by a 2-week rest during each 6 week treatment cycle (Verschraegen, 1997)

CNS tumor, recurrent glioblastoma (unlabeled use): 125 mg/m² over 90 minutes once every 2 weeks (in combination with bevacizumab). NOTE: in patients taking concurrent antiepileptic enzyme-inducing medications irinotecan dose was increased to 340 mg/m² (Friedman, 2009; Vredenburgh, 2007).

Esophageal cancer, metastatic or locally advanced (unlabeled use): 65 mg/m²/dose over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) (Ajani, 2002; Ilson, 1999) or 80 mg/m²/dose weekly for 6 weeks of a 7-week treatment cycle (in combination with leucovorin and fluorouracil) (Dank, 2008) or 250 mg/m²/dose every 3 weeks (in combination with capecitabine) (Leary, 2009; Moehler, 2010)

Gastric cancer, metastatic or locally advanced (unlabeled use): 65 mg/m²/dose over 90 minutes days 1, 8, 15, and 22 of a 6-week treatment cycle (in combination with cisplatin) (Ajani, 2002) or 180 mg/m²/dose over 90 minutes every 2 weeks (in combination with leucovorin and fluorouracil) (Bouche, 2004) or 80 mg/m²/dose weekly for 6 weeks of a 7-week treatment cycle (in combination with leucovorin and fluorouracil) (Dank, 2008) or 250 mg/m²/dose every 3 weeks (in combination with capecitabine) (Moehler, 2010)

Nonsmall cell lung cancer, advanced (unlabeled use): 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin) (Ohe, 2007)

Pancreatic cancer, advanced (unlabeled use): FOLFIRINOX regimen: 180 mg/m²/dose over 90 minutes every 2 weeks (Conroy, 2005; Conroy, 2010)

Small cell lung cancer, extensive stage (unlabeled use): 60 mg/m² days 1, 8, and 15 every 4 weeks (in combination with cisplatin) (Noda, 2002) or 65 mg/m² days 1 and 8 every 3 weeks (in combination with cisplatin) (Hanna, 2006) or 175 mg/m² day 1 every 3 weeks (in combination with carboplatin) (Hermes, 2008) or 50 mg/m² days 1, 8 and 15 every 4 weeks (in combination with carboplatin) (Schmittel, 2006)

Elderly:

Weekly dosing schedule: No dosing adjustment is recommended

Every 3-week dosing colorectal cancer schedule: Recommended initial dose is 300 mg/m²/dose for patients ≥70 years

Dosing adjustment in renal impairment: Effects have not been evaluated; use caution, not recommended for use in patients on dialysis

Dosing adjustment in hepatic impairment:

Liver metastases with normal hepatic function: No adjustment required

Bilirubin >ULN to ≤2 mg/dL: Consider reducing initial dose by one dose level

Bilirubin >2 mg/dL: Use is not recommended

The following guidelines have been used by some clinicians: Bilirubin 1.5-3 mg/dL: Administer 75% of dose (Floyd, 2006)

Dosage adjustment for toxicities: It is recommended that new courses begin only after the granulocyte count recovers to ≥1500/mm³, the platelet counts recovers to ≥100,000/mm³, and treatment-related diarrhea has fully resolved. Depending on the patient's ability to tolerate therapy, doses should be adjusted in increments of 25-50 mg/m². Treatment should be delayed 1-2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consider discontinuing irinotecan. See tables.

Dosage: Combination Regimens

Brain tumors: Bevacizumab-Irinotecan (Glioblastoma)

Colorectal cancer:

Bevacizumab + FOLFIRI (Colorectal)

Cetuximab (Biweekly)-Irinotecan

Cetuximab + FOLFIRI (Colorectal)

Cetuximab-Irinotecan (Colorectal)

Fluorouracil-Leucovorin-Irinotecan (Saltz Regimen)

FOLFIRI (Colorectal Cancer)

FOLFOXIRI (Colorectal)

FU-LV-CPT-11

Panitumumab + FOLFIRI (Colorectal)

Esophageal cancer:

Irinotecan-Capecitabine (Esophageal Cancer)

Irinotecan-Cisplatin (Esophageal Cancer)

Irinotecan-Fluorouracil-Leucovorin (Esophageal Cancer)

Gastric cancer:

Irinotecan-Capecitabine (Gastric Cancer)

Irinotecan-Cisplatin (Gastric Cancer)

Irinotecan-Leucovorin-Fluorouracil (Gastric Cancer)

Lung cancer (nonsmall cell): Cisplatin-Irinotecan (NSCLC)

Lung cancer (small cell):

Carboplatin-Irinotecan (Small Cell Lung Cancer)

Cisplatin-Irinotecan (Small Cell Lung Cancer)

Pancreatic cancer: FOLFIRINOX (Pancreatic Cancer)

Sarcoma: Irinotecan-Temozolomide (Ewing's Sarcoma)

Administration: I.V.

Administer by I.V. infusion, usually over 90 minutes. Premedication with dexamethasone and a 5-HT₃ blocker is recommended 30 minutes prior to administration; prochlorperazine may be considered for subsequent use. Consider premedication of atropine 0.25-1 mg I.V. or SubQ in patients with cholinergic symptoms (eg, increased salivation, diaphoresis, abdominal cramping) or diarrhea.

The recommended regimen to manage late diarrhea is loperamide 4 mg orally at onset of late diarrhea, followed by 2 mg every 2 hours (or 4 mg every 4 hours at night) until 12 hours have passed without a bowel movement. If diarrhea recurs, then repeat administration. Loperamide should not be used for more than 48 consecutive hours.

Administration: I.V. Detail

pH: 3-3.8

Monitoring Parameters

CBC with differential, platelet count, and hemoglobin with each dose; bilirubin, electrolytes (with severe diarrhea); bowel movements and hydration status; monitor infusion site for signs of inflammation and avoid extravasation

A test is available for genotyping of UGT1A1; however, guidelines for use are not established and not recommended in patients who have experienced toxicity as a dose reduction is already recommended (NCCN Colon Cancer Guidelines v.1.2011)

Dietary Considerations

Contains sorbitol; do not use in patients with hereditary fructose intolerance.

Patient Education

This drug can only be administered by infusion. Report immediately any burning, pain, redness, or swelling at infusion site. Maintain adequate hydration, unless instructed to restrict fluid intake. May cause severe diarrhea; follow instructions for taking antidiarrheal medication (do not use antidiarrheal medication for longer than 48 consecutive hours). Report immediately if diarrhea persists or you experience signs of dehydration (eg, fainting, dizziness, lightheadedness). You may be more susceptible to infection. You may experience nausea, vomiting, or hair loss (will regrow after treatment is completed). Report immediately persistent diarrhea, unresolved nausea or vomiting, alterations in urinary pattern (increased or decreased), opportunistic infection (fever, chills, unusual bruising or bleeding, fatigue, purulent vaginal discharge, unhealed mouth sores), chest pain, or respiratory difficulty.

Additional Information

Patients who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia; a decreased dose is recommended. Clinical research of patients who are heterozygous for UGT1A1*28 have been variable for increased neutropenic risk and such patients have tolerated normal starting doses. An FDA-approved test (Invader® Molecular Assay) is available for clinical determination of UGT phenotype.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Increased salivation, mucositis, and stomatitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Dizziness and insomnia are common

Mental Health: Effects on Psychiatric Treatment

May cause myelosuppression; use caution with clozapine and carbamazepine; concurrent use with prochlorperazine has produced akathisia. Two severe (life-threatening) forms of diarrhea may occur; these effects may be additive with concurrent use of SSRIs, lithium, or valproate; use caution.

Nursing: Physical Assessment/Monitoring

Use caution and closely monitor use for patients with increased risk of neutropenia, previous pelvic or abdominal radiation, and elderly patients with comorbid conditions. Premedicate with antiemetic (emetic potential moderate). Infusion site must be monitored to prevent extravasation. Assess CBC with differential and platelet count. Monitor for neutropenia, immediate or delayed diarrhea (can be fatal), sepsis, mucositis, and/or stomatitis.

Oncology: Emetic Potential

Moderate (30% to 90%)

Oncology: Vesicant

May be an irritant

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as hydrochloride: 20 mg/mL (2 mL, 5 mL, 25 mL)

Camptosar®: 20 mg/mL (2 mL, 5 mL, 15 mL) [contains sorbitol]

References

Ajani JA, Baker J, Pisters PW, et al, “CPT-11 Plus Cisplatin in Patients With Advanced, Untreated Gastric or Gastroesophageal Junction Carcinoma: Results of a Phase II Study,” Cancer, 2002, 94(3):641-6.

Bouché O, Raoul JL, Bonnetain F, et al, “Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803,” J Clin Oncol, 2004, 22(21):4319-28.

Casey DA, Wexler LH, Merchant MS, et al, “Irinotecan and Temozolomide for Ewing Sarcoma: The Memorial Sloan-Kettering Experience,” Pediatr Blood Cancer, 2009, 53(6):1029-34.

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International Brand Names

• Campto (AT, BE, BF, BG, BJ, CH, CI, CL, CZ, DE, DK, EE, ES, ET, FI, FR, GB, GH, GM, GN, GR, HK, HN, ID, IE, IL, IT, JP, KE, KP, LR, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, PH, PK, PL, PT, RU, SC, SD, SE, SG, SK, SL, SN, TH, TN, TR, TW, TZ, UG, ZA, ZM, ZW)
• Camptolem (TH)
• Camptosar (AR, AU, BO, BR, CN, CO, CR, DO, EC, GT, MX, NI, NZ, PA, PE, PR, SV, UY, VE)
• Camtecan (KP)
• Crabcan (KP)
• Efixano (PY)
• Herocan (TW)
• Indotecan (KP)
• Innocan (TW)
• Irenax (TW)
• Irican (PH)
• Irino (TH)
• Irinocyt (CO)
• Irinogen (EC)
• Irinoll (TH)
• Irinotel (IN, TH, TW)
• Irinotesin (HK, PH, SG)
• Iritecan (KP)
• Irnocam (MY)
• Linatecan (PE)
• Lritecin (KP)
• Pipetecan (AR)
• Terican (MX)
• Topotecin (JP)

Lexi-Comp.com

Last full review/revision February 2012

Content last modified February 2012